Conditions: COVID-19
Keywords: DHODH inhibition antiviral coronavirus SARS-CoV-2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. All subjects will receive standard of care (SOC) per institutional guidelines for treatment of hospitalized patients with COVID-19 infection. In addition to SOC, the brequinar group will receive 5 daily doses of brequinar 100 mg.

Detailed description:
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 infection. Subjects will be randomly assigned in a 1:2 ratio to SOC alone or SOC plus brequinar. The SOC plus brequinar group will receive 5 daily doses of brequinar 100 mg on Days 1 - 5 in addition to SOC. Physical examinations, vital signs, laboratory assessments, SARS-CoV-2 testing, and other observations will be conducted by experienced personnel throughout the study based on the Schedule of Events. Blood chemistry tests include blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin, total protein, albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, and calcium), lactate dehydrogenase (LDH). Plasma will be collected for inflammatory markers such as D-dimer, ferritin, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Pro-inflammatory markers will be measured. Serum is to be collected for research purposes. Hematology tests include hemoglobin, hematocrit, complete blood count with full differential, and platelet count. Nasopharyngeal swabs for viral load will be collected Days 1, 3, 5, 7, and 15. Survival will be assessed through Day 29.

Arms:
arm 1: Subjects are hospitalized for COVID-19 and will receive all supportive/interventional care per institutional guidelines. arm 2: Subjects will receive standard of care plus brequinar 100 mg daily (Study Days 1-5).

Interventions: intervention 1: Brequinar intervention 2: Standard of Care
Intervention descriptions: intervention 1: DHODH inhibitor, 100 mg daily x 5 days intervention 2: Standard of Care per institutional guidelines for COVID-19 patients

Protocol document:
Prot_002.pdf: 
CCB-CRISIS-01 
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in 
hospitalized adults with coronavirus-19 (COVID-19) 
NCT04425252 
Original Protocol Date: 03/31/2020 
Amendment 01 Date: 04/10/2020 
Amendment 02 Date: 05/01/2020 
Amendment 03 Date: 06/05/2020 
Amendment 04 Date: 07/06/2020 
Amendment 05 Date: 07/31/2020 
Amendment 06 Date: 08/05/2020 
Amendment 07 Date: 09/10/2020 
 
 


Table of Contents
16.1.1 Protocol and protocol amendments....................................................................................
Protocol dated March 31, 2020 .....................................................................................................
APPROVALS AND REVISION HISTORY....................................................................
TITLE PAGE ....................................................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF FIGURES...........................................................................................................
Figure 3-1 DHODH...............................................................................................
Figure 3-2 IMPDH ................................................................................................
Figure 3-3 Changes in viral load versus day of symptom onset - COVID-19......
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
3  INTRODUCTION.........................................................................................................
3.1 Background .....................................................................................................
3.2 Coronavirus-19 (COVID-19) ........................................................................
3.2.1 Coronavirus Biology ........................................................................
3.3  Host Nucleotide Synthesis .............................................................................
3.4  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.5  Inosine monophosphate dehydrogenase (IMPDH) ......................................
3.6  Brequinar........................................................................................................
3.7  Ribavirin.........................................................................................................
3.8  Rationale for the Planned Trial ......................................................................
3.8.1 Brequinar Dose Selection.................................................................
3.8.2 Ribavirin Dose Selection..................................................................
3.8.3    Risk/Benefit of Brequinar .............................................................
3.9  Risk/benefit of Ribavirin................................................................................
3.10 Risks Associated with Participation in the Clinical Study............................
3.11 Possible Interactions with Concomitant Medical Treatments.......................
3.11.1 CYP Interactions ............................................................................
3.12 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 ............................................................................................................
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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............................................................................................
7.4 Inclusion of Women and Minorities................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Study Medications...................................................................
8.1.1 Brequinar..........................................................................................
8.1.2 Ribavirin...........................................................................................
8.2 Treatment Administration ...............................................................................
8.2.1 Safety/Tolerability............................................................................
8.3 Study Discontinuation.....................................................................................
8.4 Concomitant Medication/Treatment ...............................................................
8.5 Treatment Compliance....................................................................................
8.6 Storage, Stability, Labeling and Packaging ....................................................
8.6.1 Storage and Stability ........................................................................
8.6.2 Labeling and Packaging ...................................................................
8.6.3 Blinding and Randomization............................................................
8.6.4 Unblinding/Expectedness.................................................................
8.6.5 Study Drug Accountability...............................................................
8.6.6 Prohibited Medications ....................................................................
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.......................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Classification of Causality ............................................................................
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10.2 Classification of Severity ..............................................................................
10.3 Serious Adverse Event (SAE) Reporting ....................................................
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.5 Pregnancies....................................................................................................
10.6 Data Safety Monitoring Board......................................................................
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-01 Schedule of Events...................................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: National Early Warning Score (NEWS2) ..............................
15.4 Appendix D: Ribavirin generic (ribavirin USP) capsules, for oral use
Summary of Product Characteristics (SPC) ........................................................
HIGHLIGHTS OF PRESCRIBING INFORMATION.........................................
INDICATIONS AND USAGE.................................................................
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DOSAGE AND ADMINISTRATION .....................................................
DOSAGE FORMS AND STRENGTHS ..................................................
CONTRAINDICATIONS.........................................................................
WARNINGS AND PRECAUTIONS.......................................................
ADVERSE REACTIONS.........................................................................
DRUG INTERACTIONS .........................................................................
USE IN SPECIFIC POPULATIONS........................................................
FULL PRESCRIBING INFORMATION: CONTENTS......................................
Tables ........................................................................................................
Table 1: Recommended Adult Dosing for Ribavirin capsules in
Combination with PegIntron.........................................................
Table 2: Recommended Pediatric Ribavirin capsules Dosing in
Combination with PegIntron.........................................................
Table 3: Recommended Ribavirin capsules Dosing in
Combination with INTRON A......................................................
Table 4: Guidelines for Dose Modification and Discontinuation
of Ribavirin capsules in combination with PegIntron or
INTRON A Bas ed on Laboratory Parameters in Adults
andPediatrics .................................................................................
Table 5: Adverse Reactions Occurring in Greater Than 5% of
Adult Subjects ...............................................................................
Table 6: Treatment-Related Adverse Reactions (Greater Than
or Equal to 10% Incidence) By Des cending Frequency .............
Table 7: Percentage of Pediatric Subjects with
Treatment-Related Adverse Reactions (in At Least 10% of All
Subjects ) ......................................................................................
Table 8: Selected Laboratory Abnormalities During Treatment
with Ribavirin and PegIntron or Ribavirin and INTRON A in
Previous ly Untreated Subjects .....................................................
Table 9: Selected Treatment-Related Adverse Reactions :
Previous ly Untreated and Relapse Adult Subjects and
Previously Untreated Pediatric Subjects .......................................
Table 10: Selected Laboratory Abnormalities During Treatment
with Ribavirin and INTRON A: Previously Untreated and
Relapse Adult Subjects and Previously Untreated Pediatric
Subjects .........................................................................................
Table 11: Mean (% CV) Pharmacokinetic Parameters for
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Ribavirin When Administered Individually to Adults..................
Table 12: Mean (% CV) Multiple-dose Pharmacokinetic
Parameters for INTRON A and Ribavirin Capsules When
Administered to Pediatric Subjects with Chronic Hepatitis C......
Table 13: Rates of Response to Combination Treatment –
Study 2 ..........................................................................................
Table 14: SVR Rate by Treatment and Baseline Weight - Study
3.....................................................................................................
Table 15: SVR Rate by Treatment – Study 4................................
Table 16: SVR Rates by Baseline Characteris tics of Prior
Treatment Failures - Study 5.........................................................
Table 17: Sustained Virologic Response Rates by Genotype
and Assigned Treatment Duration – Pediatric Trial......................
Table 18: Virologic and Histologic Responses : Previously
Untreated Subjects.........................................................................
Table 19: Virologic and Histologic Responses : Relapse
Subjects .........................................................................................
Table 20: Virologic Response: Previously Untreated Pediatric
Subjects .........................................................................................
Figures.......................................................................................................
Figure 1: Structural Formula.........................................................
1 INDICATIONS AND USAGE..............................................................
1.1 Chronic Hepatitis C (CHC) ...................................................
2 DOSAGE AND ADMINISTRATION ..................................................
2.1 General Dosing Information....................................................
2.2 Ribavirin capsules /PegIntron Combination Therapy.............
2.3 Ribavirin capsules /INTRON A Combination Therapy..........
2.4 Testing Prior to Initiation of Ribavirin capsules.....................
2.5 Dose Modifications .................................................................
2.6 Discontinuation of Dosing ......................................................
3 DOSAGE FORMS AND STRENGTHS ...............................................
4 CONTRAINDICATIONS......................................................................
5 WARNINGS AND PRECAUTIONS....................................................
5.1 Embryo-Fetal Toxicity............................................................
5.2 Anemia ....................................................................................
5.3 Pancreatitis ..............................................................................
5.4 Pulmonary Disorders...............................................................
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5.5 Ophthalmologic Dis orders .....................................................
5.6 Laboratory Tests......................................................................
5.7 Dental and Periodontal Disorders ...........................................
5.8 Concomitant Administration of Azathioprine.........................
5.9 Impact on Growth in Pediatric Patients...................................
5.10 Not Recommended for Monotherapy and Risks
Associated with Combination Therapy.........................................
6 ADVERSE REACTIONS......................................................................
6.1 Clinical Trials Experience.......................................................
6.2 Postmarketing Experiences .....................................................
7 DRUG INTERACTIONS ......................................................................
7.1 Didanosine...............................................................................
7.2 Nucleoside Analogues.............................................................
7.3 Drugs Metabolized by Cytochrome P-450..............................
7.4 Azathioprine............................................................................
8 USE IN SPECIFIC POPULATIONS.....................................................
8.1 Pregnancy................................................................................
8.2 Lactation..................................................................................
8.3 Females and Males of Reproductive Potential........................
8.4 Pediatric Use ...........................................................................
8.5 Geriatric Use ...........................................................................
8.6 Organ Transplant Recipients...................................................
8.7 HIV or HBV Co-infection.......................................................
10 OVERDOSAGE...................................................................................
11 DESCRIPTION....................................................................................
12 CLINICAL PHARMACOLOGY ........................................................
12.1 Mechanism of Action............................................................
12.3 Pharmacokinetics ..................................................................
12.4 Microbiology.........................................................................
13 NONCLINICAL TOXICOLOGY .......................................................
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility .........
13.2 Animal Toxicology and Pharmacology.................................
14 CLINICAL STUDIES..........................................................................
14.1 Ribavirin/PegIntron Combination Therapy...........................
14.2 Ribavirin/INTRON A Combination Therapy .......................
16 HOW SUPPLIED/STORAGE AND HANDLING .............................
17 PATIENT COUNSELING INFORMATION......................................
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MEDICATION GUIDE............................................................................
LABEL......................................................................................................
Protocol dated April 10, 2020 .......................................................................................................
APPROVALS AND REVISION HISTORY....................................................................
TITLE PAGE ....................................................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF FIGURES...........................................................................................................
Figure 3-1 DHODH...............................................................................................
Figure 3-2 IMPDH ................................................................................................
Figure 3-3 Changes in viral load versus day of symptom onset - COVID-19......
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Background .....................................................................................................
3.2 Coronavirus-19 (COVID-19) ........................................................................
3.2.1 Coronavirus Biology ........................................................................
3.3  Host Nucleotide Synthesis .............................................................................
3.4  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.5  Inosine monophosphate dehydrogenase (IMPDH) ......................................
3.6  Brequinar........................................................................................................
3.7  Ribavirin.........................................................................................................
3.8  Rationale for the Planned Trial ......................................................................
3.8.1 Brequinar Dose Selection.................................................................
3.8.2 Ribavirin Dose Selection..................................................................
3.8.3    Risk/Benefit of Brequinar .............................................................
3.9  Risk/benefit of Ribavirin................................................................................
3.10 Risks Associated with Participation in the Clinical Study............................
3.11 Possible Interactions with Concomitant Medical Treatments.......................
3.11.1 CYP Interactions ............................................................................
3.12 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.....................................................................................................
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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............................................................................................
7.4 Inclusion of Women and Minorities................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Study Medications...................................................................
8.1.1 Brequinar..........................................................................................
8.1.2 Ribavirin...........................................................................................
8.2 Treatment Administration ...............................................................................
8.2.1 Safety/Tolerability............................................................................
8.3 Study Discontinuation.....................................................................................
8.4 Concomitant Medication/Treatment ...............................................................
8.5 Treatment Compliance....................................................................................
8.6 Storage, Stability, Labeling and Packaging ....................................................
8.6.1 Storage and Stability ........................................................................
8.6.2 Labeling and Packaging ...................................................................
8.6.3 Blinding and Randomization............................................................
8.6.4 Unblinding/Expectedness.................................................................
8.6.5 Study Drug Accountability...............................................................
8.6.6 Prohibited Medications ....................................................................
8.6.7 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.......................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Classification of Causality ............................................................................
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10.2 Classification of Severity ..............................................................................
10.3 Serious Adverse Event (SAE) Reporting ....................................................
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.5 Pregnancies....................................................................................................
10.6 Data Safety Monitoring Board......................................................................
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-01 Schedule of Events...................................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: National Early Warning Score (NEWS2) ..............................
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment
Guidance................................................................................................................
15.5 Appendix E: Ribavirin generic (ribavirin USP) capsules, for oral use
Summary of Product Characteristics (SPC) ........................................................
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HIGHLIGHTS OF PRESCRIBING INFORMATION.............................
INDICATIONS AND USAGE.....................................................
DOSAGE AND ADMINISTRATION .........................................
DOSAGE FORMS AND STRENGTHS ......................................
CONTRAINDICATIONS.............................................................
WARNINGS AND PRECAUTIONS...........................................
ADVERSE REACTIONS.............................................................
DRUG INTERACTIONS .............................................................
USE IN SPECIFIC POPULATIONS............................................
FULL PRESCRIBING INFORMATION: CONTENTS..........................
Tables ........................................................................................................
Table 1: Recommended Adult Dosing for Ribavirin capsules in
Combination with PegIntron.........................................................
Table 2: Recommended Pediatric Ribavirin capsules Dosing in
Combination with PegIntron.........................................................
Table 3: Recommended Ribavirin capsules Dosing in
Combination with INTRON A......................................................
Table 4: Guidelines for Dose Modification and Discontinuation
of Ribavirin capsules in combination with PegIntron or
INTRON A Based on Laboratory Parameters in Adults and
Pediatrics.......................................................................................
Table 5: Adverse Reactions Occurring in Greater Than 5% of
Adult Subjects ...............................................................................
Table 6: Treatment-Related Advers e Reactions (Greater Than
or Equal to 10% Incidence) By Descending Frequency ..............
Table 7: Percentage of Pediatric Subjects with
Treatment-Related Advers eReactions (in At Leas t 10% of All
Subjects ) ......................................................................................
Table 8: Selected Laboratory Abnormalities During Treatment
with Ribavirin and PegIntron orRibavirin and INTRON A in
Previous ly Untreated Subjects .....................................................
Table 9: Selected Treatment-Related Advers e Reactions :
Previously Untreated and Relapse Adult Subjects and
Previously Untreated Pediatric Subjects .......................................
Table 10: Selected Laboratory Abnormalities During Treatment
with Ribavirin and INTRON A:Previous ly Untreated and
Relaps e Adult Subjects and Previous ly Untreated Pediatric
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Subjects .........................................................................................
Table 11: Mean (% CV) Pharmacokinetic Parameters for
Ribavirin When Adminis teredIndividually to Adults..................
Table 12: Mean (% CV) Multiple-dose Pharmacokinetic
Parameters for INTRON A and Ribavirin Capsules When
Administered to Pediatric Subjects with Chronic Hepatitis C......
Table 13: Rates of Response to Combination Treatment –
Study 2 ..........................................................................................
Table 14: SVR Rate by Treatment and Baseline Weight - Study
3.....................................................................................................
Table 15: SVR Rate by Treatment – Study 4................................
Table 16: SVR Rates by Baseline Characteristics of Prior
Treatment Failures - Study 5.........................................................
Table 17: Sustained Virologic Response Rates by Genotype
and Assigned Treatment Duration –Pediatric Trial.......................
Table 18: Virologic and Histologic Responses : Previously
Untreated Subjects.........................................................................
Table 19: Virologic and Histologic Responses : Relapse
Subjects .........................................................................................
Table 20: Virologic Response: Previously Untreated Pediatric
Subjects .........................................................................................
Figure 1: Structural Formula.........................................................
1 INDICATIONS AND USAGE..............................................................
1.1 Chronic Hepatitis C (CHC) ...............................................................
2 DOSAGE AND ADMINISTRATION ..................................................
2.1 General Dosing Information....................................................
2.2 Ribavirin capsules /PegIntron Combination Therapy.............
2.3 Ribavirin capsules /INTRON A Combination Therapy..........
2.4 Testing Prior to Initiation of Ribavirin capsules.....................
2.5 Dose Modifications .................................................................
2.6 Discontinuation of Dosing ......................................................
3 DOSAGE FORMS AND STRENGTHS ...............................................
4 CONTRAINDICATIONS......................................................................
5 WARNINGS AND PRECAUTIONS....................................................
5.1 Embryo-Fetal Toxicity............................................................
5.2 Anemia ....................................................................................
5.3 Pancreatitis ..............................................................................
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5.4 Pulmonary Disorders...............................................................
5.5 Ophthalmologic Disorders ......................................................
5.6 Laboratory Tests......................................................................
5.7 Dental and Periodontal Disorders ...........................................
5.8 Concomitant Administration of Azathioprine.........................
5.9 Impact on Growth in Pediatric Patients...................................
5.10 Not Recommended for Monotherapy and Risks
Associated with Combination Therapy.........................................
6 ADVERSE REACTIONS......................................................................
6.1 Clinical Trials Experience.......................................................
6.2 Postmarketing Experiences .....................................................
7 DRUG INTERACTIONS ......................................................................
7.1 Didanosine...............................................................................
7.2 Nucleoside Analogues.............................................................
7.3 Drugs Metabolized by Cytochrome P-450..............................
7.4 Azathioprine............................................................................
8 USE IN SPECIFIC POPULATIONS.....................................................
8.1 Pregnancy................................................................................
8.2 Lactation..................................................................................
8.3 Females and Males of Reproductive Potential........................
8.4 Pediatric Use ...........................................................................
8.5 Geriatric Use ...........................................................................
8.6 Organ Transplant Recipients...................................................
8.7 HIV or HBV Co-infection.......................................................
10 OVERDOSAGE...................................................................................
11 DESCRIPTION....................................................................................
12 CLINICAL PHARMACOLOGY ........................................................
12.1 Mechanism of Action............................................................
12.3 Pharmacokinetics ..................................................................
12.4 Microbiology.........................................................................
13 NONCLINICAL TOXICOLOGY .......................................................
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility .........
13.2 Animal Toxicology and Pharmacology.................................
14 CLINICAL STUDIES..........................................................................
14.1 Ribavirin/PegIntron Combination Therapy...........................
14.2 Ribavirin/INTRON A Combination Therapy .......................
16 HOW SUPPLIED/STORAGE AND HANDLING .............................
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17 PATIENT COUNSELING INFORMATION......................................
MEDICATION GUIDE............................................................................
LABEL......................................................................................................
Protocol dated May 01 2020 .........................................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF FIGURES...........................................................................................................
Figure 3-1. DHODH is amitochondrial enzyme ...................................................
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Background .....................................................................................................
3.2 Coronavirus-19 (COVID-19) ........................................................................
3.2.1 Coronavirus Biology ........................................................................
3.3 Host Nucleotide Synthesis ..............................................................................
3.4 Dihydroorotate dehydrogenase (DHODH ......................................................
3.5 Brequinar.........................................................................................................
3.6 Rationale for the Planned Trial .......................................................................
3.6.1 Brequinar Dose Selection.................................................................
3.6.2 Risk/Benefit of Brequinar ................................................................
3.7 Risks Associated with Participation in the Clinical Study..............................
3.8 Possible Interactions with Concomitant Medical Treatments.........................
3.8.1 CYP Interactions ..............................................................................
3.9 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............................................................................................
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Protocol dated June 05, 2020 ............................................................................................
TABLE OF CONTENTS......................................................................................
LIST OF FIGURES...............................................................................................
Figure 3-1 DHODH...................................................................................
ABBREVIATIONS...............................................................................................
2 SYNOPSIS.........................................................................................................
STUDY PERSONNEL .........................................................................................
3 INTRODUCTION..............................................................................................
3.1 Background .........................................................................................
3.2 Coronavirus-19 (COVID-19) ............................................................
3.2.1 Coronavirus Biology ............................................................
3.3  Host Nucleotide Synthesis .................................................................
3.4  Dihydroorotate dehydrogenase (DHODH) ......................................
3.5  Brequinar............................................................................................
3.6  Rationale for the Planned Trial ..........................................................
3.6.1 Brequinar Dose Selection.....................................................
3.6.2    Risk/Benefit of Brequinar .................................................
3.7 Risks Associated with Participation in the Clinical Study..................
3.8 Possible Interactions with Concomitant Medical Treatments.............
3.8.1 CYP Interactions ..................................................................
3.9 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................................................................................
7.4 Inclusion of Women and Minorities....................................................
8 STUDY TREATMENTS...................................................................................
8.1 Description of Study Medications.......................................................
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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 Hospital Discharge Prior to Study Day 15..........................................
8.6 Concomitant Medication/Treatment ...................................................
8.7 Treatment Compliance........................................................................
8.8 Storage, Stability, Labeling and Packaging ........................................
8.8.1 Storage and Stability ............................................................
8.8.2 Labeling and Packaging .......................................................
8.8.3 Blinding and Randomization................................................
8.8.4 Unblinding/Expectedness.....................................................
8.8.5 Study Drug Accountability...................................................
8.9 Prohibited Medications .......................................................................
8.10 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...........................................................
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.................................
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10.9 Data Safety Monitoring Board..........................................................
10.9.1 DSMB Safety Review Schedule ........................................
11 STATISTICAL CONSIDERATIONS.............................................................
11.1 Study Populations for Analysis.........................................................
11.2 Safety Analyses.................................................................................
11.3 Efficacy Analyses..............................................................................
11.4 DHO and Brequinar Concentration Levels.......................................
11.5 Sample Size Considerations..............................................................
11.6 Randomization ..................................................................................
11.7 Pooling of Study Centers ..................................................................
11.8 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-01 Schedule of Events.........................
15.2 Appendix B: Investigator's Statement and Agreement .....................
15.3 Appendix C: National Early Warning Score (NEWS2) ..................
15.4 Appendix D: Massachusetts General Hospital COVID-19
Treatment Guidance..................................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Study Medications...................................................................
8.1.1 Brequinar..........................................................................................
8.2 Treatment Administration ...............................................................................
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8.2.1 Safety/Tolerability............................................................................
8.3 Study Discontinuation.....................................................................................
8.4 Hospital Discharge Prior to Study Day 15......................................................
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.......................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Classification of Causality ............................................................................
10.2 Classification of Severity ..............................................................................
10.3 Serious Adverse Event (SAE) Reporting ....................................................
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.5 Pregnancies....................................................................................................
10.6 Safety Monitoring for Hematologic Toxicities.............................................
10.7 Data Safety Monitoring Board......................................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 DHO and Brequinar Concentration Levels...................................................
11.5 Sample Size Considerations..........................................................................
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11.6 Randomization ..............................................................................................
11.7 Pooling of Study Centers ..............................................................................
11.8 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-01 Schedule of Events......................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: National Early Warning Score (NEWS2) ..............................
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment
Guidance................................................................................................................
Protocol dated July 06, 2020.........................................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF FIGURES...........................................................................................................
Figure 3-1 DHODH...............................................................................................
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Background .....................................................................................................
3.2 Coronavirus-19 (COVID-19) ........................................................................
3.2.1 Coronavirus Biology ........................................................................
3.3  Host Nucleotide Synthesis .............................................................................
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3.4  Dihydroorotate dehydrogenase \(DHODH\)
..............................................
3.5  Brequinar........................................................................................................
3.6  Rationale for the Planned Trial ......................................................................
3.6.1 Brequinar Dose Selection.................................................................
3.6.2    Risk/Benefit of Brequinar .............................................................
3.7 Risks Associated with Participation in the Clinical Study..............................
3.8 Possible Interactions with Concomitant Medical Treatments.........................
3.8.1 CYP Interactions ..............................................................................
3.9 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............................................................................................
7.4 Inclusion of Women and Minorities................................................................
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 Hospital Discharge Prior to Study Day 15......................................................
8.6 Concomitant Medication/Treatment ...............................................................
8.7 Treatment Compliance....................................................................................
8.8 Storage, Stability, Labeling and Packaging ....................................................
8.8.1 Storage and Stability ........................................................................
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8.8.2 Labeling and Packaging ...................................................................
8.8.3 Blinding and Randomization............................................................
8.8.4 Unblinding/Expectedness.................................................................
8.8.5 Study Drug Accountability...............................................................
8.9 Prohibited Medications ...................................................................................
8.10 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.......................................................................
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 Safety Monitoring Board......................................................................
10.9.1 DSMB Safety Review Schedule ....................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 DHO and Brequinar Concentration Levels...................................................
11.5 Sample Size Considerations..........................................................................
11.6 Randomization ..............................................................................................
11.7 Pooling of Study Centers ..............................................................................
11.8 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
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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-01 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: National Early Warning Score (NEWS2) ..............................
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment
Guidance................................................................................................................
Protocol dated July 31, 2020.........................................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF FIGURES...........................................................................................................
Figure 3-1 DHODH...............................................................................................
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Background .....................................................................................................
3.2 Coronavirus-19 (COVID-19) ........................................................................
3.2.1 Coronavirus Biology ........................................................................
3.3  Host Nucleotide Synthesis .............................................................................
3.4  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.5  Brequinar........................................................................................................
3.6  Rationale for the Planned Trial ......................................................................
3.6.1 Brequinar Dose Selection.................................................................
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3.6.2    Risk/Benefit of Brequinar .............................................................
3.7 Risks Associated with Participation in the Clinical Study..............................
3.8 Possible Interactions with Concomitant Medical Treatments.........................
3.8.1 CYP Interactions ..............................................................................
3.9 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............................................................................................
7.4 Inclusion of Women and Minorities................................................................
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 Hospital Discharge Prior to Study Day 15......................................................
8.6 Concomitant Medication/Treatment ...............................................................
8.7 Treatment Compliance....................................................................................
8.8 Storage, Stability, Labeling and Packaging ....................................................
8.8.1 Storage and Stability ........................................................................
8.8.2 Labeling and Packaging ...................................................................
8.8.3 Blinding and Randomization............................................................
8.8.4 Unblinding/Expectedness.................................................................
8.8.5 Study Drug Accountability...............................................................
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8.9 Prohibited Medications ...................................................................................
8.10 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.......................................................................
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 Safety Monitoring Board......................................................................
10.9.1 DSMB Safety Review Schedule ....................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 DHO and Brequinar Concentration Levels...................................................
11.5 Sample Size Considerations..........................................................................
11.6 Randomization ..............................................................................................
11.7 Pooling of Study Centers ..............................................................................
11.8 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 Investigator's Performance............................................................................
12.2 Confidentiality...............................................................................................
12.3 Source Documentation..................................................................................
12.4 Data Collection..............................................................................................
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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-01 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: National Early Warning Score (NEWS2) ..............................
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment
Guidance................................................................................................................
Protocol dated August 05, 2020....................................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF FIGURES...........................................................................................................
Figure 3-1 DHODH...............................................................................................
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Background .....................................................................................................
3.2 Coronavirus-19 (COVID-19) ........................................................................
3.2.1 Coronavirus Biology ........................................................................
3.3  Host Nucleotide Synthesis .............................................................................
3.4  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.5  Brequinar........................................................................................................
3.6  Rationale for the Planned Trial ......................................................................
3.6.1 Brequinar Dose Selection.................................................................
3.6.2    Risk/Benefit of Brequinar .............................................................
3.7 Risks Associated with Participation in the Clinical Study..............................
3.8 Possible Interactions with Concomitant Medical Treatments.........................
3.8.1 CYP Interactions ..............................................................................
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3.9 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............................................................................................
7.4 Inclusion of Women and Minorities................................................................
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 Hospital Discharge Prior to Study Day 15......................................................
8.6 Concomitant Medication/Treatment ...............................................................
8.7 Treatment Compliance....................................................................................
8.8 Storage, Stability, Labeling and Packaging ....................................................
8.8.1 Storage and Stability ........................................................................
8.8.2 Labeling and Packaging ...................................................................
8.8.3 Blinding and Randomization............................................................
8.8.4 Unblinding/Expectedness.................................................................
8.8.5 Study Drug Accountability...............................................................
8.9 Prohibited Medications ...................................................................................
8.10 Study Adjustments Due to COVID-19..........................................................
9 CONDUCT OF THE TRIAL.........................................................................................
9.1 Ethical and Regulatory Considerations...........................................................
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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.......................................................................
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 Safety Monitoring Board......................................................................
10.9.1 DSMB Safety Review Schedule ....................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 DHO and Brequinar Concentration Levels...................................................
11.5 Sample Size Considerations..........................................................................
11.6 Randomization ..............................................................................................
11.7 Pooling of Study Centers ..............................................................................
11.8 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................................................................................
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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-01 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: National Early Warning Score (NEWS2) ..............................
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment
Guidance................................................................................................................
Protocol dated September 10, 2020...............................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF FIGURES...........................................................................................................
Figure 3-1 DHODH...............................................................................................
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Background .....................................................................................................
3.2 Coronavirus-19 (COVID-19) ........................................................................
3.2.1 Coronavirus Biology ........................................................................
3.3  Host Nucleotide Synthesis .............................................................................
3.4  Dihydroorotate dehydrogenase (DHODH) ..................................................
3.5  Brequinar........................................................................................................
3.6  Rationale for the Planned Trial ......................................................................
3.6.1 Brequinar Dose Selection.................................................................
3.6.2    Risk/Benefit of Brequinar .............................................................
3.7 Risks Associated with Participation in the Clinical Study..............................
3.8 Possible Interactions with Concomitant Medical Treatments.........................
3.8.1 CYP Interactions ..............................................................................
3.9 Steps to be Taken to Control or Mitigate Risks ..............................................
4 TRIAL OBJECTIVES....................................................................................................
4.1 Primary Objective ...........................................................................................
4.2 Secondary Objectives......................................................................................
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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............................................................................................
7.4 Inclusion of Women and Minorities................................................................
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 Hospital Discharge Prior to Study Day 15......................................................
8.6 Concomitant Medication/Treatment ...............................................................
8.7 Treatment Compliance....................................................................................
8.8 Storage, Stability, Labeling and Packaging ....................................................
8.8.1 Storage and Stability ........................................................................
8.8.2 Labeling and Packaging ...................................................................
8.8.3 Blinding and Randomization............................................................
8.8.4 Unblinding/Expectedness.................................................................
8.8.5 Study Drug Accountability...............................................................
8.9 Prohibited Medications ...................................................................................
8.10 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.................................................................................................
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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.......................................................................
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 Safety Monitoring Board......................................................................
10.9.1 DSMB Safety Review Schedule ....................................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 DHO and Brequinar Concentration Levels...................................................
11.5 Sample Size Considerations..........................................................................
11.6 Randomization ..............................................................................................
11.7 Pooling of Study Centers ..............................................................................
11.8 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.............................................................................................................
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13.5  Confidentiality..............................................................................................
13.6  Finance .........................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events.....................................
15.2 Appendix B: Investigator's Statement and Agreement .................................
15.3 Appendix C: National Early Warning Score (NEWS2) ..............................
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment
Guidance................................................................................................................
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16.1.1 
Protocol and protocol amendments 
 
Protocol dated 31March 2020 
Protocol dated 10 April 2020 
Protocol dated 05 June 2020 
Protocol dated 06 July 2020 
Protocol dated 31 July 2020 
Protocol dated 05 August 2020 
Protocol dated 10 September 2020 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 1 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of combined suppression of host nucleotide 
synthesis in hospitalized adults with coronavirus-19 (COVID-19) 
 
Study No: CCB-CRISIS-01 
Version Date:  31 March 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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 2 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 16 
3.1 Background ................................................................................................................ 16 
3.2 Coronavirus-19 (COVID-19) ..................................................................................... 16 
3.2.1 Coronavirus Biology .................................................................................................... 16 
3.3 Host Nucleotide Synthesis ......................................................................................... 16 
3.4 Dihydroorotate dehydrogenase (DHODH) ................................................................ 17 
3.5 Inosine monophosphate dehydrogenase (IMPDH) .................................................... 17 
3.6 Brequinar .................................................................................................................... 17 
3.7 Ribavirin ..................................................................................................................... 18 
3.8 Rationale for the Planned Trial .................................................................................. 18 
3.8.1 Brequinar Dose Selection ............................................................................................. 20 
3.8.2 Ribavirin Dose Selection .............................................................................................. 20 
3.8.3 Risk/Benefit of Brequinar ............................................................................................ 21 
3.9 Risk/benefit of Ribavirin ............................................................................................ 21 
3.10 Risks Associated with Participation in the Clinical Study ......................................... 22 
3.11 Possible Interactions with Concomitant Medical Treatments .................................... 22 
3.11.1 
CYP Interactions ..................................................................................................... 22 
3.12 Steps to be Taken to Control or Mitigate Risks ......................................................... 23 
4 TRIAL OBJECTIVES ........................................................................................................ 24 
4.1 Primary Objective ...................................................................................................... 24 
4.2 Secondary Objectives ................................................................................................. 24 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 24 
5 TRIAL DESIGN ................................................................................................................. 25 
6 TRIAL ENDPOINTS.......................................................................................................... 26 
6.1 Primary Endpoint ....................................................................................................... 26 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 3 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
6.2 Secondary Endpoints .................................................................................................. 26 
6.3 EXPLORATORY Endpoints ..................................................................................... 26 
7 TRIAL POPULATION ....................................................................................................... 27 
7.1 Number of Subjects .................................................................................................... 27 
7.2 Inclusion criteria ......................................................................................................... 27 
7.3 Exclusion Criteria ....................................................................................................... 27 
7.4 Inclusion of Women and Minorities........................................................................... 28 
8 STUDY TREATMENTS .................................................................................................... 29 
8.1 Description of Study Medications .............................................................................. 29 
8.1.1 Brequinar ...................................................................................................................... 29 
8.1.2 Ribavirin ....................................................................................................................... 29 
8.2 Treatment Administration .......................................................................................... 29 
8.2.1 Safety/Tolerability ........................................................................................................ 29 
8.3 Study Discontinuation ................................................................................................ 30 
8.4 Concomitant Medication/Treatment .......................................................................... 30 
8.5 Treatment Compliance ............................................................................................... 31 
8.6 Storage, Stability, Labeling and Packaging ............................................................... 31 
8.6.1 Storage and Stability .................................................................................................... 31 
8.6.2 Labeling and Packaging ............................................................................................... 31 
8.6.3 Blinding and Randomization ........................................................................................ 32 
8.6.4 Unblinding/Expectedness ............................................................................................. 32 
8.6.5 Study Drug Accountability ........................................................................................... 32 
8.6.6 Prohibited Medications................................................................................................. 33 
9 CONDUCT OF THE TRIAL.............................................................................................. 34 
9.1 Ethical and Regulatory Considerations ...................................................................... 34 
9.2 Informed Consent ....................................................................................................... 34 
9.3 Institutional Review Board / Ethics Committees ....................................................... 35 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 4 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
9.4 Schedule of Events ..................................................................................................... 35 
9.5 Study Conduct ............................................................................................................ 36 
9.5.1 Unscheduled Visits ....................................................................................................... 38 
9.6 Compliance with Study Procedures ........................................................................... 38 
9.7 Early Withdrawal from the Study .............................................................................. 38 
9.8 Early Termination of the Study .................................................................................. 39 
10 ADVERSE EVENT REPORTING..................................................................................... 40 
10.1 Classification of Causality ......................................................................................... 41 
10.2 Classification of Severity ........................................................................................... 42 
10.3 Serious Adverse Event (SAE) Reporting ................................................................... 42 
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 44 
10.5 Pregnancies................................................................................................................. 44 
10.6 Data Safety Monitoring Board ................................................................................... 45 
11 STATISTICAL CONSIDERATIONS................................................................................ 46 
11.1 Study Populations for Analysis .................................................................................. 46 
11.2 Safety Analyses .......................................................................................................... 46 
11.3 Efficacy Analyses ....................................................................................................... 46 
11.4 Sample Size Considerations ....................................................................................... 46 
11.5 Randomization ........................................................................................................... 46 
11.6 Pooling of Study Centers............................................................................................ 47 
11.7 Interim Analysis ......................................................................................................... 47 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 48 
12.1 Investigator’s Performance ........................................................................................ 48 
12.2 Confidentiality ............................................................................................................ 48 
12.3 Source Documentation ............................................................................................... 48 
12.4 Data Collection ........................................................................................................... 49 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 49 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 5 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
12.6 Non-Protocol Research .............................................................................................. 50 
12.7 Publication .................................................................................................................. 50 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 51 
13.1 General ....................................................................................................................... 51 
13.2 Indemnity ................................................................................................................... 51 
13.3 Data Monitoring ......................................................................................................... 51 
13.4 Audit ........................................................................................................................... 51 
13.5 Confidentiality ............................................................................................................ 52 
13.6 Finance ....................................................................................................................... 52 
14 REFERENCES ................................................................................................................... 53 
15 APPENDICES .................................................................................................................... 55 
15.1 Appendix A:  CCB-01 Schedule of Events ................................................................ 55 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 57 
15.3 Appendix C: National Early Warning Score (NEWS2) ............................................. 58 
15.4 Appendix D: Ribavirin generic (ribavirin USP) capsules, for oral use Summary of 
Product Characteristics (SPC) ............................................................................. 59 
 
 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 6 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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 
Figure 3-2.  IMPDH catalyzes the conversion of IMP to XMP in the synthesis of guanosine 
monophosphate. .................................................................................................... 17 
Figure 3-3. Changes in viral load versus day of symptom onset – COVID-19 ............................ 20 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 7 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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 
BID 
Bis in die (two times a day) 
BRQ 
Brequinar 
BUN 
Blood urea nitrogen 
C6min 
Concentration at 6 minutes 
CHO/HGPRT 
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase 
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 
HER 
Electronic health record 
ESR 
Erythrocyte Sedimentation Rate 
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 
IMPDH 
Inosine-5’-monophosphate 
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 
SARS 
Severe Acute Respiratory Syndrome 
SOC 
Standard of Care 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 8 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Abbreviation 
Definition 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
UMP 
Uridine 5’-monophosphatase 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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03 May 2021
Appendix 16.1.1
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Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 10 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
to SOC, the brequinar plus ribavirin group will receive brequinar 500 mg/m2 on 
Day 1 plus ribavirin 400 mg BID on Days 1 through 5. There are no restrictions on 
concomitant medications or treatments other than those contraindicated for use 
with ribavirin. 
Additional subjects may be enrolled following data review. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 
1 (Day 1 may take place on the same day if entry criteria data are available). Study 
procedures are presented in detail in the procedures section, see below. Subjects 
will be followed through Day 15 with mortality assessed at Day 29. 
If discharge occurs prior to Day 5 for subjects in the brequinar plus ribavirin 
treatment group, the subject will be provided with sufficient ribavirin to take at 
home to complete the treatment course. In this case, the subject is to return to the 
clinic for Day 7 and Day 15 visits.  
Study information such as vital signs is to be collected using the available EHR 
data when possible. 
Sample Size: 
Approximately 72 subjects will be randomized to either brequinar or brequinar plus 
ribavirin or standard of care in a 1:1:1 ratio (approximately 24 subjects on 
brequinar, 24 subjects on the brequinar plus ribavirin combination, and 24 assigned 
to standard of care). Additional subjects may be enrolled following data review. 
Number of Sites: 
1 - 5 
Study Period: 
An enrollment period of 3 months is expected. 
Inclusion 
Criteria: 
 
1. Willing and able to provide written informed consent for the trial (or 
designated care giver/healthcare power of attorney may consent if subject 
unable per institutional guidelines). 
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-cleared commercial or 
public health assay. 
4. Life expectancy > 48h in the opinion of the investigator. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown and 
ribavirin is contraindicated in women who are pregnant as well as in the 
male partners of women who are pregnant. For this reason, women of child-
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Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 11 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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 
treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study. participation, and 
for 90 days after completion of brequinar administration and for 6 months 
after completion of ribavirin administration. 
7. Male subjects must agree to refrain from sperm donation from initial study 
drug administration until 90 days after the last dose of brequinar and for 6 
months after completion of ribavirin administration. 
Exclusion 
Criteria: 
1 In intensive care unit (ICU) or equivalent level of care or expected to 
require ICU level of care within next 24 hours. 
2 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 
3 Active malignancy other than squamous cell carcinoma; anticancer 
treatment such as chemotherapy or radiation therapy within the past month. 
4 Estimated creatinine clearance < 50 mL/min. 
5 Nursing women or women of childbearing potential (WOCBP) with a 
positive pregnancy test. 
6 Treatment with ribavirin, mycophenolate, leflunomide or teriflunomide, 
didanosine, azathioprine, tacrolimus, sirolimus, or pre-existing prednisone 
at higher than 20 mg daily (ongoing or within 2 weeks of study entry). 
7 Stevens-Johnson Syndrome or other hypersensitivity reactions to ribavirin 
or any component of the product. 
Treatment 
All subjects will receive standard of care (SOC) per institutional guidelines. 
Subjects will be randomly assigned to SOC alone or SOC plus brequinar alone (1 
dose of brequinar 500 mg/m2) or SOC plus brequinar plus ribavirin (brequinar 500 
mg/m2 on Day 1 plus ribavirin 400 mg BID on Days 1 through 5). 
Procedures 
Screening Visit (Study Day -1) 
These procedures must be completed within 24h prior to starting dosing. Obtain 
the subject’s written informed consent (be sure to note time of consent), then 
collect baseline information. 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 44 of 582


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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 14 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
home to complete the treatment course. In this case, the subject is to return to the 
clinic for Day 7 and Day 15 visits.  
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected beginning from the time of informed consent 
through at least 14 days after the final dose of study medication. 
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   
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). 
Subject demographics and baseline characteristics will be summarized. Subject 
data listings will also be provided.  
Safety and tolerability will be assessed in terms of AEs, SAEs, safety laboratory 
data, and vital signs.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of treatment-emergent adverse events (TEAEs), defined as 
AEs 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, vital sign 
measurements, and other clinical measures will be summarized using appropriate 
descriptive statistics. 
 
 
 
Clinical Study Report 
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03 May 2021
Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 15 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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:  
Sharon Levy, MD 
Title: 
Prosoft Clinical 
Telephone No.: 
M: (610) 316-9764 
O: (484) 320-2062 
E-mail: 
s.levy@prosoftclinical.com 
Sharon.levy27@gmail.com 
 
 
LEAD INVESTIGATOR 
Name: 
Michael K. Mansour, MD 
Title: 
Assistant Professor of Medicine 
Affiliation: 
Massachusetts General Hospital 
Telephone No.: 
(617) 849-2608 
Pager No.: 
(617) 726-2000 
E-mail: 
mkmansour@mgh.harvard.edu 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
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03 May 2021
Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 16 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
3 
 INTRODUCTION 
3.1 Background 
3.2 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]).  
3.2.1 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 [22]). 
3.3  Host Nucleotide Synthesis 
Host de novo nucleotide synthesis is divided into two arms: purine 
synthesis (A, G) and pyrimidine synthesis (U, T, C). Host de novo 
pyrimidine synthesis generates uridine monophosphate (UMP) as 
the building block for all pyrimidine ribonucleotides and 
deoxyribonucleotides (Figure 3-1). Host de novo purine synthesis 
has more redundancy with parallel paths of adenosine and 
guanosine synthesis.  
These pathways of pyrimidine and purine synthesis are non-
overlapping and differ in two salient aspects: [1] the pool of 
intracellular purines (A, G) tends to be larger than the pool of 
pyrimidines (U, T, C) and [2] there exists no salvage pathway for 
the synthesis of UMP, the fundamental building block of 
 
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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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 17 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
pyrimidines. For these reasons, inhibition of enzymatic steps upstream of UMP (Figure 3-1) leads 
to a more rapid and more profound depletion of intracellular pyrimidines than inhibition of 
enzymatic steps upstream of GMP (Figure 3-2).  
3.4  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.  
3.5  Inosine monophosphate dehydrogenase (IMPDH)  
Inosine monophosphate dehydrogenase (IMPDH) catalyzes the 
conversion of IMP to XMP en route to the de novo synthesis of 
GMP (Figure 3-2). Inhibition of IMPDH results in a depletion of 
intracellular guanosine monophosphate.  
3.6  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. 
The antiviral activity of brequinar has been demonstrated in studies of rotavirus replication in 
human intestinal Caco2 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 [13]). 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 
Figure 
3-2. 
 
IMPDH 
catalyzes the conversion of 
IMP 
to 
XMP 
in the 
synthesis 
of 
guanosine 
monophosphate.  
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
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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]). 
3.7  Ribavirin 
Ribavirin is an FDA-approved anti-viral agent and is marketed in combination with interferon alfa-
2b for the treatment of chronic hepatitis C (ribavirin generic SPC, Appendix D, Section 15.4).  
Ribavirin is a purine nucleoside analog with multiple mechanisms of action. It is known to inhibit 
the host enzyme inosine-5’-monophosphate dehydrogenase (IMPDH), the enzyme that catalyzes 
the conversion of inosine 5’-phosphate (IMP) to xanthosine 5’-phosphate (XMP), the first 
committed and rate-limiting step in the de novo synthesis of guanine nucleotides. In addition, 
ribavirin binds to and inhibits the SARS-CoV-2 viral enzyme – the RNA dependent RNA 
polymerase (RdRp) (Elfiky et al., 2020 [26]). And finally, another important mechanism of action 
that may contribute to ribavirin’s antiviral effect is the ability to act as a ribonucleotide analog 
which can be incorporated into the viral RNA genome and lead to detrimental mutations in a 
process termed hypermutagenesis (Ortega-Prieto et al., 2013 [24]). 
In pre-clinical studies, ribavirin has a demonstrated broad spectrum in vitro anti-viral activity and 
acts as an immunomodulator in a mouse hepatitis coronavirus model (Ning et al, 1998 [21]). 
Ribavirin and mycophenolate mofetil (a more potent IMPDH inhibitor) were proposed for the 
treatment of MERS CoV infection with hints of clinical activity in small case studies (Ghamdi et 
al., 2016 [11]; Chong et al., 2015 [12]). Ribavirin as a single agent showed hints of activity in the 
previous SARS outbreak (Poutanen et al., 2003 [25]). Ribavirin and other IMPDH inhibitors are 
currently being proposed as possible treatments for the current COVID-19 pandemic (Gordon et 
al., 2020 [26]). Ribavirin as a single-agent may not be highly-effective based on the clinical 
progression of patients with SARS who were treated only with ribavirin (Peiris et al., 2003 [18]). 
There is currently an active combination trial of lopinavir/ritonavir, ribavirin and IFN-beta in Hong 
Kong for COVID-19 (NCT04276688).  
3.8  Rationale for the Planned Trial 
The CRISIS trial studies standard of care (SOC), SOC with DHODH inhibition, and SOC with 
DHODH inhibition and IMPDH inhibition. SOC is evolving rapidly for COVID-19 and at 
institutions includes approved FDA drugs such as lopinavir/ritonavir that have shown activity in 
coronaviruses. These may be combined into this trial.  
In particular this trial combines brequinar – an inhibitor of host pyrimidine synthesis (DHODH) – 
with the anti-viral ribavirin, a nucleoside analog that acts as an inhibitor of host IMPDH and an 
inhibitor of the viral RNA dependent RNA polymerase (RdRp). In addition, the misincorporation 
of ribavirin as a nucleoside analog into the replicating viral genome will be accentuated because 
the dose of ribavirin will be diluted into a smaller pool of host nucleotides, thereby increasing its 
effective intracellular concentration (Liu et al., 2020 [27]).  
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The temporary depletion of the host pyrimidine and purine pools in combination with the ribavirin 
effect on viral RdRp is hypothesized to lead to a significant reduction in virus replication at a 
critical point in the COVID-19 disease, restoring the balance in favor of the host immune system 
for ultimate clearance of SARS-CoV-2. This combination has been recently been shown to be 
effective in a pre-clinical model of disease where the authors demonstrated that inhibitors of 
DHODH could potentiate the activity of inhibitors of RdRp in the treatment of dengue virus, 
another single-stranded RNA virus (Liu et al., 2020 [27]).  
DHODH is already considered a potential therapeutic target in antiviral, oncology and autoimmune 
indications. Multiple doses of high-potency DHODH inhibitors are under investigation in the 
treatment of patients with hematologic malignancies. In addition to an anticancer effect when 
delivered in multiple high-doses, DHODHi may also prove effective in inhibiting viral replication 
by starving the host cell - and thus the replicating virus - of nucleotides, thereby acutely reducing 
the viral load in diseases such as COVID-19.  
Emerging data from SARS-CoV-2 infections show peaks of viral load 5 to 6 days after the onset 
of symptoms; the viremia then resolves within 10-14 days. This may be distinct from previous 
coronavirus infections where viral loads peaked approximately 10 days after the start of 
symptoms (Peiris et al., 2003 [18]). The timed and transient inhibition of DHODH and depletion 
of host pyrimidine nucleotides during the early period of the disease is expected to suppress 
viral replication during its peak and decrease viral load, leading to a rapid resolution of clinical 
symptoms.  
Due to the relatively short course of active viral replication in COVID-19, a single dose of 
brequinar administered at the right time may provide clinical benefit in patients requiring 
hospitalization due to the coronavirus infection. See Figure 3-3 for changes in viral load versus 
day of symptom onset in two patients with SARS-CoV-2 (Pan et al., 2020 [19]). 
Clear Creek hypothesizes that the timed inhibition of DHODHi or DHODHi + IMPDHi and 
depletion of host pyrimidine and purine nucleotides during the period of increased viral load will 
suppress viral replication leading to a more rapid resolution of clinical symptoms.  
 
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Figure 3-3. Changes in viral load versus day of symptom onset – COVID-19 
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.  
It is also hypothesized that the suppression of host nucleotide synthesis and therefore viral 
replication would be most effective early in the course of disease while there is still ongoing viral 
replication.  
3.8.1 Brequinar Dose Selection 
Safety data from previous oncology clinical studies of brequinar with maximum tolerated doses as 
high as 2250 mg/m2 repeated every 3 weeks and from the active brequinar study in acute myeloid 
leukemia (AML) patients suggest that a single dose of 500 mg/m2 p.o. will be safe and well 
tolerated. Brequinar has in vitro antiviral EC50s that range from 0.04-1.0 µM that equal 0.016-
0.40 µg/mL of brequinar. If the effective concentration to inhibit 90% of virus replication (EC90) 
is assumed to be one log great, then a plasma concentration of 0.1-4 µg/mL would be needed. A 
single oral dose of 500 mg/m2 maintains a plasma level of at least 4 µg/mL for 48-72 hours (see 
Brequinar IB [5]). 
3.8.2 Ribavirin Dose Selection 
Ribavirin is marketed in combination with interferon-alpha for treatment of chronic hepatitis 
caused by the RNA virus hepatitis C. The proposed dose for the COVID-19 study is based on the 
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ribavirin generic Summary of Product Characteristics (SPC) found in Section 15.4. In chronic 
hepatitis C patients, ribavirin at 400 mg BID has shown 13% anemia when combined with 
interferon. Ribavirin suppressed viral load with some activity when given for SARS in 2003 at 400 
mg TID. At that dose, 8% (of 75) or 0% (of 31) patients developed anemia (Peiris et al., 2003 
[18]; So et al., 2003 [28]). The CRISIS trial will administer ribavirin at the labelled dose of 400 
mg BID for 5 days. Given the recent evidence in a pre-clinical dengue virus model of disease that 
the misincorporation of ribavirin as a nucleoside analog into the replicating viral genome will be 
accentuated because the dose of ribavirin will be diluted into a smaller pool of host nucleotides, 
the labeled dose of 400 mg two times a day (BID) chosen should provide optimal safety with the 
potential for a benefit in combination with brequinar (Liu et al., 2020 [27]). 
3.8.3    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], more than 800 cancer patients 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. Brequinar has also been utilized in 
studies 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. While no 
DHODHi has been tested to date in the clinic for infection with SARS-CoV-2 and no brequinar 
safety information is available in treatment of this disease, DHODHi therapy in the context of trials 
for patients with cancer has the expected side-effects of mucositis and bone marrow suppression. 
Chronic DHODHi therapy in patients with autoimmune disease has the expected (and desired) 
effects on T-cell suppression (activated T-cells have a particular dependence on pyrimidine 
synthesis). However, a single, relatively low dose of brequinar such as that proposed for 
administration in this study should be safe, well tolerated and manifest none of these potential 
side-effects.  
The possible benefit in using brequinar to treat SARS-CoV-2 infection is the hypothesis that a 
single dose of brequinar will suppress host de novo pyrimidine synthesis for a period of up to 72 
hours thus decreasing viral load. As discussed above, inhibition of DHODH is expected to reduce 
the ability of the virus to replicate and it is for this reason that study CCB-CRISIS-01 will 
administer brequinar to patients with COVID-19. 
3.9  Risk/benefit of Ribavirin 
Risks associated with ribavirin administration in 40% or greater of adult patients receiving 
ribavirin with interferon included fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and 
anxiety/emotional lability/irritability. Additional safety information is provided in the ribavirin 
generic SPC (Section 15.4).  
The possible benefit in using ribavirin to treat SARS-CoV-2 infection is the hypothesis that the 
expected suppression of host nucleotide synthesis associated with ribavirin will prevent viral 
replication when used in conjunction with brequinar thereby reducing viral load. 
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3.10 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of 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 drug administration. The 
majority of these adverse effects have been less than grade IV in severity and resolve following 
discontinuation of dosing.  
Risks associated with ribavirin administration in hepatitis C patients who also received interferon-
alpha are presented in the ribavirin generic SPC found in Section 15.4. The most commonly 
reported adverse reactions in adult subjects receiving PegIntron or INTRON A in combination 
with ribavirin were fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and 
anxiety/emotional lability/irritability. 
3.11 Possible Interactions with Concomitant Medical Treatments 
While not previously tested in patients with viral infections, brequinar has been administered to 
subjects taking a variety of concomitant medications that are typical in cancer patients. 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. Brequinar has also been used concomitantly with antibiotics, antifungals and other critical 
care medications. 
 
There is no experience with brequinar for treatment of SARS-CoV-2 and other severe viral 
infections and no formal interaction studies have been conducted.  
 
Experience with use of ribavirin and interferon in treatment of hepatitis C has concluded that 
ribavirin should not be given with nucleoside reverse transcriptase inhibitors such as didanosine 
or with azathioprine. There is limited experience with ribavirin for treatment of SARS-CoV-2 and 
other severe viral infections and no formal interaction studies have been conducted for use of 
ribavirin with concomitant medications that are typical in these patients. Ribavirin should be taken 
with food, when possible. See ribavirin generic package insert, Appendix D Section 15.4. 
3.11.1 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). 
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Results of in vitro studies using both human and rat liver microsome preparations indicated little 
or no cytochrome P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-
450 enzyme-based interactions (ribavirin generic SPC Appendix D Section 15.4). 
3.12 Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated in a hospital setting by highly experienced infectious disease specialists 
and other qualified staff familiar with the treatment of severe viral infections and their 
complications. 
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5 
TRIAL DESIGN 
This will be a phase 1a randomized, open label, multi-center study with approximately 72 subjects. 
All subjects will receive standard of care per institutional guidelines for treatment of patients with 
SARS-CoV-2 infection. In addition to standard of care, the brequinar alone group will receive 1 
dose of brequinar 500 mg/m2. In addition to standard of care, the brequinar plus ribavirin group 
will receive brequinar 500 mg/m2 on Day 1 plus ribavirin 400 mg BID on Days 1 through 5. There 
are no restrictions on concomitant medications or treatments other than those contraindicated for 
use with ribavirin (see ribavirin generic SPC, Appendix D Section 15.4). 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Study procedures are presented in 
detail in Section 8. Subjects will be followed through Day 15, with mortality assessed on Day 29. 
Additional subjects may be enrolled following data review. 
If discharge occurs prior to Day 5 for subjects in the brequinar plus ribavirin treatment group, the 
subject will be provided with sufficient ribavirin to take at home to complete the treatment course. 
In this case, the subject is to return to the clinic for Day 7 and Day 15 visits.  
Missed assessments for discharged subjects (e.g. those collected on Day 6) will not be considered 
protocol deviations. 
Study information such as vital signs is to be collected using the available EHR data when possible.
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7 
TRIAL POPULATION 
7.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 72 subjects have completed the study. Additional subjects may be enrolled 
following data review. Subjects will be randomized to either brequinar or brequinar plus ribavirin 
or standard of care in a 1:1:1 ratio (approximately 24 subjects on brequinar, 24 subjects on the 
brequinar plus ribavirin combination, and 24 assigned to standard of care).  
7.2 Inclusion criteria 
1. Willing and able to provide written informed consent for the trial (or designated care 
giver/healthcare power of attorney may consent if subject unable per institutional 
guidelines). 
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 Food and Drug Administration (FDA)-cleared 
commercial or public health assay. 
4. Life expectancy > 48h in the opinion of the investigator. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men treated or enrolled on this protocol must also agree to 
use adequate contraception prior to the study, for the duration of study. participation, and 
for 90 days after completion of brequinar administration and for 6 months after completion 
of ribavirin administration. 
7. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of brequinar and for 6 months after 
completion of ribavirin administration.  
7.3 Exclusion Criteria 
1. In intensive care unit (ICU) or equivalent level of care or expected to require ICU level of 
care within next 24 hours. 
2. 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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3. Active malignancy other than squamous cell carcinoma; anticancer treatment such as 
chemotherapy or radiation therapy within the past month. 
4. Estimated creatinine clearance < 50 mL/min. 
5. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy 
test. 
6. Treatment with ribavirin, mycophenolate, leflunomide or teriflunomide, didanosine, 
azathioprine, tacrolimus, sirolimus, or pre-existing prednisone at higher than 20 mg daily 
(ongoing or within 2 weeks of study entry). 
7. Stevens-Johnson Syndrome or other hypersensitivity reactions to ribavirin or any 
component of the product. 
7.4 Inclusion of Women and Minorities 
Adult men and women of all races and ethnic groups are eligible for this trial. 
 
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8 
STUDY TREATMENTS 
8.1 Description of Study Medications 
8.1.1 Brequinar 
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be a single oral dose of 500 
mg/m2. The initial brequinar dose should be administered as soon as possible based on the 
availability of the investigational pharmacy. 
8.1.2 Ribavirin 
Ribavirin will be supplied as 200 mg capsules. Ribavirin should be taken with food, when possible. 
Dosing will be 400 mg BID for 5 days (Days 1 – 5) approximately 8 AM and 8 PM ± 4 hours.  
8.2 Treatment Administration 
This will be a phase 1a randomized, open label, multi-center study with approximately 72 subjects. 
All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 
infection. Subjects will be randomly assigned in a 1:1:1 ratio to standard of care alone, standard 
of care plus brequinar, or standard of care plus brequinar plus ribavirin. The brequinar alone group 
will receive 1 dose of brequinar 500 mg/m2 on Day 1. The brequinar plus ribavirin group will 
receive brequinar 500 mg/m2 on Day 1 along with ribavirin 400 mg BID x 5 days (study days 1 – 
5). 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE).  
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 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 most instances, brequinar-related toxicities were clinically manageable and reversible upon 
discontinuation of brequinar treatment. In a study where brequinar was dosed twice-weekly to 
solid tumor subjects, no drug-related deaths occurred. Stomatitis/mucositis was observed in 13 of 
the 19 (68%) patients across all doses. Mild to moderate (Grades 1 and 2) stomatitis was observed 
in 10 patients with a more severe (Grade 3) stomatitis seen in 3 patients at doses over 600 mg/m2. 
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One patient at 600 mg/m2 had drug discontinuation due to drug-related stomatitis. 
Myelosuppression was the main dose-limiting toxicity (DLT) with thrombocytopenia (Grades 1-
4), observed after 2 to 9 doses above 600 mg/m2. Three patients in the ongoing AML study 
experienced severe (Grade 3 or 4) mucositis following administration of two or more doses of 
brequinar. Any of these events reported with brequinar use can be serious in nature and may result 
in death.  
A single dose of brequinar at a low level relative to those administered in the cancer studies noted 
above is expected to be safe and well tolerated in the COVID-19 population. 
For ribavirin, the primary toxicity is hemolytic anemia which has been reported in approximately 
13% of subjects taking ribavirin and interferon alfa-2a on a chronic basis in combination with 
PegIntron A for hepatitis C. The most commonly reported adverse reactions in adult subjects 
receiving PegIntron or INTRON A in combination with ribavirin were fatigue/asthenia, headache, 
rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability. See the ribavirin generic 
SPC for complete ribavirin safety information (ribavirin generic SPC, Section 15.4). It is expected 
that the proposed acute use of ribavirin using the 400 mg BID x 5-day regimen will 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 15 (or longer if needed to follow up 
study medication-related adverse events). Mortality is assessed at Day 29. 
After treatment, participants will be monitored through Study Day 15. Participants may 
discontinue from the study by withdrawing consent at any time or for any reason as presented in 
Section 9.7. 
If discharge occurs prior to Day 5 for subjects in the brequinar plus ribavirin treatment group, the 
subject will be provided with sufficient ribavirin to take at home to complete the treatment course. 
In this case, the subject is to return to the clinic for Day 7 and Day 15 visits.  
The reason for study discontinuation will be recorded in the source document and the eCRF.  
8.4 Concomitant Medication/Treatment 
Record the name, start date, indication for use, 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. The use of other DHODH inhibitors and IMPDH 
inhibitors are not permitted during the study including ribavirin, mycophenolate, leflunomide or 
teriflunomide (see Section 8.6.6).  
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03 May 2021
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 31 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
8.5 Treatment Compliance 
Compliance will be assessed by reviewing the subject’s EHR and other study records as 
appropriate. 
8.6 Storage, Stability, Labeling and Packaging 
8.6.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.6.2 Labeling and Packaging  
Each brequinar bottle/dispensing container for subject use will be labeled with at least the 
following information: 
For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: 100 or 250 mg Brequinar capsules 
For oral use only. Take with approximately 8 ounces water. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 32 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Each ribavirin bottle/dispensing container for subject use will be labeled with at least the following 
information: 
For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: Ribavirin capsules (dosing per body weight) 
For oral use only. Take with approximately 8 ounces water and with food 
(when possible) 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
 
8.6.3 Blinding and Randomization 
The trial will be conducted in an open-label manner with random assignment to standard of care, 
standard of care plus brequinar or standard of care plus the brequinar plus ribavirin combination. 
The brequinar and ribavirin capsules will be provided to each participating institution in bulk to 
be dispensed by the institution’s pharmacist per the designated mg/m2 dose (for brequinar) and 
ribavirin 400 mg BID x 5 days for each subject. Randomization assignments will be provided by 
the sponsor. 
8.6.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment will be known for 
each subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the protocol and the brequinar IB or the ribavirin SPC or are commonly associated 
with COVID-19 or similar severe viral illnesses and their complications.   
8.6.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 33 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
The Investigator must keep a record of all study medication received, used and discarded.  It must 
be clear from the records whether the subject received study medication or was assigned to 
standard of care. 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 detailing 
how to calculate the mg/m2 dose together with examples of combinations of the 100 and 250 mg 
capsules to provide the most efficient use of the clinical supplies.  
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. 
8.6.6 Prohibited Medications 
The use of didanosine and azathioprine are not permitted during the study. The use of other 
DHODH inhibitors and IMPDH inhibitors such as mycophenolate, leflunomide or teriflunomide 
are not permitted during the study. 
 
Clinical Study Report 
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CONFIDENTIAL
03 May 2021
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 34 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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) 
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.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures.  Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be subject to review by the Sponsor; a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
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Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
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Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 69 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 70 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 71 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 40 of 59 
PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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 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. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. 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.   
Any serious adverse events (SAEs) experienced after 30 days post the last dose of study drug 
should only be reported to the sponsor if the investigator suspects a causal relationship to the 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, or require therapy. 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the End of Study and Death forms.  
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 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 72 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 73 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 74 of 582


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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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All SAEs will be reported to the IRB periodically, at the end of the study or per local institutional 
guidelines.   
10.4 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 Medical Monitor 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 is to 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 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to 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 knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must 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.   
10.5 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 the Sponsor Contact 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 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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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 pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as 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-
up with 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. 
10.6 Data Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be established to provide independent oversight 
to this trial.  The primary responsibility of the DSMB 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 DSMB will be detailed in a separate DSMB charter.  
The DSMB 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.  Following such a review, the DSMB Chair will 
advise the Sponsor that the study be stopped, a treatment arm dropped, or that the study may 
continue per protocol. 
 
 
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DATE: 31MAR2020 
 
 
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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 analyses will be based on the ITT population, which is defined as all randomized subjects.   
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, Vital Signs, 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 (TEAEs), defined as AEs occurring after 
randomization, will be tabulated by MedDRA preferred term and system organ class, and by 
severity and relationship to study treatment. All laboratory results and vital sign measurements 
will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will be assessed in terms of mortality, hospitalization status and duration, NEWS2 score, 
viral load (plasma and nasopharyngeal), and inflammatory markers. 
11.4 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 72 
subjects are planned to be entered in this trial.  Additional subjects may be enrolled following data 
review. 
11.5 Randomization 
A randomization scheme will be provided by the Sponsor to ensure subjects are randomly assigned 
to SOC, SOC + brequinar, or SOC + the brequinar plus ribavirin combination in a 1:1:1 ratio.  
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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. 
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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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 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.   
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 
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PROTOCOL VERSION: FINAL Ver.1.0 
DATE: 31MAR2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
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.   
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 eo we minimize
mortality for COVID-19 and other emerging disease outbreaks.
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. Ghamdi Al M, Alghamdi KM, Ghandoora Y, Alzahrani A, Salah F, Alsulami A, et al.
Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus
(MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia.
BMC Infect Dis. 2016 Apr 21;16(1):174.
12. Chong YP, Song JY, Seo YB, Choi J-P, Shin H-S, Rapid Response Team. Antiviral
Treatment Guidelines for Middle East Respiratory Syndrome. Infect Chemother. 2015
Sep;47(3):212–22.
13. 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.
14. Kentsis A, Volpon L, Topisirovic I, et al. Further evidence that ribavirin interacts with
eIF4E. RNA. 2005:11:1762-1766.
15. Assouline S, Culjikovic B, Cocokakis E, Rousseau C, Beslu N, Amri A, Caplan S, Leber
B, Rou D-C, Miller W, and Borden K. Molecular targeting of the oncogene eIF4E in acute
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myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood. 2009 
May 11;114(2):257-60. 
16. Tan K, Culjkovic B, Amri A, Borden K. Ribavirin targets eIF4E dependent Akt survival 
signaling. Biochim Biophys Res Commu. 2008;375:341-345. 
17. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and 
epidemiology of 2019 novel coronavirus: implications for virus origins and receptor 
binding. Lancet 2020; 395: 565-74. 
18. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community 
outbreak of coronavirus-associated SARS pneumonia: a prospective 
study. Lancet. 2003; 361: 1767-1772 
19. Pan Y, Zhang D, Yang P, Poon L, and Wang Q. Viral load of SARS-CoV-2 in clinical 
Samples. Lancet February 24, 2020.  
20. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the 
assessment of acute-illness severity in the NHS. Updated report of a working party. 
London: RCP, 2017. 
21. Ning Q, Brown D, Paodo J, et al. Ribavirin inhibits viral-induced macrophage production 
of TNF, IL-1, he procoagulant fgl2 prothrombinase and preserves Th1 cytokine production 
but inhibits Th2 cytokine response. J Immunol 1998; 160:3487. 
22. 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). 
23. Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci. 
2020 May 1;248:117477. 
24. Ortega-Prieto AM, Sheldon J, Grande-Pérez A, Tejero H, Gregori J, Quer J, et al. 
Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis. 
PLoS ONE. 2013;8(8):e71039. 
25. Poutanen SM, Low DE, Henry B, Finkelstein S, Rose D, Green K, et al. Identification of 
severe acute respiratory syndrome in Canada. N Engl J Med. 2003 May 15;348(20):1995–
2005. 
26. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O’Meara MJ et al. A SARS-CoV-
2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-
Repurposing. bioRxiv. 2020 Mar 22; 2020.03.22.002386v3. 
27. 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. 
28. So LK, Lau AC, Yam LY, et al. Development of a standard treatment protocol for severe 
acute respiratory syndrome. Lancet 2003;361:1615–7. 
 
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15 APPENDICES 
15.1 Appendix A:  CCB-01 Schedule of Events 
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CCB-CRISIS-01  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2 - D7 
Final Visit  
D15 
F/U  
Phone 
Call 
2 weeks/Survival 
Informed Consent 
X 
 
 
 
 
AE/Concomitant Medications  
X 
X 
X 
X 
X 
Medical history / History of current illness 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Physical Exam incl. height and weight 
X 
X 
 
 
 
Vital Signs including BP, pulse, respirations, 
temperature, pO2 
X 
X 
X 
X 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
Hematology/Chemistry/Inflammatory 
Markers/Serum for research purposes 
X 
X 
X 
X 
 
Plasma collection for viral load 
 
X (pre-dose) 
X 
X 
 
Swab collection for nasopharyngeal (or if 
collection kit not available, oropharyngeal) viral 
load 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Clinical SARS-CoV-2 testing 
X 
 
 
X 
 
Hospital Status 
 
X 
X 
X 
 
NEWS2 Criteria 
X 
X 
X 
X 
 
Dispense Study Medication  
 
X 
X (D2 – 5 if assigned to 
ribavirin combination) 
X 
 
Survival Assessment Day 29 
 
 
 
 
X 
 
 
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15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-01 
STUDY TITLE:  The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of combined suppression of host nucleotide synthesis in hospitalized 
adults with coronavirus-19 (COVID-19). 
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: __________________ 
 
Site Address: 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
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15.3 Appendix C: National Early Warning Score (NEWS2)   
 
Use SpO2 Scale 2 if target range is 88 – 92%, e.g., in hypercapnic respiratory failure. 
 
National Early Warning System Score (NEWS) 2  Royal College of Physicians 2017 [20] 
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15.4 Appendix D: Ribavirin generic (ribavirin USP) capsules, for oral use Summary of 
Product Characteristics (SPC) 
 
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RIBAVIRIN - ribavirin capsule  
Aurobindo Pharma Limited
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RIBAVIRIN CAPSULES safely and
effectively. See full prescribing information for RIBAVIRIN CAPSULES.
RIBAVIRIN capsules, for oral use
Initial U.S. Approval: 1998
WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC
ANEMIA, and MONOTHERAPY NOT RECOMMENDED
See full prescribing information for complete boxed warning.
Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed
to ribavirin.  Therefore, ribavirin therapy is contraindicated in women who are pregnant and in the
male partners of women who are pregnant. Avoid pregnancy during therapy and for 6 months after
completion of treatment in both female patients and in female partners of male patients who are
taking ribavirin therapy. (4, 5.1, 8.1, 8.3, 13.1)
The hemolytic anemia associated with ribavirin therapy may result in worsening of cardiac disease
that has led to fatal and nonfatal myocardial infarctions.  Patients with a history of significant or
unstable cardiac disease should not be treated with ribavirin. (2.5, 5.2, 6.1)
Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C. (5.10)
INDICATIONS AND USAGE
Ribavirin capsules are a nucleoside analogue indicated in combination with interferon alfa-2b (pegylated and nonpegylated)
for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age or older with compensated liver disease. (1.1)
Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy:
previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1
infection.
DOSAGE AND ADMINISTRATION
Ribavirin capsules are administered according to body weight. (2.1, 2.2, 2.3)
Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal dysfunction.
(2.5, 2.6, 12.3)
DOSAGE FORMS AND STRENGTHS
Ribavirin Capsules USP 200 mg (3)
CONTRAINDICATIONS
Pregnancy and men whose female partners are pregnant (4, 5.1, 8.1, 8.3)
Known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema
multiforme to ribavirin  or any component of the product (4)
Autoimmune hepatitis (4)
Hemoglobinopathies (4)
Creatinine clearance less than 50 mL/min (4, 12.3)
 Coadministration with didanosine (4, 7.1)
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: May cause fetal harm. Patients should have a negative pregnancy test prior to therapy and use
effective contraception and undergo periodic pregnancy tests. (5.1, 8.1, 8.3)
Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation
of therapy:
Hemolytic anemia may occur with a significant initial drop in hemoglobin. (5.2)
Pancreatitis. (5.3)
Pulmonary infiltrates or pulmonary function impairment. (5.4)
New or worsening ophthalmologic disorders. (5.5)
Severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.
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(5.6)
Dental/periodontal disorders reported with combination therapy. (5.7)
Concomitant administration of azathioprine. (5.8)
Weight loss and growth inhibition reported during combination therapy in pediatric patients. Long-term growth
inhibition (height) reported in some patients. (5.9)
Monotherapy with ribavirin is not permitted. (5.10)
ADVERSE REACTIONS
Hemolytic anemia occurred in more than 10% of adult patients receiving ribavirin/PegIntron or INTRON A combination
therapy. (6.1)
Most common adverse reactions (40% or greater) in adult patients receiving ribavirin/PegIntron or INTRON A
combination therapy are injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and
anxiety/emotional lability/irritability. (6.1) Most common adverse reactions (greater than 25%) in pediatric patients
receiving ribavirin/PegIntron therapy are: pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and
vomiting. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Nucleoside analogues: Closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce
dose or discontinue interferon, ribavirin or both with worsening toxicities. (7.2)
USE IN SPECIFIC POPULATIONS
Pediatrics: Safety and efficacy in patients less than 3 years old have not been established. (8.4)
Organ transplant recipients: Safety and efficacy not studied. (8.6)
Co-infected patients: Safety and efficacy with HIV or HBV co-infection have not been established. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 2/2020
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC ANEMIA, and MONOTHERAPY
NOT RECOMMENDED
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C (CHC)
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
2.2 Ribavirin capsules/PegIntron Combination Therapy
2.3 Ribavirin capsules/INTRON A Combination Therapy
2.4 Testing Prior to Initiation of Ribavirin capsules
2.5 Dose Modifications
2.6 Discontinuation of Dosing
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
5.2 Anemia
5.3 Pancreatitis
5.4 Pulmonary Disorders
5.5 Ophthalmologic Disorders
5.6 Laboratory Tests
5.7 Dental and Periodontal Disorders
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5.8 Concomitant Administration of Azathioprine
5.9 Impact on Growth in Pediatric Patients
5.10 Not Recommended for Monotherapy and Risks Associated with Combination Therapy
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experiences
7 DRUG INTERACTIONS
7.1 Didanosine
7.2 Nucleoside Analogues
7.3 Drugs Metabolized by Cytochrome P-450
7.4 Azathioprine
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Organ Transplant Recipients
8.7 HIV or HBV Co-infection
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and Pharmacology
14 CLINICAL STUDIES
14.1 Ribavirin/PegIntron Combination Therapy
14.2 Ribavirin/INTRON A Combination Therapy
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*
FULL PRESCRIBING INFORMATION
Sections or subsections omitted from the full prescribing information are not listed.
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WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC ANEMIA, and
MONOTHERAPY NOT RECOMMENDED
Significant teratogenic and embryocidal effects have been demonstrated in all animal
species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days
and may persist in non-plasma compartments for as long as 6 months. Therefore,
ribavirin therapy is contraindicated in women who are pregnant and in the male partners
of women who are pregnant. Avoid pregnancy during therapy and for 6 months after
completion of treatment in both female patients and in female partners of male patients
who are taking ribavirin therapy. Effective contraception must be utilized during
treatment and during the 6-month post-treatment follow-up period [see Contraindications
(4), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3), and Nonclinical
Toxicology (13.1)].
Hemolytic anemia has been reported with ribavirin therapy. The anemia associated with
ribavirin therapy may result in worsening of cardiac disease that has led to fatal and
nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac
disease should not be treated with ribavirin [see Dosage and Administration (2.5), Warnings
and Precautions (5.2), and Adverse Reactions (6.1)].
Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus
infection and should not be used alone for this indication [see Warnings and Precautions
(5.10)].
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C (CHC)
Ribavirin capsules in combination with interferon alfa-2b (pegylated and nonpegylated) are indicated for
the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age and older with compensated liver
disease [see Warnings and Precautions (5.9, 5.10), and Use in Specific Populations (8.4)].
The following points should be considered when initiating ribavirin capsules combination therapy with
PegIntron
or INTRON A :
Combination therapy with ribavirin capsules/PegIntron is preferred over ribavirin
capsules/INTRON A as this combination provides substantially better response rates [see Clinical
Studies (14)].
 Patients with the following characteristics are less likely to benefit from re-treatment after failing a
course of therapy: previous nonresponse, previous pegylated interferon treatment, significant
bridging fibrosis or cirrhosis, and genotype 1 infection [see Clinical Studies (14)].
 No safety and efficacy data are available for treatment duration lasting longer than one year.    
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
Do not open, crush or break ribavirin capsules. Ribavirin capsules should be taken with food [see
Clinical Pharmacology (12.3)].
2.2 Ribavirin capsules/PegIntron Combination Therapy
Adult Patients
The recommended dose of ribavirin capsules when used in combination with PegIntron is 800 mg to
® 
®
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1,400 mg based on patient body weight in two divided doses (see Table 1). Refer to PegIntron labeling
for PegIntron dosing information.
Duration of Treatment – Interferon Alpha-naïve Patients
The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be
considered in patients who do not achieve at least a 2 log
 drop or loss of hepatitis C virus (HCV)-
RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with
genotype 2 and 3 should be treated for 24 weeks.
Duration of Treatment – Re-treatment with PegIntron/Ribavirin capsules of Prior Treatment Failures
The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV
genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at Week 12 of therapy, or
whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR
and discontinuation of therapy should be considered [see Clinical Studies (14.1)].
Table 1: Recommended Adult Dosing for Ribavirin capsules in Combination with PegIntron
Body Weight (kg) 
Ribavirin capsules Daily
Dose 
Ribavirin Number of Capsules 
Less than 66
800 mg/day
2 x 200 mg capsules AM
2 x 200 mg capsules PM
66 to 80
1,000 mg/day
2 x 200 mg capsules AM
3 x 200 mg capsules PM
81 to 105
1,200 mg/day
3 x 200 mg capsules AM
3 x 200 mg capsules PM
Greater than 105
1,400 mg/day
3 x 200 mg capsules AM
4 x 200 mg capsules PM
Pediatric Patients
Dosing of ribavirin capsules in pediatric patients is determined by body weight. The recommended dose
of ribavirin capsules when used in combination with PegIntron in pediatric patients ages 3 to 17 years is
15 mg/kg/day in two divided doses (see Table 2). Refer to PegIntron labeling for PegIntron dosing
information. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2
and 3 should be treated for 24 weeks.
Table 2: Recommended Pediatric Ribavirin capsules Dosing in Combination with PegIntron
* Ribavirin Oral Solution may be used in any patient regardless of body weight.
Body Weight (kg) 
Ribavirin capsules Daily
Dose 
Ribavirin Number of Capsules 
Less than 47
15 mg/kg/day
Use Ribavirin Oral Solution*
47 to 59
800 mg/day
2 x 200 mg capsules AM
2 x 200 mg capsules PM
60 to 73
1,000 mg/day
2 x 200 mg capsules AM
3 x 200 mg capsules PM
Greater than 73
1,200 mg/day
3 x 200 mg capsules AM
3 x 200 mg capsules PM
10
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2.3 Ribavirin capsules/INTRON A Combination Therapy
Adults
Duration of Treatment – Interferon Alpha-naïve Patients
The recommended dose of ribavirin capsules when used in combination with INTRON A depends on
the patient’s body weight (see Table 3). Refer to Intron A labeling for interferon dosing information.
The recommended duration of treatment for patients previously untreated with interferon is 24 to 48
weeks. The duration of treatment should be individualized to the patient depending on baseline disease
characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage (1.1), 
Adverse Reactions (6.1), and Clinical Studies (14)]. After 24 weeks of treatment, virologic response
should be assessed. Treatment discontinuation should be considered in any patient who has not achieved
an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy
data for treatment duration lasting longer than 48 weeks in the previously untreated patient population.
Duration of Treatment – Re-treatment with INTRON A/Ribavirin capsules in Relapse Patients
In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of
treatment is 24 weeks.
Table 3: Recommended Ribavirin
capsules Dosing in Combination with
INTRON A
Body
Weight
Ribavirin Capsules
At least
75 kg
 2 x 200 mg capsules AM 
 3 x 200 mg capsules PM daily
orally 
Greater than
75 kg
 3 x 200 mg capsules AM 
 3 x 200 mg capsules PM daily
orally 
Pediatrics The recommended dose of ribavirin capsules when used in combination with INTRON A is
15 mg/kg per day orally in two divided doses (see Table 2). Refer to Intron A labeling for interferon
dosing information.
The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24
weeks of treatment, virologic response should be assessed. Treatment discontinuation should be
considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay
by this time. The recommended duration of treatment for pediatric patients with genotype 2 and 3 is 24
weeks.
2.4 Testing Prior to Initiation of Ribavirin capsules
The following laboratory tests are recommended in all patients treated with ribavirin capsules prior to
initiation of treatment and periodically thereafter.
Standard hematologic tests - including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and
as clinically appropriate [see Warnings and Precautions (5.2, 5.6)], complete and differential white
 
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blood cell counts, and platelet count.
 Blood chemistries - liver function tests and TSH.
 Pregnancy - in women of childbearing potential.
 ECG [see Warnings and Precautions (5.2)].
2.5 Dose Modifications
If severe adverse reactions or laboratory abnormalities develop during ribavirin capsules combination
therapy, modify or discontinue the dose until the adverse reaction abates or decreases in severity (see
Table 4) [see Warnings and Precautions (5)]. If intolerance persists after dose adjustment, combination
therapy should be discontinued. Refer to PegIntron labeling for additional information regarding dose
reduction of PegIntron.
Dose reduction in pediatric patients is accomplished by modifying the recommended ribavirin capsules
dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8
mg/kg/day, if needed (see Table 4).
Ribavirin capsules are contraindicated in patients with creatinine clearance less than 50 mL/min [see
Contraindications (4)]. Patients with impaired renal function and those over the age of 50 should be
carefully monitored with respect to development of anemia [see Warnings and Precautions (5.2), Use in
Specific Populations (8.5), and Clinical Pharmacology (12.3)].
Ribavirin capsules should be administered with caution to patients with pre-existing cardiac disease.
Assess cardiovascular status before initiation of treatment and during therapy. If there is any
deterioration of cardiovascular status, discontinue combination therapy [see Warnings and Precautions
(5.2)].
                              
In patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the
hemoglobin decreases by 2 g/dL or more during any 4-week period. If the hemoglobin level remains
below 12 g/dL after 4 weeks on a reduced dose, discontinue combination therapy.
Modify or discontinue ribavirin capsules dosing in any patient whose hemoglobin level falls below 10
g/dL (see Table 4) [see Warnings and Precautions (5.2)].
Table 4: Guidelines for Dose Modification and Discontinuation of Ribavirin capsules in
combination with PegIntron or INTRON A Based on Laboratory Parameters in Adults and
Pediatrics
Laboratory
Parameters 
Reduce Ribavirin
capsules  Daily Dose
(see note 1) if: 
Reduce PegIntron or 
INTRON A Dose 
(see note 2) if: 
Discontinue Therapy if: 
WBC
N/A
1.0 to <1.5 x 10 /L
<1.0 x 10 /L
Neutrophils
N/A
0.5 to <0.75 x 10 /L
<0.5 x 10 /L
Platelets
N/A
25 to < 50 x 10 /L (adults)
<25 x 10 /L (adults)
N/A
50 to <70 x 10 /L (pediatrics)
<50 x 10 /L (pediatrics)
Creatinine
N/A
N/A
>2 mg/dL (pediatrics)
Hemoglobin in
patients without
history of
cardiac disease
8.5 to <10 g/dL
N/A
<8.5 g/dL
Reduce Ribavirin capsules Dose by 200 mg/day and
9
9
9
9
9
9
9
9
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Note 1: Adult patients: 1  dose reduction of ribavirin is by 200 mg/day (except in patients receiving the
1,400 mg, dose reduction should be by 400 mg/day). If needed, 2
 dose reduction of ribavirin is by an
additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg
capsule in the morning and two 200 mg capsules in the evening.
            Pediatric patients: 1  dose reduction of ribavirin is to 12 mg/kg/day, 2
 dose reduction of
ribavirin is to 8 mg/kg/day.
Note 2: Adult patients treated with ribavirin capsules and PegIntron: 1
dose reduction of PegIntron is to
1 mcg/kg/week. If needed, 2
dose reduction of PegIntron is to 0.5 mcg/kg/week.
            Pediatric patients treated with ribavirin capsules and PegIntron: 1
dose reduction of PegIntron is
to 40 mcg/m /week, 2
dose reduction of PegIntron is to 20 mcg/m /week. 
For patients on ribavirin capsules/INTRON A combination therapy: reduce INTRON A dose by 50%.
 Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease
greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly
evaluations and hematology testing.
 These guidelines are for patients with stable cardiac disease. Patients with a history of significant or
unstable cardiac disease should not be treated with PegIntron/ribavirin capsules combination therapy
[see Warnings and Precautions (5.2)].
 
 
PegIntron or INTRON A Dose by Half if: 
 
Hemoglobin in
patients with
history of stable
cardiac
disease
 
≥2 g/dL decrease in hemoglobin during any four-week
period during treatment
<8.5 g/dL or <12 g/dL
after four weeks of dose
reduction
Refer to labeling for INTRON A or PegIntron for additional information about how to reduce an
INTRON A or PegIntron dose.
2.6 Discontinuation of Dosing
Adults In HCV genotype 1, interferon-alfa-naïve patients receiving PegIntron in combination with
ribavirin, discontinue therapy if there is not at least a 2 log
 drop or loss of HCV-RNA at 12 weeks of
therapy, or if HCV-RNA levels remain detectable after 24 weeks of therapy. Regardless of genotype,
previously treated patients who have detectable HCV-RNA at Week 12 or 24 are highly unlikely to
achieve SVR and discontinuation of therapy should be considered.
Pediatrics (3 to 17 years of age) In patients receiving PegIntron/ribavirin capsules combination
(excluding HCV Genotype 2 and 3), discontinue therapy at 12 weeks if HCV-RNA has dropped less
than 2 log
 compared to pretreatment level, or at 24 weeks if HCV-RNA is still detectable.
3 DOSAGE FORMS AND STRENGTHS
Ribavirin Capsules USP, 200 mg are white/white, size ‘1’ hard gelatin capsule filled with white to
off-white granular powder and imprinted with ‘E’ on white cap and ‘81’ on white body with black ink.  
4 CONTRAINDICATIONS
Ribavirin capsules combination therapy is contraindicated in:
pregnancy. Ribavirin capsules may cause fetal harm when administered to a pregnant woman.
Ribavirin capsules are contraindicated in women who are pregnant or planning to become pregnant.
If a patient becomes pregnant while taking ribavirin capsules, the patient should be apprised of the
potential hazard to the fetus [see Warnings and Precautions (5.1), and Use in Specific Populations
st
nd
st
nd
st 
nd 
st 
2
nd 
2
*
†
*†
10
10
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(8.1, 8.3)].
men whose female partners are pregnant [see Use in Specific Populations (8.3)]
patients with known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal
necrolysis, and erythema multiforme to ribavirin or any component of the product
 patients with autoimmune hepatitis
 patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
 patients with creatinine clearance less than 50 mL/min [see Clinical Pharmacology (12.3)]
 when coadministered with didanosine because exposure to the active metabolite of didanosine
(dideoxyadenosine 5’-triphosphate) is increased. Fatal hepatic failure, as well as peripheral
neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, has been reported in
patients receiving didanosine in combination with ribavirin [see Drug Interactions (7.1)].   
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
Ribavirin capsules may cause birth defects, miscarriage or stillbirth. Ribavirin therapy should not be
started until a report of a negative pregnancy test has been obtained immediately prior to planned
initiation of therapy. Patients should use effective contraception and have periodic monitoring with
pregnancy tests during treatment and during the 6-month period after treatment has been stopped.
Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients.
Ribavirin has demonstrated significant teratogenic and embryocidal effects in all animal species tested.
These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin
[see Boxed Warning, Contraindications (4), and Use in Specific Populations (8.1, 8.3)].
5.2 Anemia
Hemolytic anemia was observed in approximately 10% of ribavirin/INTRON A-treated subjects in
clinical trials. The anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy.
Because the initial drop in hemoglobin may be significant, obtain hemoglobin or hematocrit levels
before the start of treatment and at Week 2 and Week 4 of therapy, or more frequently if clinically
indicated. Patients should then be followed as clinically appropriate [see Dosage and Administration
(2.5, 2.6)].
Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin.
Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy.
Patients with pre-existing cardiac disease should have electrocardiograms administered before
treatment and should be appropriately monitored during therapy. If there is any deterioration of
cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (2.5,
2.6)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of
significant or unstable cardiac disease should not use ribavirin.
5.3 Pancreatitis
Suspend ribavirin and INTRON A or PegIntron combination therapy in patients with signs and symptoms
of pancreatitis and discontinue in patients with confirmed pancreatitis.
5.4 Pulmonary Disorders
Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension,
and pneumonia, have been reported during ribavirin with alpha interferon combination therapy;
occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of
sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function
impairment, closely monitor the patient, and if appropriate, discontinue combination therapy.
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5.5 Ophthalmologic Disorders
Ribavirin is used in combination therapy with INTRON A or PegIntron. Refer to labeling for PegIntron
for additional information.
5.6 Laboratory Tests
PegIntron in combination with ribavirin may cause severe decreases in neutrophil and platelet counts,
and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.
Obtain hematology and blood chemistry testing in patients on PegIntron/ribavirin combination therapy
before the start of treatment and then periodically thereafter. In the adult clinical trial, complete blood
counts (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT,
bilirubin, and uric acid) were measured during the treatment period at Weeks 2, 4, 8, 12, and then at 6-
week intervals, or more frequently if abnormalities developed. In pediatric subjects, the same laboratory
parameters were evaluated with additional assessment of hemoglobin at treatment Week 6. TSH levels
were measured every 12 weeks during the treatment period. HCV-RNA should be measured
periodically during treatment [see Dosage and Administration (2)].
5.7 Dental and Periodontal Disorders
Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or
peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and
mucous membranes of the mouth during long-term treatment with the combination of ribavirin and
pegylated or nonpegylated interferon alfa-2b. Advise patients to brush their teeth thoroughly twice
daily and have regular dental examinations. If vomiting occurs, advise patients to rinse out their mouth
thoroughly afterwards.
5.8 Concomitant Administration of Azathioprine
Pancytopenia (marked decreases in red blood cells, neutrophils, and platelets) and bone marrow
suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant
administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8),
myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and
concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Discontinue
PegIntron, ribavirin, and azathioprine for pancytopenia, and do not reintroduce pegylated
interferon/ribavirin with concomitant azathioprine [see Drug Interactions (7.4)].
5.9 Impact on Growth in Pediatric Patients
Data on the effects of PegIntron and ribavirin on growth come from an open-label study in subjects 3
through 17 years of age, in which weight and height changes were compared to U.S. normative
population data. In general, the weight and height gain of pediatric subjects treated with PegIntron and
ribavirin lagged behind that predicted by normative population data for the entire length of treatment.
Severely inhibited growth velocity (less than 3
percentile) was observed in 70% of the subjects while
on treatment. Following treatment, rebound growth and weight gain occurred in most subjects. Long-
term follow-up data in pediatric subjects, however, indicates that PegIntron in combination therapy with
ribavirin may induce a growth inhibition that results in reduced adult height in some patients [see Adverse
Reactions (6.1)].
Similarly, an impact on growth was seen in subjects after treatment with ribavirin and INTRON A
combination therapy for one year. In a long-term follow-up trial of a limited number of these subjects,
combination therapy resulted in reduced final adult height in some subjects [see Adverse Reactions (6.1)].
5.10 Not Recommended for Monotherapy and Risks Associated with Combination Therapy
Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic
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hepatitis C virus infection; therefore, ribavirin capsules must not be used alone. The safety and efficacy
of ribavirin capsules have only been established when used together with INTRON A or PegIntron (not
other interferons) as combination therapy.
The safety and efficacy of ribavirin with INTRON A or PegIntron combination therapy for the treatment
of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established.
Ribavirin capsules should not be used for these indications.
There are significant adverse reactions caused by ribavirin/INTRON A or PegIntron combination
therapy, including severe depression and suicidal or homicidal ideation, hemolytic anemia, suppression
of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and
diabetes. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily
adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up.
Labeling for INTRON A and PegIntron should be reviewed in their entirety for additional safety
information prior to initiation of combination treatment.
6 ADVERSE REACTIONS
The following serious adverse drug reactions are discussed in other sections of the labeling:
Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)]
Anemia [see Warnings and Precautions (5.2)]
Pancreatitis [see Warnings and Precautions (5.3)]
Pulmonary Disorders [see Warnings and Precautions (5.4)]
Ophthalmic Disorders [see Warnings and Precautions (5.5)]
Dental and Periodontal Disorders [see Warnings and Precautions (5.7)]
Impact on Growth in Pediatric Patients [see Warnings and Precautions (5.9)]   
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in clinical practice.
Clinical trials with ribavirin in combination with PegIntron or INTRON A have been conducted in over
7,800 subjects from 3 to 76 years of age.
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within
the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred
in approximately 10% of patients [see Warnings and Precautions (5.2)].
Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most
commonly reported adverse reactions in adult subjects receiving PegIntron or INTRON A in
combination with ribavirin were injection site inflammation/reaction, fatigue/asthenia, headache, rigors,
fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in
pediatric subjects, ages 3 and older, receiving ribavirin in combination with PegIntron or INTRON A
were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.
The Adverse Reactions section references the following clinical trials:
Ribavirin/PegIntron Combination therapy trials:
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Clinical Study 1 – evaluated PegIntron monotherapy (not further described in this label; see
labeling for PegIntron for information about this trial).
Study 2 – evaluated ribavirin 800 mg/day flat dose in combination with 1.5 mcg/kg/week
PegIntron or with INTRON A.
Study 3 – evaluated PegIntron/weight-based ribavirin in combination with PegIntron/flat dose
ribavirin regimen.
Study 4 – compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination
with ribavirin and a third treatment group receiving Pegasys
(180 mcg/week)/Copegus
(1000
to 1200 mg/day).
Study 5 – evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based ribavirin in
prior treatment failure subjects.
PegIntron/Ribavirin Combination Therapy in Pediatric Patients
Ribavirin/INTRON A Combination Therapy trials for adults and pediatrics
Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with
PegIntron with or without ribavirin [see Boxed Warning, Warnings and Precautions (5)]. The most
common serious events occurring in subjects treated with PegIntron and ribavirin were depression and
suicidal ideation [see Warnings and Precautions (5.10)], each occurring at a frequency of less than 1%.
Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents,
compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up [see Warnings
and Precautions (5.10)]. The most common fatal reaction occurring in subjects treated with PegIntron
and ribavirin was cardiac arrest, suicidal ideation, and suicide attempt [see Warnings and Precautions
(5.10)], all occurring in less than 1% of subjects.
Adverse Reaction - Ribavirin/PegIntron Combination Therapy
Adult Subjects
Adverse reactions that occurred in the clinical trial at greater than 5% incidence are provided by
treatment group from the ribavirin/PegIntron Combination Therapy (Study 2) in Table 5.
Table 5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects
Adverse Reactions 
Percentage of Subjects
Reporting Adverse Reactions* 
Adverse Reactions 
Percentage of Subjects
Reporting Adverse Reactions* 
PegIntron 
1.5
mcg/kg/Ribavirin
(N=511)
INTRON
A/Ribavirin
(N=505)
PegIntron 
1.5
mcg/kg/Ribavirin
  (N=511)
INTRON
A/Ribavirin
(N=505)
Application Site 
 
Musculoskeletal 
 
    Injection Site
Inflammation
 
    Injection Site
Reaction
25
 
58
18
 
36
    Myalgia
56
50
    Arthralgia
34
28
Autonomic Nervous
System 
 
    Musculoskeletal
Pain
21
19
    Dry Mouth
12
8
Psychiatric 
 
    Increased
Sweating
11
7
    Insomnia
40
41
    Flushing
4
3
    Depression
31
34
Anxiety/Emotional
® 
® 
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A subject may have reported more than one adverse reaction within a body system/organ class
category.
Body as a Whole 
 
    Anxiety/Emotional
    Lability/Irritability
47
47
    Fatigue/Asthenia
66
63
    Concentration
Impaired
17
21
    Headache
62
58
    Agitation
8
5
    Rigors
48
41
    Nervousness
6
6
    Fever
46
33
Reproductive,
Female 
 
    Weight Loss
29
20
    Menstrual
Disorder
7
6
    Right Upper
Quadrant Pain
12
6
Resistance
Mechanism 
 
    Chest Pain
8
7
    Viral Infection
12
12
    Malaise
4
6
    Fungal Infection
6
1
Central/Peripheral Nervous System 
Respiratory System
 
    Dizziness
21
17
    Dyspnea
26
24
Endocrine 
 
    Coughing
23
16
    Hypothyroidism
5
4
    Pharyngitis
12
13
Gastrointestinal 
 
    Rhinitis
8
6
    Nausea
43
33
    Sinusitis
6
5
    Anorexia
32
27
Skin and
Appendages 
 
    Diarrhea
22
17
    Alopecia
36
32
    Vomiting
14
12
    Pruritus
29
28
    Abdominal Pain
13
13
    Rash
24
23
    Dyspepsia
9
8
    Skin Dry
24
23
    Constipation
5
5
Special Senses,
Other 
 
Hematologic
Disorders 
 
    Taste Perversion
9
4
    Neutropenia
26
14
Vision Disorders 
 
    Anemia
12
17
    Vision Blurred
5
6
    Leukopenia
6
5
    Conjunctivitis
4
5
    Thrombocytopenia
5
2
 
Liver and Biliary
System 
 
    Hepatomegaly
4
4
Table 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or
equal to 10% incidence.
Table 6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence) By
Descending Frequency
 
Study 4 
Percentage of Subjects Reporting Treatment-Related Adverse Reactions 
Adverse Reactions 
PegIntron 1.5 mcg/kg
with  Ribavirin 
(N=1019) 
PegIntron 1 mcg/kg
with  Ribavirin
(N=1016) 
Pegasys 180 mcg with
Copegus 
(N=1035) 
    Fatigue
67
68
64
* 
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    Headache
50
47
41
    Nausea
40
35
34
    Chills
39
36
23
    Insomnia
38
37
41
    Anemia
35
30
34
    Pyrexia
35
32
21
    Injection Site Reactions
34
35
23
    Anorexia
29
25
21
    Rash
29
25
34
    Myalgia
27
26
22
    Neutropenia
26
19
31
    Irritability
25
25
25
    Depression
25
19
20
    Alopecia
23
20
17
    Dyspnea
21
20
22
    Arthralgia
21
22
22
    Pruritus
18
15
19
    Influenza-like Illness
16
15
15
    Dizziness
16
14
13
    Diarrhea
15
16
14
    Cough
15
16
17
    Weight Decreased
13
10
10
    Vomiting
12
10
9
    Unspecified Pain
12
13
9
    Dry Skin
11
11
12
    Anxiety
11
11
10
    Abdominal Pain
10
10
10
    Leukopenia
9
7
10
The incidence of serious adverse reactions was comparable in all trials. In Study 2, the incidence of
serious adverse reactions was 17% in the PegIntron/ribavirin groups compared to 14% in the INTRON
A/ribavirin group. In Study 3, there was a similar incidence of serious adverse reactions reported for
the weight-based ribavirin group (12%) and for the flat-dose ribavirin regimen.
In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy.
Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up
period. In Study 2, many subjects continued to experience adverse reactions several months after
discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing
adverse reactions by body class in the PegIntron 1.5/ribavirin group was 33% (psychiatric), 20%
(musculoskeletal), and 10% (for endocrine and for GI). In approximately 10 to 15% of subjects, weight
loss, fatigue, and headache had not resolved.
There have been 28 subject deaths that occurred during treatment or follow-up in Studies 2, 3, and 4. In
Study 2, there was 1 suicide in a subject receiving PegIntron/ribavirin combination therapy; and 1 subject
death in the INTRON A/ribavirin group (motor vehicle accident). In Study 3, there were 14 deaths, 2 of
which were probable suicides and 1 was an unexplained death in a person with a relevant medical
history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects who received
PegIntron/ribavirin combination therapy, 5 in the PegIntron 1.5 mcg/ribavirin arm (N=1019) and 1 in the
PegIntron 1 mcg/ribavirin arm (N=1016), and 6 of which occurred in subjects receiving
Pegasys/Copegus (N=1035); there were 3 suicides that occurred during the off treatment follow-up
period in subjects who received PegIntron (1.5 mcg/kg)/ribavirin combination therapy.
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In Studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with ribavirin,
discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON
A in combination with ribavirin. In Study 3, 15% of subjects receiving PegIntron in combination with
weight-based ribavirin and 14% of subjects receiving PegIntron with flat-dose ribavirin discontinued
therapy due to an adverse reaction. The most common reasons for discontinuation were related to known
interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse
reactions. In Study 4, 13% of subjects in the PegIntron 1.5 mcg/ribavirin arm, 10% in the PegIntron 1
mcg/ribavirin arm, and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.
In Study 2, dose reductions for ribavirin were similar across all three groups [see Clinical Studies
(14.1)], 33 to 35%. The most common reasons for dose modifications were neutropenia (18%), or
anemia (9%) (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and
thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently
with weight-based ribavirin dosing compared to flat dosing (29% and 23%, respectively). In Study 4,
16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with ribavirin, with an
additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events
compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135
mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring a second dose
reduction to 90 mcg/week with Pegasys.
In the PegIntron/ribavirin combination trials the most common adverse reactions were psychiatric, which
occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric
adverse reactions included most commonly depression, irritability, and insomnia, each reported by
approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and
suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation
[see Warnings and Precautions (5)]. In Study 4, psychiatric adverse reactions occurred in 58% of
subjects in the PegIntron 1.5 mcg/ribavirin arm, 55% of subjects in the PegIntron 1 mcg/ribavirin arm,
and 57% of subjects in the Pegasys 180 mcg/Copegus arm.
In Study 2, PegIntron/ribavirin combination therapy induced fatigue or headache in approximately two-
thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of
these systemic symptoms (e.g., fever and headache) tended to decrease as treatment continued.
Subjects receiving ribavirin/PegIntron as re-treatment after failing a previous interferon combination
regimen reported adverse reactions similar to those previously associated with this regimen during
clinical trials of treatment-naïve subjects.
Pediatric Subjects
In general, the adverse reaction profile in the pediatric population was similar to that observed in adults.
In the pediatric trial, the most prevalent adverse reactions were pyrexia (80%), headache (62%),
neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%).
The majority of adverse reactions were mild or moderate in severity. Severe adverse reactions were
reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%),
headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this
subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and
depression (1%; 1/107). Five subjects received levothyroxine treatment, three with clinical
hypothyroidism and two with asymptomatic TSH elevations. Weight and height gain of pediatric
subjects treated with PegIntron plus ribavirin lagged behind that predicted by normative population data
for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was
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observed in 70% of the subjects while on treatment.
Dose modifications of PegIntron and/or ribavirin were required in 25% of subjects due to treatment-
related adverse reactions, most commonly for anemia, neutropenia and weight loss. Two subjects (2%;
2/107) discontinued therapy as the result of an adverse reaction.
Adverse reactions that occurred with a greater than or equal to 10% incidence in the pediatric trial
subjects are provided in Table 7.
Table 7: Percentage of Pediatric Subjects with Treatment-Related Adverse
Reactions (in At Least 10% of All Subjects)
System Organ Class
     Preferred Term
All Subjects 
(N=107)
Blood and Lymphatic System Disorders 
    Neutropenia
33%
    Anemia
11%
    Leukopenia
10%
Gastrointestinal Disorders 
    Abdominal Pain
21%
    Abdominal Pain Upper
12%
    Vomiting
27%
    Nausea
18%
General Disorders and Administration Site Conditions 
    Pyrexia
80%
    Fatigue
30%
    Injection-site Erythema
29%
    Chills
21%
    Asthenia
15%
    Irritability
14%
Investigations 
    Weight Loss
19%
Metabolism and Nutrition Disorders 
    Anorexia
29%
    Decreased Appetite
22%
Musculoskeletal and Connective Tissue Disorders 
    Arthralgia
17%
    Myalgia
17%
Nervous System Disorders 
    Headache
62%
    Dizziness
14%
Skin and Subcutaneous Tissue Disorders 
    Alopecia
17%
Ninety-four of 107 subjects enrolled in a 5-year follow-up trial. The long-term effects on growth were
less in subjects treated for 24 weeks than in those treated for 48 weeks. Twenty-four percent of
subjects (11/46) treated for 24 weeks and 40% of subjects (19/48) treated for 48 weeks had a >15
percentile height-for-age decrease from pre-treatment baseline to the end of 5-year follow-up. Eleven
percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks had a
>30 percentile height-for-age decrease from pre-treatment baseline to the end of the 5-year follow-up.
While observed across all age groups, the highest risk for reduced height at the end of long-term
follow-up appeared to be initiation of combination therapy during the years of expected peak growth
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velocity [see Warnings and Precautions (5.9)].
Laboratory Values
Adult and Pediatric Subjects
 
The adverse reaction profile in Study 3, which compared PegIntron/weight-based ribavirin combination
to a PegIntron/flat dose ribavirin regimen, revealed an increased rate of anemia with weight-based
dosing (29% vs. 19% for weight-based vs. flat dose regimens, respectively). However, the majority of
cases of anemia were mild and responded to dose reductions.
Changes in selected laboratory values during treatment in combination with ribavirin treatment are
described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose
reduction or permanent discontinuation from therapy [see Dosage and Administration (2.5)]. Changes in
selected laboratory values during therapy are described in Table 8. Most of the changes in laboratory
values in the PegIntron/ribavirin trial with pediatrics were mild or moderate.
Table 8: Selected Laboratory Abnormalities During Treatment with Ribavirin and PegIntron or
Ribavirin and INTRON A in Previously Untreated Subjects
Laboratory Parameters  
Percentage of Subjects 
Adults (Study 2) 
Pediatrics 
PegIntron/ 
Ribavirin 
(N=511)
INTRON A/
Ribavirin 
(N=505)
PegIntron/Ribavirin
(N=107)  
Hemoglobin (g/dL) 
    9.5 to <11.0
26
27
30
    8.0 to <9.5
3
3
2
    6.5 to 7.9
0.2
0.2
-
Leukocytes (x 10 /L) 
    2.0 to 2.9
46
41
39
    1.5 to <2.0
24
8
3
    1.0 to 1.4
5
1
-
Neutrophils (x 10 /L) 
    1.0 to 1.5
33
37
35
    0.75 to <1.0
25
13
26
    0.5 to <0.75
18
7
13
    <0.5
4
2
3
Platelets (x 10 /L) 
    70 to 100
15
5
1
    50 to <70
3
0.8
-
    30 to 49
0.2
0.2
-
    25 to <50
-
-
1
Total Bilirubin                                                             (mg/dL) 
(µmole/L) 
    1.5 to 3.0
10
13
-
    1.26 to 2.59 x ULN  
-
-
7
    3.1 to 6.0
0.6
0.2
-
    2.6 to 5 x ULN  
-
-
-
    6.1 to 12.0
0
0.2
-
ALT (U/L) 
    2 x Baseline
0.6
0.2
1
    2.1 to 5 x Baseline
3
1
5
*
*
9
9
9
†
†
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* The table summarizes the worst category observed within the period per subject per laboratory test.
Only subjects with at least one treatment value for a given laboratory test are included.
 ULN=Upper limit of normal.
    5.1 to 10 x Baseline
0
0
3
Hemoglobin. In Study 2, hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects. In
Study 3, 47% of subjects receiving weight-based dosing of ribavirin and 33% on flat-dose ribavirin had
decreases in hemoglobin levels to less than 11 g/dL. Reductions in hemoglobin to less than 9 g/dL
occurred more frequently in subjects receiving weight-based dosing compared to flat dosing (4% and
2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the
PegIntron/ribavirin and INTRON A/ribavirin groups. In Study 4, subjects receiving PegIntron (1.5
mcg/kg)/ribavirin had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to
less than 8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases
occurred in 26% and 4% of subjects, respectively. On average, hemoglobin levels became stable by
treatment Weeks 4 to 6. The typical pattern observed was a decrease in hemoglobin levels by treatment
Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment [see
Dosage and Administration (2.5)].
Neutrophils. In Study 2, decreases in neutrophil counts were observed in a majority of adult subjects
treated with PegIntron/ribavirin (85%) and INTRON A/ribavirin (60%). Severe, potentially life-
threatening neutropenia (less than 0.5 x 10 /L) occurred in approximately 4% of subjects treated with
PegIntron/ribavirin and 2% of subjects treated with INTRON A/ribavirin. Eighteen percent of subjects
receiving PegIntron/ribavirin required modification of interferon dosage. Few subjects (less than 1%)
required permanent discontinuation of treatment. Neutrophil counts generally returned to pre-treatment
levels 4 weeks after cessation of therapy [see Dosage and Administration (2.5)].
Platelets. In Study 2, platelet counts decreased to less than 100,000/mm in approximately 20% of
subjects treated with PegIntron alone or with ribavirin and in 6% of adult subjects treated with INTRON
A/ribavirin. Severe decreases in platelet counts (less than 50,000/mm ) occur in less than 4% of adult
subjects. In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PegIntron,
respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of
therapy [see Dosage and Administration (2.5)].
Thyroid Function. In Study 2, clinically apparent thyroid disorders occurred among subjects treated with
either INTRON A or PegIntron (with or without ribavirin) at a similar incidence (5% for
hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while
on treatment and during the follow-up period. At the end of the follow-up period, 7% of subjects still
had abnormal TSH values.
Bilirubin and Uric Acid. In Study 2, 10 to 14% of subjects developed hyperbilirubinemia and 33 to 38%
developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout.
Adverse Reactions with Ribavirin/INTRON A Combination Therapy
Adult Subjects
In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued
therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon-only
arms. Selected treatment-related adverse reactions that occurred in the U.S.  trials with incidence 5% or
greater are provided by treatment group (see Table 9). In general, the selected treatment-related adverse
reactions were reported with lower incidence in the international trials as compared to the U.S. trials,
except for asthenia, influenza-like symptoms, nervousness, and pruritus.
†
9
3 
3
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p
,
y p
,
,
p
Pediatric Subjects
In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse
reactions. Dose modifications were required in 30% of subjects, most commonly for anemia and
neutropenia. In general, the adverse-reaction profile in the pediatric population was similar to that
observed in adults. Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred
more frequently in pediatric subjects compared to adult subjects. Conversely, pediatric subjects
experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea,
and pruritus compared to adult subjects. Selected treatment-related adverse reactions that occurred with
incidence 5% or greater among all pediatric subjects who received the recommended dose of
ribavirin/INTRON A combination therapy are provided in Table 9.
Table 9: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse
Adult Subjects and Previously Untreated Pediatric Subjects
Subjects 
Reporting 
Adverse 
Reactions* 
Percentage of Subjects 
U.S. Previously Untreated Study 
U.S. Relapse Study 
Pediatric
Subjects 
24 weeks of treatment 
48 weeks of
treatment 
24 weeks of treatment 
48 weeks
of 
treatment 
INTRON
A/ 
Ribavirin
(N=228) 
INTRON
A/ 
 Placebo 
 (N=231) 
INTRON
A/
Ribavirin
(N=228) 
INTRON
A/
Placebo 
(N=225) 
INTRON
A/
Ribavirin 
 (N=77) 
INTRON
A/
Placebo 
 (N=76) 
INTRON
A/
Ribavirin
(N=118) 
Application Site Disorders 
    Injection Site
    Inflammation 
13
10
12
14
6
8
14
    Injection Site
Reaction 
7
9
8
9
5
3
19
Body as a Whole - General Disorders 
    Headache 
63
63
66
67
66
68
69
    Fatigue 
68
62
70
72
60
53
58
    Rigors 
40
32
42
39
43
37
25
    Fever 
37
35
41
40
32
36
61
    Influenza-like
Symptoms 
14
18
18
20
13
13
31
    Asthenia 
9
4
9
9
10
4
5
    Chest Pain 
5
4
9
8
6
7
5
Central & Peripheral Nervous System Disorders 
    Dizziness 
17
15
23
19
26
21
20
Gastrointestinal System Disorders 
    Nausea
38
35
46
33
47
33
33
    Anorexia
27
16
25
19
21
14
51
    Dyspepsia
14
6
16
9
16
9
<1
    Vomiting
11
10
9
13
12
8
42
Musculoskeletal System Disorders 
    Myalgia
61
57
64
63
61
58
32
    Arthralgia
30
27
33
36
29
29
15
    Musculoskeletal
20
26
28
32
22
28
21
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* Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse
reaction within a body system/organ class category.
Pain
20
26
28
32
22
28
21
Psychiatric Disorders 
    Insomnia 
39
27
39
30
26
25
14
    Irritability 
23
19
32
27
25
20
10
    Depression 
32
25
36
37
23
14
13
    Emotional
   Lability 
7
6
11
8
12
8
16
    Concentration   
Impaired 
11
14
14
14
10
12
5
    Nervousness 
4
2
4
4
5
4
3
Respiratory System Disorders 
    Dyspnea
19
9
18
10
17
12
5
    Sinusitis
9
7
10
14
12
7
<1
Skin and Appendages Disorders 
    Alopecia 
28
27
32
28
27
26
23
    Rash 
20
9
28
8
21
5
17
    Pruritus 
21
9
19
8
13
4
12
Special Senses, Other Disorders 
    Taste
Perversion 
7
4
8
4
6
5
<1
During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile
assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment
decrease of 9%). A general reversal of these trends was noted during the 24-week post-treatment
period. Long-term data in a limited number of patients, however, suggests that combination therapy may
induce a growth inhibition that results in reduced final adult height in some patients [see Warnings and
Precautions (5.9)].
Laboratory Values
Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets)
during therapy are described below (see Table 10).
Hemoglobin. Hemoglobin decreases among subjects receiving ribavirin therapy began at Week 1, with
stabilization by Week 4. In previously untreated subjects treated for 48 weeks, the mean maximum
decrease from baseline was 3.1 g/dL in the U.S. trial and 2.9 g/dL in the international trial. In relapse
subjects, the mean maximum decrease from baseline was 2.8 g/dL in the U.S. trial and 2.6 g/dL in the
international trial. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation
of therapy in most subjects.
Bilirubin and Uric Acid. Increases in both bilirubin and uric acid, associated with hemolysis, were noted
in clinical trials. Most changes were moderate and reversed within 4 weeks after treatment
discontinuation. This observation occurred most frequently in subjects with a previous diagnosis of
Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.
Table 10: Selected Laboratory Abnormalities During Treatment with Ribavirin and INTRON A:
Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects
 
Percentage of Subjects 
U S Previously Untreated Study
U S Relapse Study
Pediatric
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U.S. Previously Untreated Study 
U.S. Relapse Study 
Subjects 
24 weeks of treatment 48 weeks of treatment24 weeks of treatment 48 weeks of
treatment 
INTRON A/
 Ribavirin 
 (N=228)
INTRON
A/ 
Placebo 
(N=231)
INTRON
A/ 
Ribavirin
(N=228)
INTRON
A/ 
Placebo 
(N=225)
INTRON
A/ 
Ribavirin
(N=77)
INTRON
A/ 
Placebo 
(N=76)
INTRON A/ 
Ribavirin 
(N=118)
Hemoglobin (g/dL) 
    9.5 to 10.9 
24
1
32
1
21
3
24
    8.0 to 9.4 
5
0
4
0
4
0
3
    6.5 to 7.9 
0
0
0
0.4
0
0
0
    <6.5 
0
0
0
0
0
0
0
Leukocytes  (x 10 /L) 
    2.0 to 2.9 
40
20
38
23
45
26
35
    1.5 to 1.9 
4
1
9
2
5
3
8
    1.0 to 1.4 
0.9
0
2
0
0
0
0
    <1.0
0
0
0
0
0
0
0
Neutrophils (x 10 /L) 
    1.0 to 1.49 
30
32
31
44
42
34
37
    0.75 to 0.99 
14
15
14
11
16
18
15
    0.5 to 0.74 
9
9
14
7
8
4
16
    <0.5 
11
8
11
5
5
8
3
Platelets (x 10 /L) 
    70 to 99 
9
11
11
14
6
12
0.8
    50 to 69 
2
3
2
3
0
5
2
    30 to 49 
0
0.4
0
0.4
0
0
0
    <30 
0.9
0
1
0.9
0
0
0
Total Bilirubin (mg/dL) 
    1.5 to 3.0
27
13
32
13
21
7
2
    3.1 to 6.0
0.9
0.4
2
0
3
0
0
    6.1 to 12.0 
0
0
0.4
0
0
0
0
      >12.0 
0
0
0
0
0
0
0
6.2 Postmarketing Experiences
The following adverse reactions have been identified and reported during post approval use of
ribavirin in combination with INTRON A or PegIntron. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure. 
Blood and Lymphatic System disorders 
    Pure red cell aplasia, aplastic anemia 
Ear and Labyrinth disorders
    Hearing disorder, vertigo
Respiratory, Thoracic and Mediastinal disorders 
    Pulmonary hypertension
Eye disorders 
    Serous retinal detachment 
Endocrine disorders 
    Diabetes
9
9
9
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7 DRUG INTERACTIONS
7.1 Didanosine
Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when
didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities; therefore,
coadministration of ribavirin capsules and didanosine is contraindicated [see Contraindications (4)].
Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in clinical trials.
7.2 Nucleoside Analogues
Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving
combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Patients receiving
interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely
monitored for treatment-associated toxicities, especially hepatic decompensation and anemia.
Discontinuation of NRTIs should be considered as medically appropriate (see labeling for individual
NRTI product). Dose reduction or discontinuation of interferon, ribavirin, or both should also be
considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g.,
Child-Pugh greater than 6).
Ribavirin may antagonize the cell culture antiviral activity of stavudine and zidovudine against HIV.
Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, stavudine, and
zidovudine, which could lead to decreased antiretroviral activity. However, in a study with another
pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or
intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of
HIV/HCV virologic suppress) interaction was observed when ribavirin and lamivudine (n=18),
stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multidrug regimen in HIV/HCV
co-infected subjects. Concomitant use of ribavirin with any of these drugs should be done with caution.
7.3 Drugs Metabolized by Cytochrome P-450
Results of in vitro studies using both human and rat liver microsome preparations indicated little or no
cytochrome P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-450 enzyme-
based drug interactions.
No pharmacokinetic interactions were noted between INTRON A and ribavirin capsules in a multiple-
dose pharmacokinetic study.
7.4 Azathioprine
The use of ribavirin for the treatment of chronic hepatitis C in patients receiving azathioprine has been
reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity.
Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of
azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine
metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity
(neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have
complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly
for the second and third months of treatment, then monthly or more frequently if dosage or other therapy
changes are necessary [see Warnings and Precautions (5.8)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
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Risk Summary
Ribavirin is contraindicated for use in pregnant women and in men whose female partners are pregnant
[see Contraindications (4)]. Based on animal data, ribavirin use in pregnancy may be associated with birth
defects. Data from the Ribavirin Pregnancy Registry are insufficient to identify a drug-associated risk
of birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Ribavirin is known to
accumulate in intracellular components from where it is cleared very slowly. In animal studies, ribavirin
exposure was shown to have teratogenic and/or embryocidal effects (see Data).
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated
background risk of major birth defects and miscarriage for the indicated population is unknown. In the
U.S. general population, the estimated background risk of major birth defects and miscarriage is 2 to 4%
and 15 to 20%, respectively.
Data
Human Data
Available data from the Ribavirin Pregnancy Registry on 88 live births from pregnancies in women
directly exposed and 98 live births from pregnancies in women indirectly exposed (by a male partner) to
ribavirin during pregnancy or during the 6 months prior to pregnancy show a higher rate of birth defects
(9.09% and 6.12%, respectively) compared to a background birth defect rate of 2.72% in the
Metropolitan Atlanta Congenital Defects Program (MACDP) birth defects surveillance system. No
pattern of birth defects can be identified from these reports. The miscarriage rate was approximately
21%. The current sample size is insufficient for reaching definitive conclusions based on statistical
analysis. Trends suggesting a common etiology or relationship with ribavirin exposure were not
observed. Methodologic limitations of the Ribavirin Pregnancy Registry include the use of MACDP as
the external comparator group. Limitations of using an external comparator include differences in
methodology and populations, as well as confounding due to the underlying disease and comorbidities.
Animal Data
Embryotoxicity/teratogenicity studies with ribavirin were conducted in rats (oral doses of 0.3, 1 and 10
mg/kg on Gestation Days 6 to 15) and rabbits (oral dose of 0.1, 0.3 and 1 mg/kg on Gestation Days 6 to
18). Ribavirin demonstrated significant embryocidal and teratogenic effects at doses well below the
recommended human dose in all animal species in which adequate studies have been conducted.
Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The
incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of
fetuses and offspring was reduced [see Contraindications (4) and Warnings and Precautions (5.1)].
8.2 Lactation
Risk Summary
There are no data on the presence of ribavirin in human milk or the effects on the breastfed infant or
milk production. The developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for ribavirin and any potential adverse effects on the breastfed infant
from ribavirin or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential
Ribavirin may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations
(8.1)].
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Pregnancy Testing
Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained
immediately prior to planned initiation of treatment. Patients should have periodic pregnancy tests during
treatment and during the 6-month period after treatment has been stopped [see Warnings and Precautions
(5.1)].
Contraception
Females of reproductive potential should use effective contraception during treatment and for 6 months
post-therapy based on a multiple-dose half-life (t
) of ribavirin of 12 days (e.g., 15 half-lives for
ribavirin clearance from the body).
Male patients and their female partners should use effective contraception during treatment with
ribavirin and for the 6-month post-therapy period [see Warnings and Precautions (5.1)].
Infertility
Based on animal data, ribavirin may impair male fertility. In animal studies, these effects were mostly
reversible within a few months after drug cessation [see Nonclinical Toxicology (13.1)].    
8.4 Pediatric Use
Safety and effectiveness of ribavirin in combination with PegIntron has not been established in pediatric
patients below the age of 3 years. For treatment with ribavirin/INTRON A, evidence of disease
progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response,
HCV genotype and viral load should be considered when deciding to treat a pediatric patient. The
benefits of treatment should be weighed against the observed safety findings.
Long-term follow-up data in pediatric subjects indicates that ribavirin in combination with PegIntron or
with INTRON A may induce a growth inhibition that results in reduced height in some patients
[see Warnings and Precautions (5.9) and Adverse Reactions (6.1)].
Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily
adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-
up [see Warnings and Precautions (5.10)]. As in adult patients, pediatric patients experienced other
psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia
[see Warnings and Precautions (5.2)].  
8.5 Geriatric Use
Clinical trials of ribavirin combination therapy did not include sufficient numbers of subjects aged 65
and over to determine if they respond differently from younger subjects.
Ribavirin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients often have decreased
renal function, care should be taken in dose selection. Renal function should be monitored and dosage
adjustments made accordingly. Ribavirin should not be used in patients with creatinine clearance less
than 50 mL/min [see Contraindications (4)].
1/2
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In general, ribavirin capsules should be administered to elderly patients cautiously, starting at the lower
end of the dosing range, reflecting the greater frequency of decreased hepatic and cardiac function, and
of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency
of anemia (67%) than younger patients (28%) [see Warnings and Precautions (5.2)].  
8.6 Organ Transplant Recipients
The safety and efficacy of INTRON A and PegIntron alone or in combination with ribavirin for the
treatment of hepatitis C in liver or other organ transplant recipients have not been established. In a small
(n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving
interferon alpha and ribavirin combination therapy was more frequent than expected from the center’s
previous experience with renal allograft recipients not receiving combination therapy. The relationship
of the renal failure to renal allograft rejection is not clear.
8.7 HIV or HBV Co-infection
The safety and efficacy of PegIntron/ribavirin and INTRON A/ribavirin for the treatment of patients
with HCV co-infected with HIV or HBV have not been established.
10 OVERDOSAGE
There is limited experience with overdosage. Acute ingestion of up to 20 g of ribavirin capsules,
INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times
the recommended doses have been reported. Primary effects that have been observed are increased
incidence and severity of the adverse reactions related to the therapeutic use of INTRON A and
ribavirin. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction
have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing
recommendations.
There is no specific antidote for INTRON A or ribavirin overdose, and hemodialysis and peritoneal
dialysis are not effective for treatment of overdose of these agents.  
11 DESCRIPTION
Ribavirin, is a synthetic nucleoside analogue (purine analogue). The chemical name of ribavirin is 1-β-
D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula (see Figure
1).
Figure 1: Structural Formula
Ribavirin USP is a white, crystalline powder. It is freely soluble in water and slightly soluble in
anhydrous alcohol. The molecular formula is C H
N O  and the molecular weight is 244.21.
Ribavirin capsules USP consist of a white to off-white granular powder in a white, opaque, gelatin
capsule. Each capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose,
8
12
4
5
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lactose monohydrate, povidone-K 30, and magnesium stearate. The capsule shell consists of titanium
dioxide, sodium lauryl sulfate, and gelatin. The capsule is printed with edible ink containing black iron
oxide.
Meets USP dissolution test 2.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ribavirin is an anti-HCV agent [see Microbiology (12.4)].  
12.3 Pharmacokinetics
Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 11. Ribavirin
was rapidly and extensively absorbed following oral administration. However, due to first-pass
metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between
dose and AUC  (AUC from time zero to last measurable concentration) following single doses of 200
to 1200 mg ribavirin. The relationship between dose and C
was curvilinear, tending to asymptote
above single doses of 400 to 600 mg.
Upon multiple oral dosing, based on AUC
, a 6-fold accumulation of ribavirin was observed in
plasma. Following oral dosing with 600 mg twice daily, steady-state was reached by approximately 4
weeks, with mean steady-state plasma concentrations of 2200 ng/mL (37%). Upon discontinuation of
dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from
nonplasma compartments.
Effect of Antacid on Absorption of Ribavirin: Coadministration of ribavirin capsules with an antacid
containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUC .
The clinical relevance of results from this single-dose study is unknown.
Table 11: Mean (% CV) Pharmacokinetic Parameters for Ribavirin When Administered
Individually to Adults
N=11.
Data obtained from a single-dose pharmacokinetic study using 
C labeled ribavirin; N=5. 
N=6.
Parameter 
Ribavirin 
Single-Dose 
600 mg 
Oral Solution (N=14) 
Single-Dose 
600 mg Capsules 
(N=12)
Multiple-Dose 
600 mg 
Capsules 
 twice daily 
(N=12)
   T
 (hr) 
1.00 (34)
1.7 (46)*
3 (60)
   C
 (ng/mL) 
872 (42)
782 (37)
3680 (85)
   AUC  (ng·hr/mL)
14,098 (38)
13,400 (48)
228,000 (25)
   T
 (hr) 
 
43.6 (47)
298 (30)
   Apparent Volume of
Distribution (L) 
 
2825 (9)  
 
   Apparent Clearance (L/hr) 
 
38.2 (40)
 
   Absolute Bioavailability 
 
64% (44)  
 
tf
max 
12hr
tf
* 
†  
14
‡  
max
max
tf
1/2
†
‡
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Tissue Distribution:  Ribavirin transport into nonplasma compartments has been most extensively studied
in red blood cells and has been identified to be primarily via an e -type equilibrative nucleoside
transporter. This type of transporter is present on virtually all cell types and may account for the
extensive volume of distribution. Ribavirin does not bind to plasma proteins.
Metabolism and Excretion:  Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation
pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis
to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole
carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 
C-ribavirin,
approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in
336 hours. Unchanged ribavirin accounted for 17% of the administered dose.
Special Populations:
Renal Dysfunction
The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of
ribavirin to non-HCV-infected subjects with varying degrees of renal dysfunction. The mean AUC
value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when
compared to control subjects (creatinine clearance greater than 90 mL/min). In subjects with creatinine
clearance values between 30 to 60 mL/min, AUC  was twofold greater when compared to control
subjects. The increased AUC  appears to be due to reduction of renal and nonrenal clearance in these
subjects. Phase 3 efficacy trials included subjects with creatinine clearance values greater than 50
mL/min. The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with
renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine
clearance less than 50 mL/min should not be treated with ribavirin [see Contraindications (4)].
Hepatic Dysfunction
The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean
AUC  values were not significantly different in subjects with mild, moderate, or severe hepatic
dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the
mean C
 values increased with severity of hepatic dysfunction and was twofold greater in subjects
with severe hepatic dysfunction when compared to control subjects.
Elderly Patients
Pharmacokinetic evaluations in elderly subjects have not been performed.
Gender
There were no clinically significant pharmacokinetic differences noted in a single-dose trial of 18 male
and 18 female subjects.
Pediatric Patients
Multiple-dose pharmacokinetic properties for ribavirin capsules and INTRON A in pediatric subjects
with chronic hepatitis C between 5 and 16 years of age are summarized in Table 12. The
pharmacokinetics of ribavirin and INTRON A (dose-normalized) are similar in adults and pediatric
subjects.
Complete pharmacokinetic characteristics of ribavirin oral solution have not been determined in
pediatric subjects. Ribavirin C
 values were similar following administration of ribavirin oral
s
14
tf
tf
tf
tf
max
min
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solution or ribavirin capsules during 48 weeks of therapy in pediatric subjects (3 to 16 years of age).
Table 12: Mean (% CV) Multiple-dose Pharmacokinetic Parameters for INTRON A and
Ribavirin Capsules When Administered to Pediatric Subjects with Chronic Hepatitis C
AUC
 (ng·hr/mL) for ribavirin; AUC
 (IU·hr/mL) for INTRON A.
ND=not done.
Parameter 
Ribavirin 
 15 mg/kg/day 
as 2 divided doses 
(N=17) 
INTRON A 3 MIU/m  
three times weekly 
(N=54) 
   T
 (hr) 
1.9 (83)
5.9 (36)
   C
(ng/mL) 
3275 (25)
51 (48)
   AUC* 
29,774 (26)
622 (48)
   Apparent Clearance L/hr/kg 
0.27 (27)
ND  
Note: numbers in parenthesis indicate % coefficient of variation.
A clinical trial in pediatric subjects with chronic hepatitis C between 3 and 17 years of age was
conducted in which pharmacokinetics for PegIntron and ribavirin (capsules and oral solution) were
evaluated. In pediatric subjects receiving body surface area-adjusted dosing of PegIntron at 60
mcg/m /week, the log transformed ratio estimate of exposure during the dosing interval was predicted
to be 58% [90% CI: 141%, 177%] higher than observed in adults receiving 1.5 mcg/kg/week. The
pharmacokinetics of ribavirin (dose-normalized) in this trial were similar to those reported in a prior
study of ribavirin in combination with INTRON A in pediatric subjects and in adults.
Effect of Food on Absorption of Ribavirin
Both AUC  and C
 increased by 70% when ribavirin capsules were administered with a high-fat meal
(841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study
[see Dosage and Administration (2)].
12.4 Microbiology
Mechanism of Action
The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully
understood. Ribavirin has direct antiviral activity in cell culture against many RNA viruses. Ribavirin
increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate
inhibits HCV polymerase in a biochemical reaction.
Antiviral Activity in Cell Culture
The antiviral activity of ribavirin in the HCV replicon is not well understood and has not been defined
because of the cellular toxicity of ribavirin. Direct antiviral activity has been observed in cell culture
of other RNA viruses. The anti-HCV activity of interferon was demonstrated in cell culture using self-
replicating HCV RNA (HCV replicon cells) or HCV infection.
Resistance
HCV genotypes show wide variability in their response to pegylated recombinant human
interferon/ribavirin therapy. Genetic changes associated with the variable response have not been
identified.
* 
12
0-24
† 
2
max
max 
†
2
tf
max
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Cross-resistance
There is no reported cross-resistance between pegylated/non-pegylated interferons and ribavirin.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic
p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on
body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended
human daily dose). Ribavirin was noncarcinogenic when administered for 2 years to rats at doses up to
40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg
adult).
Mutagenesis
Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity
assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was
observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of
1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum
recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay
in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male
gametes.
Impairment of Fertility
In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular
degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day,
based on body surface area adjustment for a 60-kg adult; 0.1 to 0.8 times the maximum human 24-hour
dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of
treatment, recovery from ribavirin-induced testicular toxicity was mostly apparent within 1 or 2
spermatogenesis cycles.
13.2 Animal Toxicology and Pharmacology
Long-term studies in the mouse and rat [18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day,
respectively (estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively,
based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times the maximum
human 24-hour dose of ribavirin)] have demonstrated a relationship between chronic ribavirin exposure
and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal
degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.
In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25, and 50 mg/kg/day,
drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma
concentrations at the human therapeutic dose) between study Days 13 and 48. Rat pups dosed from
postnatal Days 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses,
which was subsequently manifested as slight decreases in body weight, crown-rump length, and bone
length. These effects showed evidence of reversibility, and no histopathological effects on bone were
observed. No ribavirin effects were observed regarding neurobehavioral or reproductive
development.  
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14 CLINICAL STUDIES
Clinical Study 1 evaluated PegIntron monotherapy. See PegIntron labeling for information about this
trial.
14.1 Ribavirin/PegIntron Combination Therapy
Adult Subjects
Study 2
A randomized trial compared treatment with two PegIntron/ribavirin regimens [PegIntron 1.5 mcg/kg
subcutaneously once weekly/ribavirin 800 mg orally daily (in divided doses); PegIntron 1.5 mcg/kg
subcutaneously once weekly for 4 weeks then 0.5 mcg/kg subcutaneously once weekly for 44
weeks/ribavirin 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU
subcutaneously three times weekly/ribavirin 1000 or 1200 mg orally daily (in divided doses)] in 1,530
adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for
24 weeks post-treatment. Eligible subjects had compensated liver disease, detectable HCV-RNA,
elevated ALT, and liver histopathology consistent with chronic hepatitis.
Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table
13). The response rate to the PegIntron 1.5 mcg/kg and ribavirin 800 mg dose was higher than the
response rate to INTRON A/ribavirin (see Table 13). The response rate to PegIntron 1.5→0.5
mcg/kg/ribavirin was essentially the same as the response to INTRON A/ ribavirin (data not shown).
Table 13: Rates of Response to Combination Treatment – Study 2
* Serum HCV-RNA was measured with a research-based quantitative polymerase chain reaction assay
by a central laboratory.
 Difference in overall treatment response (PegIntron/ribavirin vs. INTRON A/ribavirin) is 6% with
95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at
baseline. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.
 
PegIntron 1.5 mcg/kg once weekly
Ribavirin 800 mg once daily 
INTRON A 3 MIU three times weekly
Ribavirin 1000/1200 mg once daily 
   Overall response*,  
52% (264/511)
46% (231/505)
   Genotype 1
41% (141/348)
33% (112/343)
   Genotype 2 to 6
75% (123/163)
73% (119/162)
Subjects with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (1.5
mcg/kg)/ribavirin (800 mg) compared to subjects with other viral genotypes. Subjects with both poor
prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a
response rate of 29% (71/247) with INTRON A/ ribavirin combination therapy.
Subjects with lower body weight tended to have higher adverse-reaction rates [see Adverse Reactions
(6.1)] and higher response rates than subjects with higher body weights. Differences in response rates
between treatment arms did not substantially vary with body weight.
Treatment response rates with PegIntron/ribavirin combination therapy were 49% in men and 56% in
women. Response rates were lower in African American and Hispanic subjects and higher in Asians
compared to Caucasians. Although African Americans had a higher proportion of poor prognostic
†
†
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factors compared to Caucasians, the number of non-Caucasians studied (11% of the total) was
insufficient to allow meaningful conclusions about differences in response rates after adjusting for
prognostic factors in this trial.
Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline,
approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction
in inflammation.
Study 3
In a large United States community-based trial, 4,913 subjects with chronic hepatitis C were randomized
to receive PegIntron 1.5 mcg/kg subcutaneously once weekly in combination with a ribavirin dose of
800 to 1400 mg (weight-based dosing [WBD]) or 800 mg (flat) orally daily (in divided doses) for 24 or
48 weeks based on genotype. Response to treatment was defined as undetectable HCV-RNA (based on
an assay with a lower limit of detection of 125 IU/mL) at 24 weeks post-treatment.
Treatment with PegIntron 1.5 mcg/kg and ribavirin 800 to 1400 mg resulted in a higher sustained
virologic response compared to PegIntron in combination with a flat 800 mg daily dose of ribavirin.
Subjects weighing greater than 105 kg obtained the greatest benefit with WBD, although a modest
benefit was also observed in subjects weighing greater than 85 to 105 kg (see Table 14). The benefit of
WBD in subjects weighing greater than 85 kg was observed with HCV genotypes 1 to 3. Insufficient
data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an
increased incidence of anemia [see Adverse Reactions (6.1)].
Table 14: SVR Rate by Treatment and Baseline Weight - Study 3
* P=0.01, primary efficacy comparison (based on data from subjects weighing 65 kg or higher at
baseline and utilizing a logistic regression analysis that includes treatment [WBD or Flat], genotype and
presence/absence of advanced fibrosis, in the model).
Treatment Group 
Subject Baseline Weight 
<65 kg 
(<143 lb) 
65 to 85 kg 
(143 to 188 lb) 
>85 to 105 kg 
(>188 to 231 lb) 
>105 kg 
(>231 lb) 
   WBD*
50% (173/348)
45% (449/994)
42% (351/835)
47% (138/292)
   Flat
51% (173/342)
44% (443/1011)
39% (318/819)
33% (91/272)
A total of 1,552 subjects weighing greater than 65 kg in Study 3 had genotype 2 or 3 and were
randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment
duration.
Study 4
A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two
PegIntron/ribavirin regimens [PegIntron 1.5 mcg/kg and 1 mcg/kg subcutaneously once weekly both in
combination with ribavirin 800 to 1400 mg PO daily (in two divided doses)] and Pegasys 180 mcg
subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in two divided
doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. In this trial, lack of early
virologic response (undetectable HCV-RNA or greater than or equal to 2 log
 reduction from
baseline) by treatment Week 12 was the criterion for discontinuation of treatment. SVR was defined as
undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 IU/mL) at 24
weeks post-treatment (see Table 15).
10
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Table 15: SVR Rate by Treatment – Study 4
% (number) of Subjects 
PegIntron 
1.5 mcg/kg/Ribavirin 
PegIntron 
1 mcg/kg/Ribavirin 
Pegasys 
180 mcg/Copegus 
40 (406/1019)
38 (386/1016)
41 (423/1035)
Overall SVR rates were similar among the three treatment groups. Regardless of treatment group, SVR
rates were lower in subjects with poor prognostic factors. Subjects with poor prognostic factors
randomized to PegIntron (1.5 mcg/kg)/ribavirin or Pegasys/Copegus, however, achieved higher SVR
rates compared to similar subjects randomized to PegIntron 1 mcg/kg/ribavirin. For the PegIntron 1.5
mcg/kg and ribavirin dose, SVR rates for subjects with and without the following prognostic factors
were as follows: cirrhosis (10% vs. 42%), normal ALT levels (32% vs. 42%), baseline viral load
greater than 600,000 IU/mL (35% vs. 61%), 40 years of age and older (38% vs. 50%), and African
American race (23% vs. 44%). In subjects with undetectable HCV-RNA at treatment Week 12 who
received PegIntron (1.5 mcg/kg)/ribavirin, the SVR rate was 81% (328/407).
Study 5 - Ribavirin/PegIntron Combination Therapy in Prior Treatment Failures
In a noncomparative trial, 2,293 subjects with moderate to severe fibrosis who failed previous treatment
with combination alpha interferon/ribavirin were re-treated with PegIntron, 1.5 mcg/kg subcutaneously,
once weekly, in combination with weight adjusted ribavirin. Eligible subjects included prior
nonresponders (subjects who were HCV-RNA positive at the end of a minimum 12 weeks of treatment)
and prior relapsers (subjects who were HCV-RNA negative at the end of a minimum 12 weeks of
treatment and subsequently relapsed after post-treatment follow-up). Subjects who were negative at
Week 12 were treated for 48 weeks and followed for 24 weeks post-treatment. Response to treatment
was defined as undetectable HCV-RNA at 24 weeks post-treatment (measured using a research-based
test, limit of detection 125 IU/mL). The overall response rate was 22% (497/2293) (99% CI: 19.5, 23.9).
Subjects with the following characteristics were less likely to benefit from re-treatment: previous
nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and
genotype 1 infection.
The re-treatment sustained virologic response rates by baseline characteristics are summarized in Table
16.
Table 16: SVR Rates by Baseline Characteristics of Prior Treatment Failures - Study 5
HCV 
Genotype/Metavir
Fibrosis Score 
Overall SVR by Previous Response and Treatment
Nonresponder 
Relapser 
interferon
alfa/ribavirin 
% (number of
subjects) 
peginterferon (2a
and 2b
combined)/ribavirin 
% (number of
subjects) 
interferon
alfa/ribavirin 
% (number of
subjects) 
peginterferon (2a and
2b combined)/ribavirin
% (number of
subjects) 
Overall
18 (158/903)
6 (30/476)
43 (130/300)
35 (113/344)
HCV 1
13 (98/761)
4 (19/431)
32 (67/208)
23 (56/243)
F2
18 (36/202)
6 (7/117)
42 (33/79)
32 (23/72)
F3
16 (38/233)
4 (4/112)
28 (16/58)
21 (14/67)
F4
7 (24/325)
4 (8/202)
26 (18/70)
18 (19/104)
HCV 2/3
49 (53/109)
36 (10/28)
67 (54/81)
57 (52/92)
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F2
68 (23/34)
56 (5/9)
76 (19/25)
61 (11/18)
F3
39 (11/28)
38 (3/8)
67 (18/27)
62 (18/29)
F4
40 (19/47)
18 (2/11)
59 (17/29)
51 (23/45)
HCV 4
17 (5/29)
7 (1/15)
88 (7/8)
50 (4/8)
Achievement of an undetectable HCV-RNA at treatment Week 12 was a strong predictor of SVR. In this
trial, 1,470 (64%) subjects did not achieve an undetectable HCV-RNA at treatment Week 12, and were
offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823
(36%) subjects who were HCV-RNA undetectable at treatment Week 12, those infected with genotype 1
had an SVR of 48% (245/507), with a range of responses by fibrosis scores (F4-F2) of 39 to 55%.
Subjects infected with genotype 2/3 who were HCV-RNA undetectable at treatment Week 12 had an
overall SVR of 70% (196/281), with a range of responses by fibrosis scores (F4-F2) of 60 to 83%.
For all genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving
SVR.
Pediatric Subjects
Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and
detectable HCV-RNA were treated with ribavirin 15 mg/kg per day and PegIntron 60 mcg/m once
weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be
followed for 24 weeks post-treatment. A total of 107 subjects received treatment, of which 52% were
female, 89% were Caucasian, and 67% were infected with HCV Genotype 1. Subjects infected with
Genotypes 1, 4 or Genotype 3 with HCV-RNA greater than or equal to 600,000 IU/mL received 48
weeks of therapy while those infected with Genotype 2 or Genotype 3 with HCV-RNA less than
600,000 IU/mL received 24 weeks of therapy. The trial results are summarized in Table 17.
Table 17: Sustained Virologic Response Rates by Genotype and Assigned Treatment Duration –
Pediatric Trial
 Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.
 N=number of responders/number of subjects with given genotype and assigned treatment duration. 
 Subjects with genotype 3 low viral load (less than 600,000 IU/mL) were to receive 24 weeks of
treatment while those with genotype 3 and high viral load were to receive 48 weeks of treatment.
                    Genotype
All Subjects 
N=107 
24 Weeks 
48 Weeks 
Virologic Response 
N
 (%) 
Virologic Response 
N
 (%) 
All  
26/27 (96.3)
44/80 (55.0)
1
-
38/72 (52.8)
2
14/15 (93.3)
-
3
12/12 (100)
2/3 (66.7)
4
-
4/5 (80.0)
14.2 Ribavirin/INTRON A Combination Therapy
Adult Subjects
2 
*
†
‡
*,†
*,†
‡
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Previously Untreated Subjects
 
Adults with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central
laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon
therapy were enrolled into two multicenter, double-blind trials (U.S. and international) and randomized to
receive ribavirin capsules 1200 mg/day (1000 mg/day for subjects weighing less than or equal to 75 kg)
and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 or 48 weeks followed by
24 weeks of off-therapy follow-up. The international trial did not contain a 24-week INTRON A and
placebo treatment arm. The U.S. trial enrolled 912 subjects who, at baseline, were 67% male, 89%
Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The international trial,
conducted in Europe, Israel, Canada, and Australia, enrolled 799 subjects (65% male, 95% Caucasian,
mean Knodell score 6.8, and 58% genotype 1).
Trial results are summarized in Table 18.
Table 18: Virologic and Histologic Responses: Previously Untreated Subjects
* Number (%) of subjects. 
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment
and during follow-up period. 
Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score
(I+II+III) improvement of greater than or equal to 2 points.
 
U.S. Trial 
International Trial 
24 weeks of treatment 
48 weeks of
treatment 
24 weeks
of
treatment 
48 weeks of
treatment 
INTRON
A/Ribavirin(N=228)
INTRON
A/Placebo
(N=231) 
INTRON
A/Ribavirin
(N=228) 
INTRON
A/Placebo
(N=225) 
INTRON
A/Ribavirin
(N=265) 
INTRON
A/Ribavirin
(N=268) 
INTRON
A/Placebo
(N=266) 
Virologic 
Response 
    Responder  
65 (29)
13 (6)
85 (37)
27 (12)
86 (32)
113 (42)
46 (17)
    Nonresponder
147 (64)
194 (84)
110 (48)
168 (75)
158 (60)
120 (45)
196 (74)
    Missing Data 
16 (7)
24 (10)
33 (14)
30 (13)
21 (8)
35 (13)
24 (9)
Histologic 
 Response 
    Improvement
102 (45)
77 (33)
96 (42)
65 (29)
103 (39)
102 (38)
69 (26)
    No
improvement 
77 (34)
99 (43)
61 (27)
93 (41)
85 (32)
58 (22)
111 (41)
    Missing Data 
49 (21)
55 (24)
71 (31)
67 (30)
77 (29)
108 (40)
86 (32)
Of subjects who had not achieved HCV-RNA below the limit of detection of the research-based assay
by Week 24 of ribavirin/INTRON A treatment, less than 5% responded to an additional 24 weeks of
combination treatment.
Among subjects with HCV Genotype 1 treated with ribavirin/INTRON A therapy who achieved HCV-
RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks
of treatment had higher virologic responses compared to those in the 24-week treatment group. There
was no observed increase in response rates for subjects with HCV non-genotype 1 randomized to
ribavirin/INTRON A therapy for 48 weeks compared to 24 weeks.
*
†
‡
†
‡
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Relapse Subjects
Subjects with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central
laboratory using a research-based RT-PCR assay) who had relapsed following one or two courses of
interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-
blind trials (U.S. and international) and randomized to receive ribavirin 1200 mg/day (1000 mg/day for
subjects weighing ≤75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24
weeks followed by 24 weeks of off-therapy follow-up. The U.S. trial enrolled 153 subjects who, at
baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58%
genotype 1. The international trial, conducted in Europe, Israel, Canada, and Australia, enrolled 192
subjects (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1). Trial results are
summarized in Table 19.
Table 19: Virologic and Histologic Responses: Relapse Subjects*
 Number (%) of subjects. 
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of
treatment and during follow-up period. 
Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score
(I+II+III) improvement of greater than or equal to 2 points.
U.S. Trial 
International Trial 
INTRON A/
Ribavirin 
(N=77)
INTRON A/
Placebo 
(N=76)
INTRON A/
Ribavirin 
(N=96)
INTRON A/
Placebo 
(N=96)
Virologic Response 
    Responder  
33 (43)
3 (4)
46 (48)
5 (5)
    Nonresponder 
36 (47)
66 (87)
45 (47)
91 (95)
    Missing Data 
8 (10)
7 (9)
5 (5)
0 (0)
Histologic Response 
    Improvement  
38 (49)
27 (36)
49 (51)
30 (31)
    No improvement 
23 (30)
37 (49)
29 (30)
44 (46)
    Missing Data 
16 (21)
12 (16)
18 (19)
22 (23)
Virologic and histologic responses were similar among male and female subjects in both the previously
untreated and relapse trials.
Pediatric Subjects
Pediatric subjects 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA
(assessed by a central laboratory using a research-based RT-PCR assay) were treated with ribavirin 15
mg/kg per day and INTRON A 3 MIU/m three times weekly for 48 weeks followed by 24 weeks of
off-therapy follow-up. A total of 118 subjects received treatment, of which 57% were male, 80%
Caucasian, and 78% genotype 1. Subjects less than 5 years of age received ribavirin oral solution and
those 5 years of age or older received either ribavirin oral solution or capsules.
Trial results are summarized in Table 20.
Table 20: Virologic Response: Previously Untreated Pediatric Subjects*
 
INTRON A 3 MIU/m  three times
weekly/Ribavirin  15 mg/kg/day 
*
† 
‡
†
‡
2 
2
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 Number (%) of subjects.
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of
treatment and during follow-up period.
   Overall Response  (N=118) 
54 (46)
   Genotype 1 (N=92) 
33 (36)
   Genotype non-1 (N=26) 
21 (81)
Subjects with viral genotype 1, regardless of viral load, had a lower response rate to INTRON
A/ribavirin combination therapy compared to subjects with genotype non-1, 36% vs. 81%. Subjects with
both poor prognostic factors (genotype 1 and high viral load) had a response rate of 26% (13/50).
16 HOW SUPPLIED/STORAGE AND HANDLING
Ribavirin Capsules USP, 200 mg are white/white, size ‘1’ hard gelatin capsule filled with white to
off-white granular powder and imprinted with ‘E’ on white cap and ‘81’ on white body with black ink.
            Bottles of 42                            NDC 65862-290-42
            Bottles of 56                            NDC 65862-290-56
            Bottles of 70                            NDC 65862-290-70
            Bottles of 84                            NDC 65862-290-84
            Bottles of 180                          NDC 65862-290-18
            Bottles of 500                          NDC 65862-290-05
 
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Anemia
The most common adverse experience occurring with ribavirin capsules is anemia, which may be
severe [see Warnings and Precautions (5.2) and Adverse Reactions (6)]. Advise patients that laboratory
evaluations are required prior to starting therapy and periodically thereafter [see Dosage and
Administration (2.4)]. Advise patients to be well hydrated, especially during the initial stages of
treatment.
Embryo-Fetal Toxicity
Inform females of reproductive potential and pregnant women that ribavirin capsules may cause birth
defects, miscarriage, and stillbirth. Advise females of reproductive potential that they must have a
pregnancy test prior to initiating treatment and periodically during therapy. Advise females of
reproductive potential and male patients with female partners of reproductive potential to use effective
contraception during treatment with ribavirin and for 6 months post therapy. Advise patients to notify the
physician immediately in the event of a pregnancy [see Contraindications (4), Warnings and Precautions
(5.1), and Use in Specific Populations (8.1, 8.3)].
Missed Dose
*
†  
†
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Inform patients that in the event a dose is missed, the missed dose should be taken as soon as possible
during the same day. Patients should not double the next dose. Advise patients to contact their healthcare
provider if they have questions.  
Dental and Periodontal Disorders
Advise patients to brush their teeth thoroughly twice daily and have regular dental examinations. If
vomiting occurs, advise patients to rinse out their mouth thoroughly afterwards [see Warnings and
Precautions (5.7)].
The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo
Pharma Limited.
Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides
MEDICATION GUIDE
Ribavirin Capsules USP
(rye'' ba vye' rin)
 
What is the most important information I should know about ribavirin capsules?
1.  Ribavirin capsules may cause birth defects, miscarriage or death of your unborn baby. Do not
take ribavirin capsules if you or your sexual partner is pregnant or plan to become pregnant. Do
not become pregnant during treatment or within 6 months after stopping treatment with ribavirin
capsules. You must use effective birth control during treatment with ribavirin capsules and for 6 months
after stopping treatment.
Females must have a pregnancy test before starting ribavirin capsules, during treatment with ribavirin
capsules, and for 6 months after the last dose of ribavirin capsules.
If you or your female sexual partner becomes pregnant during treatment with ribavirin
capsules or within 6 months after you stop taking ribavirin capsules, tell your healthcare
provider right away.
2.  Ribavirin capsules may cause a significant drop in your red blood cell count and cause anemia
in some cases. Anemia has been associated with worsening of heart problems, and in rare cases
can cause a heart attack and death. Tell your healthcare provider if you have ever had any heart
problems. Ribavirin capsules may not be right for you. Get medical help right away if you experience
chest pain.
3.  Do not take ribavirin capsules alone to treat chronic hepatitis C infection. Ribavirin capsules
should be used in combination with either interferon alfa-2b or peginterferon alfa-2b to treat chronic
hepatitis C infection.
What are ribavirin capsules?   
Ribavirin capsules are a medicine used with either interferon alfa-2b or peginterferon alfa-2b to treat
chronic (lasting a long time) hepatitis C infection in people 3 years and older with liver disease.
It is not known if ribavirin capsules use for longer than 1 year is safe and will work.
It is not known if ribavirin capsules use in children younger than 3 years old is safe and will work.
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Who should not take ribavirin capsules?
See “What is the most important information I should know about ribavirin capsules?”
Do not take ribavirin capsules if you have:
ever had serious allergic reactions to the ingredients in ribavirin capsules. See the end of this
Medication Guide for a complete list of ingredients.
certain types of hepatitis (autoimmune hepatitis).
certain blood disorders (hemoglobinopathies).
severe kidney disease.
taken or currently take didanosine.
Talk to your healthcare provider before taking ribavirin capsules if you have any of these conditions.
What should I tell my healthcare provider before taking ribavirin capsules?
Before you take ribavirin capsules, tell your healthcare provider if you have or ever had:
treatment for hepatitis C that did not work for you
breathing problems. Ribavirin capsules may cause or worsen breathing problems you already have.
vision problems. Ribavirin capsules may cause eye problems or worsen eye problems you already
have. You should have an eye exam before you start treatment with ribavirin capsules.
certain blood disorders such as anemia (low red blood cell count)
high blood pressure, heart problems, or have had a heart attack. Your healthcare provider should
check your blood and heart before you start treatment with ribavirin capsules.
thyroid problems
liver problems other than hepatitis C infection
human immunodeficiency virus (HIV) or any immunity problems
mental health problems, including depression and thoughts of hurting yourself or others
kidney problems
an organ transplant
diabetes. Ribavirin capsules may make your diabetes worse or harder to treat.
any other medical condition
are breastfeeding. It is not known if ribavirin passes into your breast milk. You and your healthcare
provider should decide if you will take ribavirin capsules or breastfeed. 
Tell your healthcare provider about all the medicines you take, including prescription medicines,
vitamins, and herbal supplements. Ribavirin capsules may affect the way other medicines work.
Especially tell your healthcare provider if you take didanosine or a medicine that contains
azathioprine.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when
you get a new medicine.
How should I take ribavirin capsules?
Take ribavirin capsules exactly as your healthcare provider tells you. Your healthcare provider will
tell you how much ribavirin capsules to take and when to take them.
Take ribavirin capsules with food.
Take ribavirin capsules whole. Do not open, break, or crush ribavirin capsules before swallowing.
If you cannot swallow ribavirin capsules whole, tell your healthcare provider.
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If you miss a dose of ribavirin capsules, take the missed dose as soon as possible during the same
day. Do not double the next dose. If you have questions about what to do, call your healthcare
provider.
If you take too much ribavirin, call your healthcare provider or go to the nearest hospital emergency
room right away.
What are the possible side effects of ribavirin capsules?
Ribavirin capsules may cause serious side effects, including:
See “What is the most important information I should know about ribavirin capsules?”
Swelling and irritation of your pancreas (pancreatitis). Symptoms may include: stomach pain,
nausea, vomiting, or diarrhea.
Serious breathing problems. Difficulty breathing may be a sign of a serious lung infection
(pneumonia) that can lead to death.
Serious eye problems that may lead to vision loss or blindness.
Dental problems. Brush your teeth well 2 times each day. Get regular dental exams. If you vomit at
any time during treatment with ribavirin capsules, rinse out your mouth well.
Severe blood disorders. You may have an increased risk of developing severe blood disorders
when ribavirin capsules is used in combination with pegylated alpha interferons and azathioprine.
Your healthcare provider should do blood tests during your treatment with ribavirin capsules in
combination with pegylated alpha interferon and azathioprine to check you for these problems.
Growth problems in children. Weight loss and slowed growth are common in children during
combination treatment with ribavirin capsules and peginterferon alfa-2b or interferon alfa-2b. Most
children will go through a growth spurt and gain weight after treatment stops. Some children may not
reach the height that they were expected to have before treatment. Talk to your healthcare provider
if you are concerned about your child’s growth during treatment with ribavirin capsules and
peginterferon alfa-2b or with ribavirin capsules and interferon alfa-2b.
Severe depression.
Thoughts of hurting yourself or others, and suicide attempts. Adults and children who take
ribavirin capsules, especially teenagers, are more likely to have suicidal thoughts or attempt to hurt
themselves while taking ribavirin capsules. Call your healthcare provider right away or go to the
nearest hospital emergency room if you have new or worse depression or thoughts about hurting
yourself or others or dying.
The most common side effects of ribavirin capsules in adults include:
flu-like symptoms - feeling tired or weak, headache, shaking chills along with high temperature
(fever), nausea, and muscle aches
mood changes, feeling irritable
The most common side effects of ribavirin capsules in children include:
fever
headache
a decrease in blood cells that fight infection (neutropenia)
tiredness
decreased appetite
vomiting
These are not all the possible side effects of ribavirin capsules. For more information ask your
healthcare provider or pharmacist.
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Call your healthcare provider if you have any side effect that bothers you or that does not go away, and
for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ribavirin capsules?
Store ribavirin capsules between 15° to 30°C (59° to 86°F).
Keep ribavirin capsules and all medicines out of the reach of children.
General information about the safe and effective use of ribavirin capsules.
It is not known if treatment with ribavirin capsules will cure hepatitis C virus infections or prevent
cirrhosis, liver failure, or liver cancer that can be caused by hepatitis C virus infections. It is not known
if taking ribavirin capsules will prevent you from infecting another person with the hepatitis C virus.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use ribavirin capsules for a condition for which it was not prescribed. Do not give ribavirin capsules to
other people, even if they have the same symptoms that you have. They may harm them.
You can ask your pharmacist or healthcare provider for information about ribavirin capsules that is
written for health professionals.
What are the ingredients in ribavirin capsules?
Active ingredient: ribavirin
Inactive ingredients: microcrystalline cellulose, lactose monohydrate, povidone-K 30, and magnesium
stearate. The capsule shell consists of titanium dioxide, sodium lauryl sulfate, and gelatin. The capsule
is printed with edible ink containing black iron oxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.
Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides
Distributed by:
Aurobindo Pharma USA, Inc. 
279 Princeton-Hightstown Road
East Windsor, NJ 08520   
Manufactured by: 
Aurobindo Pharma Limited 
Hyderabad-500 038, India
Revised: 02/2020
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 200 mg (500 Capsules Bottle)
NDC 65862-290-05 
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Rx only 
Ribavirin Capsules USP 
200 mg 
PHARMACIST: Dispense the accompanying 
Medication Guide to each patient.  
AUROBINDO     500 Capsules 
 
 
RIBAVIRIN  
ribavirin capsule
Product Information
Product T ype
HUMAN PRESCRIPTION DRUG
Item Code (Source)
NDC:65862-290
Route of Administration
ORAL
Active Ingredient/Active Moiety
Ingredient Name
Basis of Strength
Strength
RIBAVIRIN (UNII: 49717AWG6K) (RIBAVIRIN - UNII:49717AWG6K)
RIBAVIRIN
200 mg
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Aurobindo Pharma Limited
Inactive Ingredients
Ingredient Name
Strength
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
 
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
 
POVIDONE K30 (UNII: U725QWY32X)
 
MAGNESIUM STEARATE (UNII: 70097M6I30)
 
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
 
SODIUM LAURYL SULFATE (UNII: 368GB5141J)
 
GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
 
FERROSOFERRIC OXIDE (UNII: XM0M87F357)
 
Product Characteristics
Color
WHITE
Score
no score
Shape
CAPSULE
Size
19mm
Flavor
Imprint Code
E;81
Contains
    
Packaging
#
Item Code
Package Description
Marketing Start Date
Marketing End Date
1 NDC:65862-290-42
42 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
2 NDC:65862-290-56
56 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
3 NDC:65862-290-70
70 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
4 NDC:65862-290-84
84 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
5 NDC:65862-290-18
180 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
6 NDC:65862-290-05
500 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
Marketing Information
Marketing Category
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date
ANDA
ANDA079117
09/17/2009
Labeler - Aurobindo Pharma Limited (650082092)
Establishment
Name
Address
ID/FEI
Business Operations
Aurobindo Pharma Limited
918917642
ANALYSIS(65862-290) , MANUFACTURE(65862-290)
 
Revised: 2/2020
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 1 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of combined suppression of host nucleotide 
synthesis in hospitalized adults with coronavirus-19 (COVID-19) 
 
Study No: CCB-CRISIS-01 
Version Date:  10 April 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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 2 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 15 
3.1 Background ................................................................................................................ 15 
3.2 Coronavirus-19 (COVID-19) ..................................................................................... 15 
3.2.1 Coronavirus Biology .................................................................................................... 15 
3.3 Host Nucleotide Synthesis ......................................................................................... 15 
3.4 Dihydroorotate dehydrogenase (DHODH) ................................................................ 16 
3.5 Inosine monophosphate dehydrogenase (IMPDH) .................................................... 16 
3.6 Brequinar .................................................................................................................... 16 
3.7 Ribavirin ..................................................................................................................... 16 
3.8 Rationale for the Planned Trial .................................................................................. 17 
3.8.1 Brequinar Dose Selection ............................................................................................. 19 
3.8.2 Ribavirin Dose Selection .............................................................................................. 19 
3.8.3 Risk/Benefit of Brequinar ............................................................................................ 19 
3.9 Risk/benefit of Ribavirin ............................................................................................ 20 
3.10 Risks Associated with Participation in the Clinical Study ......................................... 20 
3.11 Possible Interactions with Concomitant Medical Treatments .................................... 20 
3.11.1 
CYP Interactions ..................................................................................................... 21 
3.12 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 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 3 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
7 TRIAL POPULATION ....................................................................................................... 25 
7.1 Number of Subjects .................................................................................................... 25 
7.2 Inclusion criteria ......................................................................................................... 25 
7.3 Exclusion Criteria ....................................................................................................... 25 
7.4 Inclusion of Women and Minorities........................................................................... 26 
8 STUDY TREATMENTS .................................................................................................... 27 
8.1 Description of Study Medications .............................................................................. 27 
8.1.1 Brequinar ...................................................................................................................... 27 
8.1.2 Ribavirin ....................................................................................................................... 27 
8.2 Treatment Administration .......................................................................................... 27 
8.2.1 Safety/Tolerability ........................................................................................................ 27 
8.3 Study Discontinuation ................................................................................................ 28 
8.4 Concomitant Medication/Treatment .......................................................................... 28 
8.5 Treatment Compliance ............................................................................................... 28 
8.6 Storage, Stability, Labeling and Packaging ............................................................... 28 
8.6.1 Storage and Stability .................................................................................................... 28 
8.6.2 Labeling and Packaging ............................................................................................... 29 
8.6.3 Blinding and Randomization ........................................................................................ 30 
8.6.4 Unblinding/Expectedness ............................................................................................. 30 
8.6.5 Study Drug Accountability ........................................................................................... 30 
8.6.6 Prohibited Medications................................................................................................. 31 
8.6.7 Study Adjustments Due to COVID-19 ......................................................................... 31 
9 CONDUCT OF THE TRIAL.............................................................................................. 32 
9.1 Ethical and Regulatory Considerations ...................................................................... 32 
9.2 Informed Consent ....................................................................................................... 32 
9.3 Institutional Review Board......................................................................................... 33 
9.4 Schedule of Events ..................................................................................................... 33 
9.5 Study Conduct ............................................................................................................ 34 
9.5.1 Unscheduled Visits ....................................................................................................... 36 
9.6 Compliance with Study Procedures ........................................................................... 36 
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PROTOCOL VERSION DATE: 10APR2020 
 
9.7 Early Withdrawal from the Study .............................................................................. 36 
9.8 Early Termination of the Study .................................................................................. 37 
10 ADVERSE EVENT REPORTING..................................................................................... 38 
10.1 Classification of Causality ......................................................................................... 39 
10.2 Classification of Severity ........................................................................................... 40 
10.3 Serious Adverse Event (SAE) Reporting ................................................................... 40 
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 41 
10.5 Pregnancies................................................................................................................. 42 
10.6 Data Safety Monitoring Board ................................................................................... 42 
11 STATISTICAL CONSIDERATIONS................................................................................ 44 
11.1 Study Populations for Analysis .................................................................................. 44 
11.2 Safety Analyses .......................................................................................................... 44 
11.3 Efficacy Analyses ....................................................................................................... 44 
11.4 Sample Size Considerations ....................................................................................... 44 
11.5 Randomization ........................................................................................................... 44 
11.6 Pooling of Study Centers............................................................................................ 44 
11.7 Interim Analysis ......................................................................................................... 45 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 46 
12.1 Investigator’s Performance ........................................................................................ 46 
12.2 Confidentiality ............................................................................................................ 46 
12.3 Source Documentation ............................................................................................... 46 
12.4 Data Collection ........................................................................................................... 47 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 47 
12.6 Non-Protocol Research .............................................................................................. 48 
12.7 Publication .................................................................................................................. 48 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 49 
13.1 General ....................................................................................................................... 49 
13.2 Indemnity ................................................................................................................... 49 
13.3 Data Monitoring ......................................................................................................... 49 
13.4 Audit ........................................................................................................................... 49 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 5 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
13.5 Confidentiality ............................................................................................................ 50 
13.6 Finance ....................................................................................................................... 50 
14 REFERENCES ................................................................................................................... 51 
15 APPENDICES .................................................................................................................... 53 
15.1 Appendix A:  CCB-01 Schedule of Events ................................................................ 53 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 54 
15.3 Appendix C: National Early Warning Score (NEWS2) ............................................. 55 
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment Guidance. ..... 56 
15.5 Appendix E: Ribavirin generic (ribavirin USP) capsules, for oral use Summary of Product 
Characteristics (SPC) .......................................................................................... 57 
 
 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 6 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
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. ........................................... 15 
Figure 3-2.  IMPDH catalyzes the conversion of IMP to XMP in the synthesis of guanosine 
monophosphate. .................................................................................................... 16 
Figure 3-3. Changes in viral load versus day of symptom onset – COVID-19 ............................ 18 
 
Clinical Study Report 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 7 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
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 
BID 
Bis in die (two times a day) 
BRQ 
Brequinar 
BUN 
Blood urea nitrogen 
C6min 
Concentration at 6 minutes 
CHO/HGPRT 
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase 
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 
EHR 
Electronic health record 
ESR 
Erythrocyte Sedimentation Rate 
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 
IMPDH 
Inosine-5’-monophosphate 
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 
SARS 
Severe Acute Respiratory Syndrome 
SOC 
Standard of Care 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
UMP 
Uridine 5’-monophosphatase 
Clinical Study Report 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 8 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
Abbreviation 
Definition 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
Clinical Study Report 
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03 May 2021
Appendix 16.1.1
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Clinical Study Report 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 10 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
procedures are presented in detail in the procedures section, see below. Subjects 
will be followed through Day 15. Mortality will be assessed at Day 29. 
If discharge occurs prior to Day 5 for subjects in the brequinar plus ribavirin 
treatment group, the subject will be provided with sufficient ribavirin to take at 
home to complete the treatment course. In this case, subsequent study visits are to 
be conducted by telephone or other digital media as per institutional guidelines.  
Study information such as hematology and chemistry and NEWS2 criteria is to be 
collected using the available EHR data. 
Sample Size: 
Approximately 72 subjects will be randomized to either brequinar or brequinar plus 
ribavirin or standard of care in a 1:1:1 ratio (approximately 24 subjects on 
brequinar, 24 subjects on the brequinar plus ribavirin combination, and 24 assigned 
to standard of care). Additional subjects may be enrolled following data review. 
Number of Sites: 
1 - 8 
Study Period: 
An enrollment period of 3 months is expected. 
Inclusion 
Criteria: 
 
1. Willing and able to provide written informed consent for the trial (or 
designated care giver/healthcare power of attorney may consent if subject 
unable per institutional guidelines). 
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-cleared commercial or 
public health assay. 
4. Life expectancy > 48h in the opinion of the investigator. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown and 
ribavirin is contraindicated in women who are pregnant as well as in the 
male partners of women who are pregnant. 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 
treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study. participation, and 
for 90 days after completion of brequinar administration and for 6 months 
after completion of ribavirin administration. 
7. Male subjects must agree to refrain from sperm donation from initial study 
drug administration until 90 days after the last dose of brequinar and for 6 
months after completion of ribavirin administration. 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
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STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Title: 
Address: 
Telephone No.: 
Fax No.: 
E-mail: 
Barbara Powers, MSN, Ph.D. 
Clinical Operations 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
484-686-0545 
617-863-2082 
bpowers@clearcreekbio.com  
MEDICAL MONITOR 
Name:  
Sharon Levy, MD 
Title: 
Prosoft Clinical 
Telephone No.: 
M: (610) 316-9764 
O: (484) 320-2062 
E-mail: 
s.levy@prosoftclinical.com
Sharon.levy27@gmail.com 
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3 
INTRODUCTION 
3.1 Background 
3.2 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]).  
3.2.1 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 
[22]). 
3.3  Host Nucleotide Synthesis 
Host de novo nucleotide synthesis is divided into two arms: purine 
synthesis (A, G) and pyrimidine synthesis (U, T, C). Host de novo 
pyrimidine synthesis generates uridine monophosphate (UMP) as 
the building block for all pyrimidine ribonucleotides and 
deoxyribonucleotides (Figure 3-1). Host de novo purine synthesis 
has more redundancy with parallel paths of adenosine and 
guanosine synthesis.  
These pathways of pyrimidine and purine synthesis are non-
overlapping and differ in two salient aspects: [1] the pool of 
intracellular purines (A, G) tends to be larger than the pool of 
pyrimidines (U, T, C) and [2] there exists no salvage pathway for 
the synthesis of UMP, the fundamental building block of 
pyrimidines. For these reasons, inhibition of enzymatic steps 
upstream of UMP (Figure 3-1) leads to a more rapid and more 
profound depletion of intracellular pyrimidines than inhibition of 
enzymatic steps upstream of GMP (Figure 3-2).  
 
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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3.4  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.  
3.5  Inosine monophosphate dehydrogenase (IMPDH)  
Inosine monophosphate dehydrogenase (IMPDH) catalyzes the 
conversion of IMP to XMP en route to the de novo synthesis of 
GMP (Figure 3-2). Inhibition of IMPDH results in a depletion of 
intracellular guanosine monophosphate.  
3.6  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. 
The antiviral activity of brequinar has been demonstrated in studies of rotavirus replication in 
human intestinal Caco2 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 [13]). 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]). 
3.7  Ribavirin 
Ribavirin is an FDA-approved anti-viral agent and is marketed in combination with interferon alfa-
2b for the treatment of chronic hepatitis C (ribavirin generic SPC, Appendix E, Section 15.5).  
Figure 
3-2. 
 
IMPDH 
catalyzes the conversion of 
IMP 
to 
XMP 
in 
the 
synthesis 
of 
guanosine 
monophosphate.  
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Ribavirin is a purine nucleoside analog with multiple mechanisms of action. It is known to inhibit 
the host enzyme inosine-5’-monophosphate dehydrogenase (IMPDH), the enzyme that catalyzes 
the conversion of inosine 5’-phosphate (IMP) to xanthosine 5’-phosphate (XMP), the first 
committed and rate-limiting step in the de novo synthesis of guanine nucleotides. In addition, 
ribavirin binds to and inhibits the SARS-CoV-2 viral enzyme – the RNA dependent RNA 
polymerase (RdRp) (Elfiky et al., 2020 [26]). And finally, another important mechanism of action 
that may contribute to ribavirin’s antiviral effect is the ability to act as a ribonucleotide analog 
which can be incorporated into the viral RNA genome and lead to detrimental mutations in a 
process termed hypermutagenesis (Ortega-Prieto et al., 2013 [24]). 
In pre-clinical studies, ribavirin has a demonstrated broad spectrum in vitro anti-viral activity and 
acts as an immunomodulator in a mouse hepatitis coronavirus model (Ning et al, 1998 [21]). 
Ribavirin and mycophenolate mofetil (a more potent IMPDH inhibitor) were proposed for the 
treatment of MERS CoV infection with hints of clinical activity in small case studies (Ghamdi et 
al., 2016 [11]; Chong et al., 2015 [12]). Ribavirin as a single agent showed hints of activity in the 
previous SARS outbreak (Poutanen et al., 2003 [25]). Ribavirin and other IMPDH inhibitors are 
currently being proposed as possible treatments for the current COVID-19 pandemic (Gordon et 
al., 2020 [26]). Ribavirin as a single-agent may not be highly-effective based on the clinical 
progression of patients with SARS who were treated only with ribavirin (Peiris et al., 2003 [18]). 
There is currently an active combination trial of lopinavir/ritonavir, ribavirin and IFN-beta in Hong 
Kong for COVID-19 (NCT04276688).  
3.8  Rationale for the Planned Trial 
The CRISIS trial studies standard of care (SOC), SOC with DHODH inhibition, and SOC with 
DHODH inhibition and IMPDH inhibition. SOC is evolving rapidly for COVID-19 and at 
institutions includes approved FDA drugs such as lopinavir/ritonavir that have shown activity in 
coronaviruses. These may be combined into this trial.  
In particular this trial combines brequinar – an inhibitor of host pyrimidine synthesis (DHODH) – 
with the anti-viral ribavirin, a nucleoside analog that acts as an inhibitor of host IMPDH and an 
inhibitor of the viral RNA dependent RNA polymerase (RdRp). In addition, the misincorporation 
of ribavirin as a nucleoside analog into the replicating viral genome will be accentuated because 
the dose of ribavirin will be diluted into a smaller pool of host nucleotides, thereby increasing its 
effective intracellular concentration (Liu et al., 2020 [27]).  
The temporary depletion of the host pyrimidine and purine pools in combination with the ribavirin 
effect on viral RdRp is hypothesized to lead to a significant reduction in virus replication at a 
critical point in the COVID-19 disease, restoring the balance in favor of the host immune system 
for ultimate clearance of SARS-CoV-2. This combination has been recently been shown to be 
effective in a pre-clinical model of disease where the authors demonstrated that inhibitors of 
DHODH could potentiate the activity of inhibitors of RdRp in the treatment of dengue virus, 
another single-stranded RNA virus (Liu et al., 2020 [27]).  
DHODH is already considered a potential therapeutic target in antiviral, oncology and autoimmune 
indications. Multiple doses of high-potency DHODH inhibitors are under investigation in the 
treatment of patients with hematologic malignancies. In addition to an anticancer effect when 
delivered in multiple high-doses, DHODHi may also prove effective in inhibiting viral replication 
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by starving the host cell - and thus the replicating virus - of nucleotides, thereby acutely reducing 
the viral load in diseases such as COVID-19.  
Emerging data from SARS-CoV-2 infections show peaks of viral load 5 to 6 days after the onset 
of symptoms; the viremia then resolves within 10-14 days. This may be distinct from previous 
coronavirus infections where viral loads peaked approximately 10 days after the start of 
symptoms (Peiris et al., 2003 [18]). The timed and transient inhibition of DHODH and depletion 
of host pyrimidine nucleotides during the early period of the disease is expected to suppress 
viral replication during its peak and decrease viral load, leading to a rapid resolution of clinical 
symptoms.  
Due to the relatively short course of active viral replication in COVID-19, a single dose of 
brequinar administered at the right time may provide clinical benefit in patients requiring 
hospitalization due to the coronavirus infection. See Figure 3-3 for changes in viral load versus 
day of symptom onset in two patients with SARS-CoV-2 (Pan et al., 2020 [19]).  
Clear Creek hypothesizes that the timed inhibition of DHODHi or DHODHi + IMPDHi and 
depletion of host pyrimidine and purine nucleotides during the period of increased viral load will 
suppress viral replication leading to a more rapid resolution of clinical symptoms.  
 
 
Figure 3-3. Changes in viral load versus day of symptom onset – COVID-19 
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.  
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It is also hypothesized that the suppression of host nucleotide synthesis and therefore viral 
replication would be most effective early in the course of disease while there is still ongoing viral 
replication.  
3.8.1 Brequinar Dose Selection 
Safety data from previous oncology clinical studies of brequinar with maximum tolerated doses as 
high as 2250 mg/m2 repeated every 3 weeks and from the active brequinar study in acute myeloid 
leukemia (AML) patients suggest that a single dose of 500 mg/m2 p.o. will be safe and well 
tolerated. Brequinar has in vitro antiviral EC50s that range from 0.04-1.0 µM that equal 0.016-
0.40 µg/mL of brequinar. If the effective concentration to inhibit 90% of virus replication (EC90) 
is assumed to be one log great, then a plasma concentration of 0.1-4 µg/mL would be needed. A 
single oral dose of 500 mg/m2 maintains a plasma level of at least 4 µg/mL for 48-72 hours (see 
Brequinar IB [5]). 
3.8.2 Ribavirin Dose Selection 
Ribavirin is marketed in combination with interferon-alpha for treatment of chronic hepatitis 
caused by the RNA virus hepatitis C. The proposed dose for the COVID-19 study is based on the 
ribavirin generic Summary of Product Characteristics (SPC) found in Section 15.5. In chronic 
hepatitis C patients, ribavirin at 400 mg BID has shown 13% anemia when combined with 
interferon. Ribavirin suppressed viral load with some activity when given for SARS in 2003 at 400 
mg TID. At that dose, 8% (of 75) or 0% (of 31) patients developed anemia (Peiris et al., 2003 
[18]; So et al., 2003 [28]). The CRISIS trial will administer ribavirin at the labelled dose of 400 
mg BID for 5 days. Given the recent evidence in a pre-clinical dengue virus model of disease that 
the misincorporation of ribavirin as a nucleoside analog into the replicating viral genome will be 
accentuated because the dose of ribavirin will be diluted into a smaller pool of host nucleotides, 
the labeled dose of 400 mg two times a day (BID) chosen should provide optimal safety with the 
potential for a benefit in combination with brequinar (Liu et al., 2020 [27]). 
3.8.3    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], more than 800 cancer patients 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. Brequinar has also been utilized in 
studies 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. While no 
DHODHi has been tested to date in the clinic for infection with SARS-CoV-2 and no brequinar 
safety information is available in treatment of this disease, DHODHi therapy in the context of trials 
for patients with cancer has the expected side-effects of mucositis and bone marrow suppression. 
Chronic DHODHi therapy in patients with autoimmune disease has the expected (and desired) 
effects on T-cell suppression (activated T-cells have a particular dependence on pyrimidine 
synthesis). However, a single, relatively low dose of brequinar such as that proposed for 
administration in this study should be safe, well tolerated and manifest none of these potential 
side-effects.  
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The possible benefit in using brequinar to treat SARS-CoV-2 infection is the hypothesis that a 
single dose of brequinar will suppress host de novo pyrimidine synthesis for a period of up to 72 
hours thus decreasing viral load. As discussed above, inhibition of DHODH is expected to reduce 
the ability of the virus to replicate and it is for this reason that study CCB-CRISIS-01 will 
administer brequinar to patients with COVID-19. 
3.9  Risk/benefit of Ribavirin 
Risks associated with ribavirin administration in 40% or greater of adult patients receiving 
ribavirin with interferon included fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and 
anxiety/emotional lability/irritability. Additional safety information is provided in the ribavirin 
generic SPC (Section 15.5).  
The possible benefit in using ribavirin to treat SARS-CoV-2 infection is the hypothesis that the 
expected suppression of host nucleotide synthesis associated with ribavirin will prevent viral 
replication when used in conjunction with brequinar thereby reducing viral load. 
3.10 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of 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 drug administration. The 
majority of these adverse effects have been less than grade IV in severity and resolve following 
discontinuation of dosing.  
Risks associated with ribavirin administration in hepatitis C patients who also received interferon-
alpha are presented in the ribavirin generic SPC found in Section 15.5. The most commonly 
reported adverse reactions in adult subjects receiving PegIntron or INTRON A in combination 
with ribavirin were fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and 
anxiety/emotional lability/irritability. 
3.11 Possible Interactions with Concomitant Medical Treatments 
While not previously tested in patients with viral infections, brequinar has been administered to 
subjects taking a variety of concomitant medications that are typical in cancer patients. 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. Brequinar has also been used concomitantly with antibiotics, antifungals and other critical 
care medications. 
 
There is no experience with brequinar for treatment of SARS-CoV-2 and other severe viral 
infections and no formal interaction studies have been conducted.  
 
Experience with use of ribavirin and interferon in treatment of hepatitis C has concluded that 
ribavirin should not be given with nucleoside reverse transcriptase inhibitors such as didanosine 
or with azathioprine. There is limited experience with ribavirin for treatment of SARS-CoV-2 and 
other severe viral infections and no formal interaction studies have been conducted for use of 
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ribavirin with concomitant medications that are typical in these patients. Ribavirin should be taken 
with food, when possible. See ribavirin generic package insert, Appendix E Section 15.5. 
3.11.1 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). 
Results of in vitro studies using both human and rat liver microsome preparations indicated little 
or no cytochrome P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-
450 enzyme-based interactions (ribavirin generic SPC Appendix E Section 15.5). 
3.12 Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated in a hospital setting by highly experienced infectious disease specialists 
and other qualified staff familiar with the treatment of severe viral infections and their 
complications. 
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5 
TRIAL DESIGN 
This will be a phase 1a randomized, open label, multi-center study with approximately 72 subjects. 
All subjects will receive standard of care per institutional guidelines for treatment of patients with 
SARS-CoV-2 infection. In addition to standard of care, the brequinar alone group will receive 1 
dose of brequinar 500 mg/m2. In addition to standard of care, the brequinar plus ribavirin group 
will receive brequinar 500 mg/m2 on Day 1 plus ribavirin 400 mg BID on Days 1 through 5.   
The Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance is provided in 
Appendix D Section 15.5. This guidance provides an example of standard of care instructions for 
treatment of COVID-19. It is not required that this guidance be used. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Study procedures are presented in 
detail in Section 8. Subjects will be followed through Day 15, with mortality assessed via a phone 
call/other digital media acceptable to institution on Day 29. 
Additional subjects may be enrolled following data review. 
If discharge occurs prior to Day 5 for subjects in the brequinar plus ribavirin treatment group, the 
subject will be provided with sufficient ribavirin to take at home to complete the treatment course. 
In this case, the Day 7 (including drug accountability) and Day 15 visits are to be conducted by 
telephone.  
It is understood that some assessments may not be conducted if the subject is unable to return to 
the clinic after discharge due to restricted travel. If an assessment is missed due to after hospital 
discharge, e.g., samples or blood draws, this will not be counted as a protocol deviation. Any of 
the study visits may be conducted via telephone if the subject has been discharged from the hospital 
and is not permitted to or is unable to return to the hospital/clinic for these visits. 
Information is to be collected using the electronic health record (EHR) whenever possible. It is not 
required to perform study-specific laboratory assessments, NEWS 2 criteria, etc. 
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7 
TRIAL POPULATION 
7.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 72 subjects have completed the study. Additional subjects may be enrolled 
following data review. Subjects will be randomized to either brequinar or brequinar plus ribavirin 
or standard of care in a 1:1:1 ratio (approximately 24 subjects on brequinar, 24 subjects on the 
brequinar plus ribavirin combination, and 24 assigned to standard of care).  
7.2 Inclusion criteria 
1. Willing and able to provide written informed consent for the trial (or designated care 
giver/healthcare power of attorney may consent if subject unable per institutional 
guidelines). 
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 Food and Drug Administration (FDA)-cleared 
commercial or public health assay. 
4. Life expectancy > 48h in the opinion of the investigator. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men treated or enrolled on this protocol must also agree to 
use adequate contraception prior to the study, for the duration of study. participation, and 
for 90 days after completion of brequinar administration and for 6 months after completion 
of ribavirin administration. 
7. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of brequinar and for 6 months after 
completion of ribavirin administration.  
8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician. 
7.3 Exclusion Criteria 
1. In intensive care unit (ICU) or equivalent level of care or expected to require ICU level of 
care within next 24 hours. 
2. 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. 
3. Active malignancy other than squamous cell carcinoma; anticancer treatment such as 
chemotherapy or radiation therapy within the past month. 
4. Estimated creatinine clearance < 50 mL/min. 
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5. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy 
test. 
6. Treatment with ribavirin, mycophenolate, leflunomide or teriflunomide, didanosine, 
azathioprine, tacrolimus, sirolimus, or pre-existing prednisone at higher than 20 mg daily 
(ongoing or within 2 weeks of study entry). 
7. Stevens-Johnson Syndrome or other hypersensitivity reactions to ribavirin or any 
component of the product. 
7.4 Inclusion of Women and Minorities 
Adult men and women of all races and ethnic groups are eligible for this trial. 
 
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8 
STUDY TREATMENTS 
8.1 Description of Study Medications 
8.1.1 Brequinar 
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be a single oral dose of 500 
mg/m2. The initial brequinar dose should be administered as soon as possible based on the 
availability of the investigational pharmacy. 
8.1.2 Ribavirin 
Ribavirin will be supplied as 200 mg capsules. Ribavirin should be taken with food, when possible. 
Dosing will be 400 mg BID for 5 days (Days 1 – 5) approximately 8 AM and 8 PM ± 4 hours.  
8.2 Treatment Administration 
This will be a phase 1a randomized, open label, multi-center study with approximately 72 subjects. 
All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 
infection. Subjects will be randomly assigned in a 1:1:1 ratio to standard of care alone, standard 
of care plus brequinar, or standard of care plus brequinar plus ribavirin. The brequinar alone group 
will receive 1 dose of brequinar 500 mg/m2 on Day 1. The brequinar plus ribavirin group will 
receive brequinar 500 mg/m2 on Day 1 along with ribavirin 400 mg BID x 5 days (study days 1 – 
5). 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE).  
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 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 most instances, brequinar-related toxicities were clinically manageable and reversible upon 
discontinuation of brequinar treatment. In a study where brequinar was dosed twice-weekly to 
solid tumor subjects, no drug-related deaths occurred. Stomatitis/mucositis was observed in 13 of 
the 19 (68%) patients across all doses. Mild to moderate (Grades 1 and 2) stomatitis was observed 
in 10 patients with a more severe (Grade 3) stomatitis seen in 3 patients at doses over 600 mg/m2. 
One patient at 600 mg/m2 had drug discontinuation due to drug-related stomatitis. 
Myelosuppression was the main dose-limiting toxicity (DLT) with thrombocytopenia (Grades 1-
4), observed after 2 to 9 doses above 600 mg/m2. Three patients in the ongoing AML study 
experienced severe (Grade 3 or 4) mucositis following administration of two or more doses of 
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brequinar. Any of these events reported with brequinar use can be serious in nature and may result 
in death.  
A single dose of brequinar at a low level relative to those administered in the cancer studies noted 
above is expected to be safe and well tolerated in the COVID-19 population. 
For ribavirin, the primary toxicity is hemolytic anemia which has been reported in approximately 
13% of subjects taking ribavirin and interferon alfa-2a on a chronic basis in combination with 
PegIntron A for hepatitis C. The most commonly reported adverse reactions in adult subjects 
receiving PegIntron or INTRON A in combination with ribavirin were fatigue/asthenia, headache, 
rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability. See the ribavirin generic 
SPC for complete ribavirin safety information (ribavirin generic SPC, Section 15.5). It is expected 
that the proposed acute use of ribavirin using the 400 mg BID x 5-day regimen will 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 15 (or longer if needed to follow up 
study medication-related adverse events). Mortality is assessed at Day 29. 
After treatment, participants will be monitored through Study Day 15. Participants may 
discontinue from the study by withdrawing consent at any time or for any reason as presented in 
Section 9.7. 
If discharge occurs prior to Day 5 for subjects in the brequinar plus ribavirin treatment group, the 
subject will be provided with sufficient ribavirin to take at home to complete the treatment course. 
In this case, conduct any subsequent visits (such as the Day 7 (including drug accountability) and 
Day 15 visits) over the phone or other digital media as permitted by the institution.  
The reason for study discontinuation will be recorded in the source document and the eCRF.  
8.4 Concomitant Medication/Treatment 
Record the name, start date, indication for use, 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. The use of other DHODH inhibitors and IMPDH 
inhibitors are not permitted during the study including ribavirin, mycophenolate, leflunomide or 
teriflunomide (see Section 8.6.6).  
8.5 Treatment Compliance 
Compliance will be assessed by reviewing the subject’s EHR and other study records as 
appropriate. 
8.6 Storage, Stability, Labeling and Packaging 
8.6.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
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8.6.2 Labeling and Packaging  
Each brequinar bottle/dispensing container for subject use will be labeled with at least the 
following information: 
For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: 100 or 250 mg Brequinar capsules 
For oral use only. Take with approximately 8 ounces water. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
 
Each ribavirin bottle/dispensing container for subject use will be labeled with at least the following 
information: 
For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: Ribavirin capsules (dosing per body weight) 
For oral use only. Take with approximately 8 ounces water and with food 
(when possible) 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
 
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8.6.3 Blinding and Randomization 
The trial will be conducted in an open-label manner with random assignment to standard of care, 
standard of care plus brequinar or standard of care plus the brequinar plus ribavirin combination. 
The brequinar and ribavirin capsules will be provided to each participating institution in bulk to 
be dispensed by the institution’s pharmacist per the designated mg/m2 dose (for brequinar) and 
ribavirin 400 mg BID x 5 days for each subject. Randomization assignments will be provided by 
the sponsor. 
8.6.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment will be known for 
each subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the protocol and the brequinar IB or the ribavirin SPC or are commonly associated 
with COVID-19 or similar severe viral illnesses and their complications.   
8.6.5 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, used and discarded.  It must 
be clear from the records whether the subject received study medication or was assigned to 
standard of care. 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 detailing 
how to calculate the mg/m2 dose together with examples of combinations of the 100 and 250 mg 
capsules to provide the most efficient use of the clinical supplies.  
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. 
If the subject is discharged prior to completing ribavirin dosing, the subject is to be given sufficient 
supplies to complete the 10-dose course. Drug accountability should be checked at the Day 7 visit 
in this case. 
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8.6.6 Prohibited Medications 
The use of didanosine and azathioprine are not permitted during the study. The use of other 
DHODH inhibitors and IMPDH inhibitors such as mycophenolate, leflunomide or teriflunomide 
are not permitted during the study. 
8.6.7 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 telephone or other digital media. Study information is to be 
collected from the EHR as much as possible such as NEWS2 Criteria, height, weight, 
hematology/chemistry. 
 
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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) 
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.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures. Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be subject to review by the Sponsor; a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. 
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 
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 169 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 37 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
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). 
 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 171 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 38 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
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 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. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. 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.   
Any serious adverse events (SAEs) experienced after 30 days post the last dose of study drug 
should only be reported to the sponsor if the investigator suspects a causal relationship to the 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, or require therapy. 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the End of Study and Death forms.  
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 progression of the disease under 
study. 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 172 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 173 of 582


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PROTOCOL NUMBER:  CCB-CRISIS-01  
Page 42 of 57 
PROTOCOL VERSION DATE: 10APR2020 
The Sponsor is to 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 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to 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 knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must 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.   
10.5 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 the Sponsor Contact 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 pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as 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-
up with 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. 
10.6 Data Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be established to provide independent oversight 
to this trial.  The primary responsibility of the DSMB 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 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
Page 43 of 57 
PROTOCOL VERSION DATE: 10APR2020 
in the trial.  The specific responsibilities of the DSMB will be detailed in a separate DSMB charter. 
The DSMB 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.  Following such a review, the DSMB Chair will 
advise the Sponsor that the study be stopped, a treatment arm dropped, or that the study may 
continue per protocol. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 44 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
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 analyses will be based on the ITT population, which is defined as all randomized subjects.   
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, NEWS2 Criteria, 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 (TEAEs), defined as AEs occurring after 
randomization, will be tabulated by MedDRA preferred term and system organ class, and by 
severity and relationship to study treatment. All laboratory results and NEWS2 Criteria will be 
summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will be assessed in terms of mortality, hospitalization status and duration, NEWS2 score, 
viral load (plasma and nasopharyngeal), and inflammatory markers. 
11.4 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 72 
subjects are planned to be entered in this trial.  Additional subjects may be enrolled following data 
review. 
11.5 Randomization 
A randomization scheme will be provided by the Sponsor to ensure subjects are randomly assigned 
to SOC, SOC + brequinar, or SOC + the brequinar plus ribavirin combination in a 1:1:1 ratio.  
11.6 Pooling of Study Centers 
Not applicable to this small, early phase study. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 45 of 57 
PROTOCOL VERSION DATE: 10APR2020 
 
11.7 Interim Analysis 
No interim analysis is planned for this trial. 
 
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 180 of 582


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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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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) 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 eo we minimize
mortality for COVID-19 and other emerging disease outbreaks.
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. Ghamdi Al M, Alghamdi KM, Ghandoora Y, Alzahrani A, Salah F, Alsulami A, et al.
Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus
(MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia.
BMC Infect Dis. 2016 Apr 21;16(1):174.
12. Chong YP, Song JY, Seo YB, Choi J-P, Shin H-S, Rapid Response Team. Antiviral
Treatment Guidelines for Middle East Respiratory Syndrome. Infect Chemother. 2015
Sep;47(3):212–22.
13. 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.
14. Kentsis A, Volpon L, Topisirovic I, et al. Further evidence that ribavirin interacts with
eIF4E. RNA. 2005:11:1762-1766.
15. Assouline S, Culjikovic B, Cocokakis E, Rousseau C, Beslu N, Amri A, Caplan S, Leber
B, Rou D-C, Miller W, and Borden K. Molecular targeting of the oncogene eIF4E in acute
myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood. 2009
May 11;114(2):257-60.
16. Tan K, Culjkovic B, Amri A, Borden K. Ribavirin targets eIF4E dependent Akt survival
signaling. Biochim Biophys Res Commu. 2008;375:341-345.
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17. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and 
epidemiology of 2019 novel coronavirus: implications for virus origins and receptor 
binding. Lancet 2020; 395: 565-74. 
18. Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community 
outbreak of coronavirus-associated SARS pneumonia: a prospective 
study. Lancet. 2003; 361: 1767-1772 
19. Pan Y, Zhang D, Yang P, Poon L, and Wang Q. Viral load of SARS-CoV-2 in clinical 
Samples. Lancet February 24, 2020.  
20. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the 
assessment of acute-illness severity in the NHS. Updated report of a working party. 
London: RCP, 2017. 
21. Ning Q, Brown D, Paodo J, et al. Ribavirin inhibits viral-induced macrophage production 
of TNF, IL-1, he procoagulant fgl2 prothrombinase and preserves Th1 cytokine production 
but inhibits Th2 cytokine response. J Immunol 1998; 160:3487. 
22. 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). 
23. Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sci. 
2020 May 1;248:117477. 
24. Ortega-Prieto AM, Sheldon J, Grande-Pérez A, Tejero H, Gregori J, Quer J, et al. 
Extinction of hepatitis C virus by ribavirin in hepatoma cells involves lethal mutagenesis. 
PLoS ONE. 2013;8(8):e71039. 
25. Poutanen SM, Low DE, Henry B, Finkelstein S, Rose D, Green K, et al. Identification of 
severe acute respiratory syndrome in Canada. N Engl J Med. 2003 May 15;348(20):1995–
2005. 
26. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O’Meara MJ et al. A SARS-CoV-
2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-
Repurposing. bioRxiv. 2020 Mar 22; 2020.03.22.002386v3. 
27. 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. 
28. So LK, Lau AC, Yam LY, et al. Development of a standard treatment protocol for severe 
acute respiratory syndrome. Lancet 2003;361:1615–7. 
 
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15 APPENDICES 
15.1 Appendix A:  CCB-01 Schedule of Events 
CCB-CRISIS-01  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2 - D7 
Final Visit  
D15 
F/U  
Phone 
Call 
2 weeks/ 
Survival 
Informed Consent 
X 
 
 
 
 
AE/Concomitant Medications  
X 
X 
X 
X 
 
Medical history / History of current illness 
X 
 
 
 
 
Demographics, collect Height and weight 
X 
 
 
 
 
Check for Physical Exam abnormalities 
X 
X 
 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
Hematology/Chemistry 
X 
X (pre-dose) 
 D7 
X 
 
Inflammatory Markers* 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Swab collection for nasopharyngeal viral load 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Clinical SARS-CoV-2 testing RT-PCR 
X 
 
 
 
 
Hospital Status 
 
X 
X D7 
X 
 
NEWS2 Criteria 
X 
X 
D3, D5, D7 
X 
 
Dispense Study Medication  
 
X 
X (D2 – 5 if 
assigned to 
ribavirin 
combination) 
X 
 
Drug Accountability 
 
 
X D7 
 
 
Survival Assessment Day 29 
 
 
 
 
X 
Collect information from available electronic health record (EHR) whenever possible; a special 
visit by research staff is not to be performed. Hematology, Results for Chemistry and available 
inflammatory markers analyzed locally are to be obtained from the EHR; do not draw another set 
of labs. Missed samples due to hospital staff too busy or for technical reasons unable to obtain 
samples will not be counted as protocol deviations. 
Note that any visits other than Screening/Day 1 may be conducted via telephone or digital media. 
Missed samples/assessments when phone visits occur will not be counted as protocol deviations. 
*Inflammatory markers including D-dimer, erythrocyte sedimentation rate (ESR), c-reactive 
protein (CRP), D-dimer, serum ferritin, and procalcitonin, IL-6 are to be collected from the EHR 
when available; otherwise process and ship samples to the central laboratory per the Laboratory 
Manual. 
 
 
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15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-01 
STUDY TITLE:  The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of combined suppression of host nucleotide synthesis in hospitalized 
adults with coronavirus-19 (COVID-19). 
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: __________________ 
 
Site Address: 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
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15.3 Appendix C: National Early Warning Score (NEWS2)  
Use SpO2 Scale 2 if target range is 88 – 92%, e.g., in hypercapnic respiratory failure. 
National Early Warning System Score (NEWS) 2  Royal College of Physicians 2017 [20] 
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15.5 Appendix E: Ribavirin generic (ribavirin USP) capsules, for oral use Summary of 
Product Characteristics (SPC) 
 
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RIBAVIRIN - ribavirin capsule  
Aurobindo Pharma Limited
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use RIBAVIRIN CAPSULES safely and
effectively. See full prescribing information for RIBAVIRIN CAPSULES.
RIBAVIRIN capsules, for oral use
Initial U.S. Approval: 1998
WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC
ANEMIA, and MONOTHERAPY NOT RECOMMENDED
See full prescribing information for complete boxed warning.
Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed
to ribavirin.  Therefore, ribavirin therapy is contraindicated in women who are pregnant and in the
male partners of women who are pregnant. Avoid pregnancy during therapy and for 6 months after
completion of treatment in both female patients and in female partners of male patients who are
taking ribavirin therapy. (4, 5.1, 8.1, 8.3, 13.1)
The hemolytic anemia associated with ribavirin therapy may result in worsening of cardiac disease
that has led to fatal and nonfatal myocardial infarctions.  Patients with a history of significant or
unstable cardiac disease should not be treated with ribavirin. (2.5, 5.2, 6.1)
Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C. (5.10)
INDICATIONS AND USAGE
Ribavirin capsules are a nucleoside analogue indicated in combination with interferon alfa-2b (pegylated and nonpegylated)
for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age or older with compensated liver disease. (1.1)
Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy:
previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1
infection.
DOSAGE AND ADMINISTRATION
Ribavirin capsules are administered according to body weight. (2.1, 2.2, 2.3)
Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal dysfunction.
(2.5, 2.6, 12.3)
DOSAGE FORMS AND STRENGTHS
Ribavirin Capsules USP 200 mg (3)
CONTRAINDICATIONS
Pregnancy and men whose female partners are pregnant (4, 5.1, 8.1, 8.3)
Known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema
multiforme to ribavirin  or any component of the product (4)
Autoimmune hepatitis (4)
Hemoglobinopathies (4)
Creatinine clearance less than 50 mL/min (4, 12.3)
 Coadministration with didanosine (4, 7.1)
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: May cause fetal harm. Patients should have a negative pregnancy test prior to therapy and use
effective contraception and undergo periodic pregnancy tests. (5.1, 8.1, 8.3)
Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation
of therapy:
Hemolytic anemia may occur with a significant initial drop in hemoglobin. (5.2)
Pancreatitis. (5.3)
Pulmonary infiltrates or pulmonary function impairment. (5.4)
New or worsening ophthalmologic disorders. (5.5)
Severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.
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(5.6)
Dental/periodontal disorders reported with combination therapy. (5.7)
Concomitant administration of azathioprine. (5.8)
Weight loss and growth inhibition reported during combination therapy in pediatric patients. Long-term growth
inhibition (height) reported in some patients. (5.9)
Monotherapy with ribavirin is not permitted. (5.10)
ADVERSE REACTIONS
Hemolytic anemia occurred in more than 10% of adult patients receiving ribavirin/PegIntron or INTRON A combination
therapy. (6.1)
Most common adverse reactions (40% or greater) in adult patients receiving ribavirin/PegIntron or INTRON A
combination therapy are injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and
anxiety/emotional lability/irritability. (6.1) Most common adverse reactions (greater than 25%) in pediatric patients
receiving ribavirin/PegIntron therapy are: pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and
vomiting. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Nucleoside analogues: Closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce
dose or discontinue interferon, ribavirin or both with worsening toxicities. (7.2)
USE IN SPECIFIC POPULATIONS
Pediatrics: Safety and efficacy in patients less than 3 years old have not been established. (8.4)
Organ transplant recipients: Safety and efficacy not studied. (8.6)
Co-infected patients: Safety and efficacy with HIV or HBV co-infection have not been established. (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 2/2020
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC ANEMIA, and MONOTHERAPY
NOT RECOMMENDED
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C (CHC)
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
2.2 Ribavirin capsules/PegIntron Combination Therapy
2.3 Ribavirin capsules/INTRON A Combination Therapy
2.4 Testing Prior to Initiation of Ribavirin capsules
2.5 Dose Modifications
2.6 Discontinuation of Dosing
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
5.2 Anemia
5.3 Pancreatitis
5.4 Pulmonary Disorders
5.5 Ophthalmologic Disorders
5.6 Laboratory Tests
5.7 Dental and Periodontal Disorders
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5.8 Concomitant Administration of Azathioprine
5.9 Impact on Growth in Pediatric Patients
5.10 Not Recommended for Monotherapy and Risks Associated with Combination Therapy
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experiences
7 DRUG INTERACTIONS
7.1 Didanosine
7.2 Nucleoside Analogues
7.3 Drugs Metabolized by Cytochrome P-450
7.4 Azathioprine
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Organ Transplant Recipients
8.7 HIV or HBV Co-infection
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and Pharmacology
14 CLINICAL STUDIES
14.1 Ribavirin/PegIntron Combination Therapy
14.2 Ribavirin/INTRON A Combination Therapy
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*
FULL PRESCRIBING INFORMATION
Sections or subsections omitted from the full prescribing information are not listed.
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WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC ANEMIA, and
MONOTHERAPY NOT RECOMMENDED
Significant teratogenic and embryocidal effects have been demonstrated in all animal
species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days
and may persist in non-plasma compartments for as long as 6 months. Therefore,
ribavirin therapy is contraindicated in women who are pregnant and in the male partners
of women who are pregnant. Avoid pregnancy during therapy and for 6 months after
completion of treatment in both female patients and in female partners of male patients
who are taking ribavirin therapy. Effective contraception must be utilized during
treatment and during the 6-month post-treatment follow-up period [see Contraindications
(4), Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3), and Nonclinical
Toxicology (13.1)].
Hemolytic anemia has been reported with ribavirin therapy. The anemia associated with
ribavirin therapy may result in worsening of cardiac disease that has led to fatal and
nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac
disease should not be treated with ribavirin [see Dosage and Administration (2.5), Warnings
and Precautions (5.2), and Adverse Reactions (6.1)].
Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus
infection and should not be used alone for this indication [see Warnings and Precautions
(5.10)].
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C (CHC)
Ribavirin capsules in combination with interferon alfa-2b (pegylated and nonpegylated) are indicated for
the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age and older with compensated liver
disease [see Warnings and Precautions (5.9, 5.10), and Use in Specific Populations (8.4)].
The following points should be considered when initiating ribavirin capsules combination therapy with
PegIntron
or INTRON A :
Combination therapy with ribavirin capsules/PegIntron is preferred over ribavirin
capsules/INTRON A as this combination provides substantially better response rates [see Clinical
Studies (14)].
 Patients with the following characteristics are less likely to benefit from re-treatment after failing a
course of therapy: previous nonresponse, previous pegylated interferon treatment, significant
bridging fibrosis or cirrhosis, and genotype 1 infection [see Clinical Studies (14)].
 No safety and efficacy data are available for treatment duration lasting longer than one year.    
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
Do not open, crush or break ribavirin capsules. Ribavirin capsules should be taken with food [see
Clinical Pharmacology (12.3)].
2.2 Ribavirin capsules/PegIntron Combination Therapy
Adult Patients
The recommended dose of ribavirin capsules when used in combination with PegIntron is 800 mg to
® 
®
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1,400 mg based on patient body weight in two divided doses (see Table 1). Refer to PegIntron labeling
for PegIntron dosing information.
Duration of Treatment – Interferon Alpha-naïve Patients
The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be
considered in patients who do not achieve at least a 2 log
 drop or loss of hepatitis C virus (HCV)-
RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with
genotype 2 and 3 should be treated for 24 weeks.
Duration of Treatment – Re-treatment with PegIntron/Ribavirin capsules of Prior Treatment Failures
The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV
genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at Week 12 of therapy, or
whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR
and discontinuation of therapy should be considered [see Clinical Studies (14.1)].
Table 1: Recommended Adult Dosing for Ribavirin capsules in Combination with PegIntron
Body Weight (kg) 
Ribavirin capsules Daily
Dose 
Ribavirin Number of Capsules 
Less than 66
800 mg/day
2 x 200 mg capsules AM
2 x 200 mg capsules PM
66 to 80
1,000 mg/day
2 x 200 mg capsules AM
3 x 200 mg capsules PM
81 to 105
1,200 mg/day
3 x 200 mg capsules AM
3 x 200 mg capsules PM
Greater than 105
1,400 mg/day
3 x 200 mg capsules AM
4 x 200 mg capsules PM
Pediatric Patients
Dosing of ribavirin capsules in pediatric patients is determined by body weight. The recommended dose
of ribavirin capsules when used in combination with PegIntron in pediatric patients ages 3 to 17 years is
15 mg/kg/day in two divided doses (see Table 2). Refer to PegIntron labeling for PegIntron dosing
information. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2
and 3 should be treated for 24 weeks.
Table 2: Recommended Pediatric Ribavirin capsules Dosing in Combination with PegIntron
* Ribavirin Oral Solution may be used in any patient regardless of body weight.
Body Weight (kg) 
Ribavirin capsules Daily
Dose 
Ribavirin Number of Capsules 
Less than 47
15 mg/kg/day
Use Ribavirin Oral Solution*
47 to 59
800 mg/day
2 x 200 mg capsules AM
2 x 200 mg capsules PM
60 to 73
1,000 mg/day
2 x 200 mg capsules AM
3 x 200 mg capsules PM
Greater than 73
1,200 mg/day
3 x 200 mg capsules AM
3 x 200 mg capsules PM
10
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2.3 Ribavirin capsules/INTRON A Combination Therapy
Adults
Duration of Treatment – Interferon Alpha-naïve Patients
The recommended dose of ribavirin capsules when used in combination with INTRON A depends on
the patient’s body weight (see Table 3). Refer to Intron A labeling for interferon dosing information.
The recommended duration of treatment for patients previously untreated with interferon is 24 to 48
weeks. The duration of treatment should be individualized to the patient depending on baseline disease
characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage (1.1), 
Adverse Reactions (6.1), and Clinical Studies (14)]. After 24 weeks of treatment, virologic response
should be assessed. Treatment discontinuation should be considered in any patient who has not achieved
an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy
data for treatment duration lasting longer than 48 weeks in the previously untreated patient population.
Duration of Treatment – Re-treatment with INTRON A/Ribavirin capsules in Relapse Patients
In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of
treatment is 24 weeks.
Table 3: Recommended Ribavirin
capsules Dosing in Combination with
INTRON A
Body
Weight
Ribavirin Capsules
At least
75 kg
 2 x 200 mg capsules AM 
 3 x 200 mg capsules PM daily
orally 
Greater than
75 kg
 3 x 200 mg capsules AM 
 3 x 200 mg capsules PM daily
orally 
Pediatrics The recommended dose of ribavirin capsules when used in combination with INTRON A is
15 mg/kg per day orally in two divided doses (see Table 2). Refer to Intron A labeling for interferon
dosing information.
The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24
weeks of treatment, virologic response should be assessed. Treatment discontinuation should be
considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay
by this time. The recommended duration of treatment for pediatric patients with genotype 2 and 3 is 24
weeks.
2.4 Testing Prior to Initiation of Ribavirin capsules
The following laboratory tests are recommended in all patients treated with ribavirin capsules prior to
initiation of treatment and periodically thereafter.
Standard hematologic tests - including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and
as clinically appropriate [see Warnings and Precautions (5.2, 5.6)], complete and differential white
 
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blood cell counts, and platelet count.
 Blood chemistries - liver function tests and TSH.
 Pregnancy - in women of childbearing potential.
 ECG [see Warnings and Precautions (5.2)].
2.5 Dose Modifications
If severe adverse reactions or laboratory abnormalities develop during ribavirin capsules combination
therapy, modify or discontinue the dose until the adverse reaction abates or decreases in severity (see
Table 4) [see Warnings and Precautions (5)]. If intolerance persists after dose adjustment, combination
therapy should be discontinued. Refer to PegIntron labeling for additional information regarding dose
reduction of PegIntron.
Dose reduction in pediatric patients is accomplished by modifying the recommended ribavirin capsules
dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8
mg/kg/day, if needed (see Table 4).
Ribavirin capsules are contraindicated in patients with creatinine clearance less than 50 mL/min [see
Contraindications (4)]. Patients with impaired renal function and those over the age of 50 should be
carefully monitored with respect to development of anemia [see Warnings and Precautions (5.2), Use in
Specific Populations (8.5), and Clinical Pharmacology (12.3)].
Ribavirin capsules should be administered with caution to patients with pre-existing cardiac disease.
Assess cardiovascular status before initiation of treatment and during therapy. If there is any
deterioration of cardiovascular status, discontinue combination therapy [see Warnings and Precautions
(5.2)].
                              
In patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the
hemoglobin decreases by 2 g/dL or more during any 4-week period. If the hemoglobin level remains
below 12 g/dL after 4 weeks on a reduced dose, discontinue combination therapy.
Modify or discontinue ribavirin capsules dosing in any patient whose hemoglobin level falls below 10
g/dL (see Table 4) [see Warnings and Precautions (5.2)].
Table 4: Guidelines for Dose Modification and Discontinuation of Ribavirin capsules in
combination with PegIntron or INTRON A Based on Laboratory Parameters in Adults and
Pediatrics
Laboratory
Parameters 
Reduce Ribavirin
capsules  Daily Dose
(see note 1) if: 
Reduce PegIntron or 
INTRON A Dose 
(see note 2) if: 
Discontinue Therapy if: 
WBC
N/A
1.0 to <1.5 x 10 /L
<1.0 x 10 /L
Neutrophils
N/A
0.5 to <0.75 x 10 /L
<0.5 x 10 /L
Platelets
N/A
25 to < 50 x 10 /L (adults)
<25 x 10 /L (adults)
N/A
50 to <70 x 10 /L (pediatrics)
<50 x 10 /L (pediatrics)
Creatinine
N/A
N/A
>2 mg/dL (pediatrics)
Hemoglobin in
patients without
history of
cardiac disease
8.5 to <10 g/dL
N/A
<8.5 g/dL
Reduce Ribavirin capsules Dose by 200 mg/day and
9
9
9
9
9
9
9
9
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Note 1: Adult patients: 1  dose reduction of ribavirin is by 200 mg/day (except in patients receiving the
1,400 mg, dose reduction should be by 400 mg/day). If needed, 2
 dose reduction of ribavirin is by an
additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg
capsule in the morning and two 200 mg capsules in the evening.
            Pediatric patients: 1  dose reduction of ribavirin is to 12 mg/kg/day, 2
 dose reduction of
ribavirin is to 8 mg/kg/day.
Note 2: Adult patients treated with ribavirin capsules and PegIntron: 1
dose reduction of PegIntron is to
1 mcg/kg/week. If needed, 2
dose reduction of PegIntron is to 0.5 mcg/kg/week.
            Pediatric patients treated with ribavirin capsules and PegIntron: 1
dose reduction of PegIntron is
to 40 mcg/m /week, 2
dose reduction of PegIntron is to 20 mcg/m /week. 
For patients on ribavirin capsules/INTRON A combination therapy: reduce INTRON A dose by 50%.
 Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease
greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly
evaluations and hematology testing.
 These guidelines are for patients with stable cardiac disease. Patients with a history of significant or
unstable cardiac disease should not be treated with PegIntron/ribavirin capsules combination therapy
[see Warnings and Precautions (5.2)].
 
 
PegIntron or INTRON A Dose by Half if: 
 
Hemoglobin in
patients with
history of stable
cardiac
disease
 
≥2 g/dL decrease in hemoglobin during any four-week
period during treatment
<8.5 g/dL or <12 g/dL
after four weeks of dose
reduction
Refer to labeling for INTRON A or PegIntron for additional information about how to reduce an
INTRON A or PegIntron dose.
2.6 Discontinuation of Dosing
Adults In HCV genotype 1, interferon-alfa-naïve patients receiving PegIntron in combination with
ribavirin, discontinue therapy if there is not at least a 2 log
 drop or loss of HCV-RNA at 12 weeks of
therapy, or if HCV-RNA levels remain detectable after 24 weeks of therapy. Regardless of genotype,
previously treated patients who have detectable HCV-RNA at Week 12 or 24 are highly unlikely to
achieve SVR and discontinuation of therapy should be considered.
Pediatrics (3 to 17 years of age) In patients receiving PegIntron/ribavirin capsules combination
(excluding HCV Genotype 2 and 3), discontinue therapy at 12 weeks if HCV-RNA has dropped less
than 2 log
 compared to pretreatment level, or at 24 weeks if HCV-RNA is still detectable.
3 DOSAGE FORMS AND STRENGTHS
Ribavirin Capsules USP, 200 mg are white/white, size ‘1’ hard gelatin capsule filled with white to
off-white granular powder and imprinted with ‘E’ on white cap and ‘81’ on white body with black ink.  
4 CONTRAINDICATIONS
Ribavirin capsules combination therapy is contraindicated in:
pregnancy. Ribavirin capsules may cause fetal harm when administered to a pregnant woman.
Ribavirin capsules are contraindicated in women who are pregnant or planning to become pregnant.
If a patient becomes pregnant while taking ribavirin capsules, the patient should be apprised of the
potential hazard to the fetus [see Warnings and Precautions (5.1), and Use in Specific Populations
st
nd
st
nd
st 
nd 
st 
2
nd 
2
*
†
*†
10
10
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(8.1, 8.3)].
men whose female partners are pregnant [see Use in Specific Populations (8.3)]
patients with known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal
necrolysis, and erythema multiforme to ribavirin or any component of the product
 patients with autoimmune hepatitis
 patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
 patients with creatinine clearance less than 50 mL/min [see Clinical Pharmacology (12.3)]
 when coadministered with didanosine because exposure to the active metabolite of didanosine
(dideoxyadenosine 5’-triphosphate) is increased. Fatal hepatic failure, as well as peripheral
neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, has been reported in
patients receiving didanosine in combination with ribavirin [see Drug Interactions (7.1)].   
5 WARNINGS AND PRECAUTIONS
5.1 Embryo-Fetal Toxicity
Ribavirin capsules may cause birth defects, miscarriage or stillbirth. Ribavirin therapy should not be
started until a report of a negative pregnancy test has been obtained immediately prior to planned
initiation of therapy. Patients should use effective contraception and have periodic monitoring with
pregnancy tests during treatment and during the 6-month period after treatment has been stopped.
Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients.
Ribavirin has demonstrated significant teratogenic and embryocidal effects in all animal species tested.
These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin
[see Boxed Warning, Contraindications (4), and Use in Specific Populations (8.1, 8.3)].
5.2 Anemia
Hemolytic anemia was observed in approximately 10% of ribavirin/INTRON A-treated subjects in
clinical trials. The anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy.
Because the initial drop in hemoglobin may be significant, obtain hemoglobin or hematocrit levels
before the start of treatment and at Week 2 and Week 4 of therapy, or more frequently if clinically
indicated. Patients should then be followed as clinically appropriate [see Dosage and Administration
(2.5, 2.6)].
Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin.
Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy.
Patients with pre-existing cardiac disease should have electrocardiograms administered before
treatment and should be appropriately monitored during therapy. If there is any deterioration of
cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (2.5,
2.6)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of
significant or unstable cardiac disease should not use ribavirin.
5.3 Pancreatitis
Suspend ribavirin and INTRON A or PegIntron combination therapy in patients with signs and symptoms
of pancreatitis and discontinue in patients with confirmed pancreatitis.
5.4 Pulmonary Disorders
Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension,
and pneumonia, have been reported during ribavirin with alpha interferon combination therapy;
occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of
sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function
impairment, closely monitor the patient, and if appropriate, discontinue combination therapy.
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5.5 Ophthalmologic Disorders
Ribavirin is used in combination therapy with INTRON A or PegIntron. Refer to labeling for PegIntron
for additional information.
5.6 Laboratory Tests
PegIntron in combination with ribavirin may cause severe decreases in neutrophil and platelet counts,
and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.
Obtain hematology and blood chemistry testing in patients on PegIntron/ribavirin combination therapy
before the start of treatment and then periodically thereafter. In the adult clinical trial, complete blood
counts (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT,
bilirubin, and uric acid) were measured during the treatment period at Weeks 2, 4, 8, 12, and then at 6-
week intervals, or more frequently if abnormalities developed. In pediatric subjects, the same laboratory
parameters were evaluated with additional assessment of hemoglobin at treatment Week 6. TSH levels
were measured every 12 weeks during the treatment period. HCV-RNA should be measured
periodically during treatment [see Dosage and Administration (2)].
5.7 Dental and Periodontal Disorders
Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or
peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and
mucous membranes of the mouth during long-term treatment with the combination of ribavirin and
pegylated or nonpegylated interferon alfa-2b. Advise patients to brush their teeth thoroughly twice
daily and have regular dental examinations. If vomiting occurs, advise patients to rinse out their mouth
thoroughly afterwards.
5.8 Concomitant Administration of Azathioprine
Pancytopenia (marked decreases in red blood cells, neutrophils, and platelets) and bone marrow
suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant
administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8),
myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and
concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Discontinue
PegIntron, ribavirin, and azathioprine for pancytopenia, and do not reintroduce pegylated
interferon/ribavirin with concomitant azathioprine [see Drug Interactions (7.4)].
5.9 Impact on Growth in Pediatric Patients
Data on the effects of PegIntron and ribavirin on growth come from an open-label study in subjects 3
through 17 years of age, in which weight and height changes were compared to U.S. normative
population data. In general, the weight and height gain of pediatric subjects treated with PegIntron and
ribavirin lagged behind that predicted by normative population data for the entire length of treatment.
Severely inhibited growth velocity (less than 3
percentile) was observed in 70% of the subjects while
on treatment. Following treatment, rebound growth and weight gain occurred in most subjects. Long-
term follow-up data in pediatric subjects, however, indicates that PegIntron in combination therapy with
ribavirin may induce a growth inhibition that results in reduced adult height in some patients [see Adverse
Reactions (6.1)].
Similarly, an impact on growth was seen in subjects after treatment with ribavirin and INTRON A
combination therapy for one year. In a long-term follow-up trial of a limited number of these subjects,
combination therapy resulted in reduced final adult height in some subjects [see Adverse Reactions (6.1)].
5.10 Not Recommended for Monotherapy and Risks Associated with Combination Therapy
Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic
rd 
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hepatitis C virus infection; therefore, ribavirin capsules must not be used alone. The safety and efficacy
of ribavirin capsules have only been established when used together with INTRON A or PegIntron (not
other interferons) as combination therapy.
The safety and efficacy of ribavirin with INTRON A or PegIntron combination therapy for the treatment
of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established.
Ribavirin capsules should not be used for these indications.
There are significant adverse reactions caused by ribavirin/INTRON A or PegIntron combination
therapy, including severe depression and suicidal or homicidal ideation, hemolytic anemia, suppression
of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and
diabetes. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily
adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up.
Labeling for INTRON A and PegIntron should be reviewed in their entirety for additional safety
information prior to initiation of combination treatment.
6 ADVERSE REACTIONS
The following serious adverse drug reactions are discussed in other sections of the labeling:
Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)]
Anemia [see Warnings and Precautions (5.2)]
Pancreatitis [see Warnings and Precautions (5.3)]
Pulmonary Disorders [see Warnings and Precautions (5.4)]
Ophthalmic Disorders [see Warnings and Precautions (5.5)]
Dental and Periodontal Disorders [see Warnings and Precautions (5.7)]
Impact on Growth in Pediatric Patients [see Warnings and Precautions (5.9)]   
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
and may not reflect the rates observed in clinical practice.
Clinical trials with ribavirin in combination with PegIntron or INTRON A have been conducted in over
7,800 subjects from 3 to 76 years of age.
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within
the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred
in approximately 10% of patients [see Warnings and Precautions (5.2)].
Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most
commonly reported adverse reactions in adult subjects receiving PegIntron or INTRON A in
combination with ribavirin were injection site inflammation/reaction, fatigue/asthenia, headache, rigors,
fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in
pediatric subjects, ages 3 and older, receiving ribavirin in combination with PegIntron or INTRON A
were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.
The Adverse Reactions section references the following clinical trials:
Ribavirin/PegIntron Combination therapy trials:
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Clinical Study 1 – evaluated PegIntron monotherapy (not further described in this label; see
labeling for PegIntron for information about this trial).
Study 2 – evaluated ribavirin 800 mg/day flat dose in combination with 1.5 mcg/kg/week
PegIntron or with INTRON A.
Study 3 – evaluated PegIntron/weight-based ribavirin in combination with PegIntron/flat dose
ribavirin regimen.
Study 4 – compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination
with ribavirin and a third treatment group receiving Pegasys
(180 mcg/week)/Copegus
(1000
to 1200 mg/day).
Study 5 – evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based ribavirin in
prior treatment failure subjects.
PegIntron/Ribavirin Combination Therapy in Pediatric Patients
Ribavirin/INTRON A Combination Therapy trials for adults and pediatrics
Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with
PegIntron with or without ribavirin [see Boxed Warning, Warnings and Precautions (5)]. The most
common serious events occurring in subjects treated with PegIntron and ribavirin were depression and
suicidal ideation [see Warnings and Precautions (5.10)], each occurring at a frequency of less than 1%.
Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents,
compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up [see Warnings
and Precautions (5.10)]. The most common fatal reaction occurring in subjects treated with PegIntron
and ribavirin was cardiac arrest, suicidal ideation, and suicide attempt [see Warnings and Precautions
(5.10)], all occurring in less than 1% of subjects.
Adverse Reaction - Ribavirin/PegIntron Combination Therapy
Adult Subjects
Adverse reactions that occurred in the clinical trial at greater than 5% incidence are provided by
treatment group from the ribavirin/PegIntron Combination Therapy (Study 2) in Table 5.
Table 5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects
Adverse Reactions 
Percentage of Subjects
Reporting Adverse Reactions* 
Adverse Reactions 
Percentage of Subjects
Reporting Adverse Reactions* 
PegIntron 
1.5
mcg/kg/Ribavirin
(N=511)
INTRON
A/Ribavirin
(N=505)
PegIntron 
1.5
mcg/kg/Ribavirin
  (N=511)
INTRON
A/Ribavirin
(N=505)
Application Site 
 
Musculoskeletal 
 
    Injection Site
Inflammation
 
    Injection Site
Reaction
25
 
58
18
 
36
    Myalgia
56
50
    Arthralgia
34
28
Autonomic Nervous
System 
 
    Musculoskeletal
Pain
21
19
    Dry Mouth
12
8
Psychiatric 
 
    Increased
Sweating
11
7
    Insomnia
40
41
    Flushing
4
3
    Depression
31
34
Anxiety/Emotional
® 
® 
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A subject may have reported more than one adverse reaction within a body system/organ class
category.
Body as a Whole 
 
    Anxiety/Emotional
    Lability/Irritability
47
47
    Fatigue/Asthenia
66
63
    Concentration
Impaired
17
21
    Headache
62
58
    Agitation
8
5
    Rigors
48
41
    Nervousness
6
6
    Fever
46
33
Reproductive,
Female 
 
    Weight Loss
29
20
    Menstrual
Disorder
7
6
    Right Upper
Quadrant Pain
12
6
Resistance
Mechanism 
 
    Chest Pain
8
7
    Viral Infection
12
12
    Malaise
4
6
    Fungal Infection
6
1
Central/Peripheral Nervous System 
Respiratory System
 
    Dizziness
21
17
    Dyspnea
26
24
Endocrine 
 
    Coughing
23
16
    Hypothyroidism
5
4
    Pharyngitis
12
13
Gastrointestinal 
 
    Rhinitis
8
6
    Nausea
43
33
    Sinusitis
6
5
    Anorexia
32
27
Skin and
Appendages 
 
    Diarrhea
22
17
    Alopecia
36
32
    Vomiting
14
12
    Pruritus
29
28
    Abdominal Pain
13
13
    Rash
24
23
    Dyspepsia
9
8
    Skin Dry
24
23
    Constipation
5
5
Special Senses,
Other 
 
Hematologic
Disorders 
 
    Taste Perversion
9
4
    Neutropenia
26
14
Vision Disorders 
 
    Anemia
12
17
    Vision Blurred
5
6
    Leukopenia
6
5
    Conjunctivitis
4
5
    Thrombocytopenia
5
2
 
Liver and Biliary
System 
 
    Hepatomegaly
4
4
Table 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or
equal to 10% incidence.
Table 6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence) By
Descending Frequency
 
Study 4 
Percentage of Subjects Reporting Treatment-Related Adverse Reactions 
Adverse Reactions 
PegIntron 1.5 mcg/kg
with  Ribavirin 
(N=1019) 
PegIntron 1 mcg/kg
with  Ribavirin
(N=1016) 
Pegasys 180 mcg with
Copegus 
(N=1035) 
    Fatigue
67
68
64
* 
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    Headache
50
47
41
    Nausea
40
35
34
    Chills
39
36
23
    Insomnia
38
37
41
    Anemia
35
30
34
    Pyrexia
35
32
21
    Injection Site Reactions
34
35
23
    Anorexia
29
25
21
    Rash
29
25
34
    Myalgia
27
26
22
    Neutropenia
26
19
31
    Irritability
25
25
25
    Depression
25
19
20
    Alopecia
23
20
17
    Dyspnea
21
20
22
    Arthralgia
21
22
22
    Pruritus
18
15
19
    Influenza-like Illness
16
15
15
    Dizziness
16
14
13
    Diarrhea
15
16
14
    Cough
15
16
17
    Weight Decreased
13
10
10
    Vomiting
12
10
9
    Unspecified Pain
12
13
9
    Dry Skin
11
11
12
    Anxiety
11
11
10
    Abdominal Pain
10
10
10
    Leukopenia
9
7
10
The incidence of serious adverse reactions was comparable in all trials. In Study 2, the incidence of
serious adverse reactions was 17% in the PegIntron/ribavirin groups compared to 14% in the INTRON
A/ribavirin group. In Study 3, there was a similar incidence of serious adverse reactions reported for
the weight-based ribavirin group (12%) and for the flat-dose ribavirin regimen.
In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy.
Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up
period. In Study 2, many subjects continued to experience adverse reactions several months after
discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing
adverse reactions by body class in the PegIntron 1.5/ribavirin group was 33% (psychiatric), 20%
(musculoskeletal), and 10% (for endocrine and for GI). In approximately 10 to 15% of subjects, weight
loss, fatigue, and headache had not resolved.
There have been 28 subject deaths that occurred during treatment or follow-up in Studies 2, 3, and 4. In
Study 2, there was 1 suicide in a subject receiving PegIntron/ribavirin combination therapy; and 1 subject
death in the INTRON A/ribavirin group (motor vehicle accident). In Study 3, there were 14 deaths, 2 of
which were probable suicides and 1 was an unexplained death in a person with a relevant medical
history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects who received
PegIntron/ribavirin combination therapy, 5 in the PegIntron 1.5 mcg/ribavirin arm (N=1019) and 1 in the
PegIntron 1 mcg/ribavirin arm (N=1016), and 6 of which occurred in subjects receiving
Pegasys/Copegus (N=1035); there were 3 suicides that occurred during the off treatment follow-up
period in subjects who received PegIntron (1.5 mcg/kg)/ribavirin combination therapy.
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In Studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with ribavirin,
discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON
A in combination with ribavirin. In Study 3, 15% of subjects receiving PegIntron in combination with
weight-based ribavirin and 14% of subjects receiving PegIntron with flat-dose ribavirin discontinued
therapy due to an adverse reaction. The most common reasons for discontinuation were related to known
interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse
reactions. In Study 4, 13% of subjects in the PegIntron 1.5 mcg/ribavirin arm, 10% in the PegIntron 1
mcg/ribavirin arm, and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.
In Study 2, dose reductions for ribavirin were similar across all three groups [see Clinical Studies
(14.1)], 33 to 35%. The most common reasons for dose modifications were neutropenia (18%), or
anemia (9%) (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and
thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently
with weight-based ribavirin dosing compared to flat dosing (29% and 23%, respectively). In Study 4,
16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with ribavirin, with an
additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events
compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135
mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring a second dose
reduction to 90 mcg/week with Pegasys.
In the PegIntron/ribavirin combination trials the most common adverse reactions were psychiatric, which
occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric
adverse reactions included most commonly depression, irritability, and insomnia, each reported by
approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and
suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation
[see Warnings and Precautions (5)]. In Study 4, psychiatric adverse reactions occurred in 58% of
subjects in the PegIntron 1.5 mcg/ribavirin arm, 55% of subjects in the PegIntron 1 mcg/ribavirin arm,
and 57% of subjects in the Pegasys 180 mcg/Copegus arm.
In Study 2, PegIntron/ribavirin combination therapy induced fatigue or headache in approximately two-
thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of
these systemic symptoms (e.g., fever and headache) tended to decrease as treatment continued.
Subjects receiving ribavirin/PegIntron as re-treatment after failing a previous interferon combination
regimen reported adverse reactions similar to those previously associated with this regimen during
clinical trials of treatment-naïve subjects.
Pediatric Subjects
In general, the adverse reaction profile in the pediatric population was similar to that observed in adults.
In the pediatric trial, the most prevalent adverse reactions were pyrexia (80%), headache (62%),
neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%).
The majority of adverse reactions were mild or moderate in severity. Severe adverse reactions were
reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%),
headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this
subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and
depression (1%; 1/107). Five subjects received levothyroxine treatment, three with clinical
hypothyroidism and two with asymptomatic TSH elevations. Weight and height gain of pediatric
subjects treated with PegIntron plus ribavirin lagged behind that predicted by normative population data
for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was
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observed in 70% of the subjects while on treatment.
Dose modifications of PegIntron and/or ribavirin were required in 25% of subjects due to treatment-
related adverse reactions, most commonly for anemia, neutropenia and weight loss. Two subjects (2%;
2/107) discontinued therapy as the result of an adverse reaction.
Adverse reactions that occurred with a greater than or equal to 10% incidence in the pediatric trial
subjects are provided in Table 7.
Table 7: Percentage of Pediatric Subjects with Treatment-Related Adverse
Reactions (in At Least 10% of All Subjects)
System Organ Class
     Preferred Term
All Subjects 
(N=107)
Blood and Lymphatic System Disorders 
    Neutropenia
33%
    Anemia
11%
    Leukopenia
10%
Gastrointestinal Disorders 
    Abdominal Pain
21%
    Abdominal Pain Upper
12%
    Vomiting
27%
    Nausea
18%
General Disorders and Administration Site Conditions 
    Pyrexia
80%
    Fatigue
30%
    Injection-site Erythema
29%
    Chills
21%
    Asthenia
15%
    Irritability
14%
Investigations 
    Weight Loss
19%
Metabolism and Nutrition Disorders 
    Anorexia
29%
    Decreased Appetite
22%
Musculoskeletal and Connective Tissue Disorders 
    Arthralgia
17%
    Myalgia
17%
Nervous System Disorders 
    Headache
62%
    Dizziness
14%
Skin and Subcutaneous Tissue Disorders 
    Alopecia
17%
Ninety-four of 107 subjects enrolled in a 5-year follow-up trial. The long-term effects on growth were
less in subjects treated for 24 weeks than in those treated for 48 weeks. Twenty-four percent of
subjects (11/46) treated for 24 weeks and 40% of subjects (19/48) treated for 48 weeks had a >15
percentile height-for-age decrease from pre-treatment baseline to the end of 5-year follow-up. Eleven
percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks had a
>30 percentile height-for-age decrease from pre-treatment baseline to the end of the 5-year follow-up.
While observed across all age groups, the highest risk for reduced height at the end of long-term
follow-up appeared to be initiation of combination therapy during the years of expected peak growth
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velocity [see Warnings and Precautions (5.9)].
Laboratory Values
Adult and Pediatric Subjects
 
The adverse reaction profile in Study 3, which compared PegIntron/weight-based ribavirin combination
to a PegIntron/flat dose ribavirin regimen, revealed an increased rate of anemia with weight-based
dosing (29% vs. 19% for weight-based vs. flat dose regimens, respectively). However, the majority of
cases of anemia were mild and responded to dose reductions.
Changes in selected laboratory values during treatment in combination with ribavirin treatment are
described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose
reduction or permanent discontinuation from therapy [see Dosage and Administration (2.5)]. Changes in
selected laboratory values during therapy are described in Table 8. Most of the changes in laboratory
values in the PegIntron/ribavirin trial with pediatrics were mild or moderate.
Table 8: Selected Laboratory Abnormalities During Treatment with Ribavirin and PegIntron or
Ribavirin and INTRON A in Previously Untreated Subjects
Laboratory Parameters  
Percentage of Subjects 
Adults (Study 2) 
Pediatrics 
PegIntron/ 
Ribavirin 
(N=511)
INTRON A/
Ribavirin 
(N=505)
PegIntron/Ribavirin
(N=107)  
Hemoglobin (g/dL) 
    9.5 to <11.0
26
27
30
    8.0 to <9.5
3
3
2
    6.5 to 7.9
0.2
0.2
-
Leukocytes (x 10 /L) 
    2.0 to 2.9
46
41
39
    1.5 to <2.0
24
8
3
    1.0 to 1.4
5
1
-
Neutrophils (x 10 /L) 
    1.0 to 1.5
33
37
35
    0.75 to <1.0
25
13
26
    0.5 to <0.75
18
7
13
    <0.5
4
2
3
Platelets (x 10 /L) 
    70 to 100
15
5
1
    50 to <70
3
0.8
-
    30 to 49
0.2
0.2
-
    25 to <50
-
-
1
Total Bilirubin                                                             (mg/dL) 
(µmole/L) 
    1.5 to 3.0
10
13
-
    1.26 to 2.59 x ULN  
-
-
7
    3.1 to 6.0
0.6
0.2
-
    2.6 to 5 x ULN  
-
-
-
    6.1 to 12.0
0
0.2
-
ALT (U/L) 
    2 x Baseline
0.6
0.2
1
    2.1 to 5 x Baseline
3
1
5
*
*
9
9
9
†
†
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* The table summarizes the worst category observed within the period per subject per laboratory test.
Only subjects with at least one treatment value for a given laboratory test are included.
 ULN=Upper limit of normal.
    5.1 to 10 x Baseline
0
0
3
Hemoglobin. In Study 2, hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects. In
Study 3, 47% of subjects receiving weight-based dosing of ribavirin and 33% on flat-dose ribavirin had
decreases in hemoglobin levels to less than 11 g/dL. Reductions in hemoglobin to less than 9 g/dL
occurred more frequently in subjects receiving weight-based dosing compared to flat dosing (4% and
2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the
PegIntron/ribavirin and INTRON A/ribavirin groups. In Study 4, subjects receiving PegIntron (1.5
mcg/kg)/ribavirin had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to
less than 8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases
occurred in 26% and 4% of subjects, respectively. On average, hemoglobin levels became stable by
treatment Weeks 4 to 6. The typical pattern observed was a decrease in hemoglobin levels by treatment
Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment [see
Dosage and Administration (2.5)].
Neutrophils. In Study 2, decreases in neutrophil counts were observed in a majority of adult subjects
treated with PegIntron/ribavirin (85%) and INTRON A/ribavirin (60%). Severe, potentially life-
threatening neutropenia (less than 0.5 x 10 /L) occurred in approximately 4% of subjects treated with
PegIntron/ribavirin and 2% of subjects treated with INTRON A/ribavirin. Eighteen percent of subjects
receiving PegIntron/ribavirin required modification of interferon dosage. Few subjects (less than 1%)
required permanent discontinuation of treatment. Neutrophil counts generally returned to pre-treatment
levels 4 weeks after cessation of therapy [see Dosage and Administration (2.5)].
Platelets. In Study 2, platelet counts decreased to less than 100,000/mm in approximately 20% of
subjects treated with PegIntron alone or with ribavirin and in 6% of adult subjects treated with INTRON
A/ribavirin. Severe decreases in platelet counts (less than 50,000/mm ) occur in less than 4% of adult
subjects. In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PegIntron,
respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of
therapy [see Dosage and Administration (2.5)].
Thyroid Function. In Study 2, clinically apparent thyroid disorders occurred among subjects treated with
either INTRON A or PegIntron (with or without ribavirin) at a similar incidence (5% for
hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while
on treatment and during the follow-up period. At the end of the follow-up period, 7% of subjects still
had abnormal TSH values.
Bilirubin and Uric Acid. In Study 2, 10 to 14% of subjects developed hyperbilirubinemia and 33 to 38%
developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout.
Adverse Reactions with Ribavirin/INTRON A Combination Therapy
Adult Subjects
In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued
therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon-only
arms. Selected treatment-related adverse reactions that occurred in the U.S.  trials with incidence 5% or
greater are provided by treatment group (see Table 9). In general, the selected treatment-related adverse
reactions were reported with lower incidence in the international trials as compared to the U.S. trials,
except for asthenia, influenza-like symptoms, nervousness, and pruritus.
†
9
3 
3
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p
,
y p
,
,
p
Pediatric Subjects
In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse
reactions. Dose modifications were required in 30% of subjects, most commonly for anemia and
neutropenia. In general, the adverse-reaction profile in the pediatric population was similar to that
observed in adults. Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred
more frequently in pediatric subjects compared to adult subjects. Conversely, pediatric subjects
experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea,
and pruritus compared to adult subjects. Selected treatment-related adverse reactions that occurred with
incidence 5% or greater among all pediatric subjects who received the recommended dose of
ribavirin/INTRON A combination therapy are provided in Table 9.
Table 9: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse
Adult Subjects and Previously Untreated Pediatric Subjects
Subjects 
Reporting 
Adverse 
Reactions* 
Percentage of Subjects 
U.S. Previously Untreated Study 
U.S. Relapse Study 
Pediatric
Subjects 
24 weeks of treatment 
48 weeks of
treatment 
24 weeks of treatment 
48 weeks
of 
treatment 
INTRON
A/ 
Ribavirin
(N=228) 
INTRON
A/ 
 Placebo 
 (N=231) 
INTRON
A/
Ribavirin
(N=228) 
INTRON
A/
Placebo 
(N=225) 
INTRON
A/
Ribavirin 
 (N=77) 
INTRON
A/
Placebo 
 (N=76) 
INTRON
A/
Ribavirin
(N=118) 
Application Site Disorders 
    Injection Site
    Inflammation 
13
10
12
14
6
8
14
    Injection Site
Reaction 
7
9
8
9
5
3
19
Body as a Whole - General Disorders 
    Headache 
63
63
66
67
66
68
69
    Fatigue 
68
62
70
72
60
53
58
    Rigors 
40
32
42
39
43
37
25
    Fever 
37
35
41
40
32
36
61
    Influenza-like
Symptoms 
14
18
18
20
13
13
31
    Asthenia 
9
4
9
9
10
4
5
    Chest Pain 
5
4
9
8
6
7
5
Central & Peripheral Nervous System Disorders 
    Dizziness 
17
15
23
19
26
21
20
Gastrointestinal System Disorders 
    Nausea
38
35
46
33
47
33
33
    Anorexia
27
16
25
19
21
14
51
    Dyspepsia
14
6
16
9
16
9
<1
    Vomiting
11
10
9
13
12
8
42
Musculoskeletal System Disorders 
    Myalgia
61
57
64
63
61
58
32
    Arthralgia
30
27
33
36
29
29
15
    Musculoskeletal
20
26
28
32
22
28
21
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* Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse
reaction within a body system/organ class category.
Pain
20
26
28
32
22
28
21
Psychiatric Disorders 
    Insomnia 
39
27
39
30
26
25
14
    Irritability 
23
19
32
27
25
20
10
    Depression 
32
25
36
37
23
14
13
    Emotional
   Lability 
7
6
11
8
12
8
16
    Concentration   
Impaired 
11
14
14
14
10
12
5
    Nervousness 
4
2
4
4
5
4
3
Respiratory System Disorders 
    Dyspnea
19
9
18
10
17
12
5
    Sinusitis
9
7
10
14
12
7
<1
Skin and Appendages Disorders 
    Alopecia 
28
27
32
28
27
26
23
    Rash 
20
9
28
8
21
5
17
    Pruritus 
21
9
19
8
13
4
12
Special Senses, Other Disorders 
    Taste
Perversion 
7
4
8
4
6
5
<1
During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile
assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment
decrease of 9%). A general reversal of these trends was noted during the 24-week post-treatment
period. Long-term data in a limited number of patients, however, suggests that combination therapy may
induce a growth inhibition that results in reduced final adult height in some patients [see Warnings and
Precautions (5.9)].
Laboratory Values
Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets)
during therapy are described below (see Table 10).
Hemoglobin. Hemoglobin decreases among subjects receiving ribavirin therapy began at Week 1, with
stabilization by Week 4. In previously untreated subjects treated for 48 weeks, the mean maximum
decrease from baseline was 3.1 g/dL in the U.S. trial and 2.9 g/dL in the international trial. In relapse
subjects, the mean maximum decrease from baseline was 2.8 g/dL in the U.S. trial and 2.6 g/dL in the
international trial. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation
of therapy in most subjects.
Bilirubin and Uric Acid. Increases in both bilirubin and uric acid, associated with hemolysis, were noted
in clinical trials. Most changes were moderate and reversed within 4 weeks after treatment
discontinuation. This observation occurred most frequently in subjects with a previous diagnosis of
Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.
Table 10: Selected Laboratory Abnormalities During Treatment with Ribavirin and INTRON A:
Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects
 
Percentage of Subjects 
U S Previously Untreated Study
U S Relapse Study
Pediatric
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U.S. Previously Untreated Study 
U.S. Relapse Study 
Subjects 
24 weeks of treatment 48 weeks of treatment24 weeks of treatment 48 weeks of
treatment 
INTRON A/
 Ribavirin 
 (N=228)
INTRON
A/ 
Placebo 
(N=231)
INTRON
A/ 
Ribavirin
(N=228)
INTRON
A/ 
Placebo 
(N=225)
INTRON
A/ 
Ribavirin
(N=77)
INTRON
A/ 
Placebo 
(N=76)
INTRON A/ 
Ribavirin 
(N=118)
Hemoglobin (g/dL) 
    9.5 to 10.9 
24
1
32
1
21
3
24
    8.0 to 9.4 
5
0
4
0
4
0
3
    6.5 to 7.9 
0
0
0
0.4
0
0
0
    <6.5 
0
0
0
0
0
0
0
Leukocytes  (x 10 /L) 
    2.0 to 2.9 
40
20
38
23
45
26
35
    1.5 to 1.9 
4
1
9
2
5
3
8
    1.0 to 1.4 
0.9
0
2
0
0
0
0
    <1.0
0
0
0
0
0
0
0
Neutrophils (x 10 /L) 
    1.0 to 1.49 
30
32
31
44
42
34
37
    0.75 to 0.99 
14
15
14
11
16
18
15
    0.5 to 0.74 
9
9
14
7
8
4
16
    <0.5 
11
8
11
5
5
8
3
Platelets (x 10 /L) 
    70 to 99 
9
11
11
14
6
12
0.8
    50 to 69 
2
3
2
3
0
5
2
    30 to 49 
0
0.4
0
0.4
0
0
0
    <30 
0.9
0
1
0.9
0
0
0
Total Bilirubin (mg/dL) 
    1.5 to 3.0
27
13
32
13
21
7
2
    3.1 to 6.0
0.9
0.4
2
0
3
0
0
    6.1 to 12.0 
0
0
0.4
0
0
0
0
      >12.0 
0
0
0
0
0
0
0
6.2 Postmarketing Experiences
The following adverse reactions have been identified and reported during post approval use of
ribavirin in combination with INTRON A or PegIntron. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure. 
Blood and Lymphatic System disorders 
    Pure red cell aplasia, aplastic anemia 
Ear and Labyrinth disorders
    Hearing disorder, vertigo
Respiratory, Thoracic and Mediastinal disorders 
    Pulmonary hypertension
Eye disorders 
    Serous retinal detachment 
Endocrine disorders 
    Diabetes
9
9
9
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7 DRUG INTERACTIONS
7.1 Didanosine
Exposure to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when
didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities; therefore,
coadministration of ribavirin capsules and didanosine is contraindicated [see Contraindications (4)].
Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic
hyperlactatemia/lactic acidosis have been reported in clinical trials.
7.2 Nucleoside Analogues
Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving
combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Patients receiving
interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely
monitored for treatment-associated toxicities, especially hepatic decompensation and anemia.
Discontinuation of NRTIs should be considered as medically appropriate (see labeling for individual
NRTI product). Dose reduction or discontinuation of interferon, ribavirin, or both should also be
considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g.,
Child-Pugh greater than 6).
Ribavirin may antagonize the cell culture antiviral activity of stavudine and zidovudine against HIV.
Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, stavudine, and
zidovudine, which could lead to decreased antiretroviral activity. However, in a study with another
pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or
intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of
HIV/HCV virologic suppress) interaction was observed when ribavirin and lamivudine (n=18),
stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multidrug regimen in HIV/HCV
co-infected subjects. Concomitant use of ribavirin with any of these drugs should be done with caution.
7.3 Drugs Metabolized by Cytochrome P-450
Results of in vitro studies using both human and rat liver microsome preparations indicated little or no
cytochrome P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-450 enzyme-
based drug interactions.
No pharmacokinetic interactions were noted between INTRON A and ribavirin capsules in a multiple-
dose pharmacokinetic study.
7.4 Azathioprine
The use of ribavirin for the treatment of chronic hepatitis C in patients receiving azathioprine has been
reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity.
Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of
azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine
metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity
(neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have
complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly
for the second and third months of treatment, then monthly or more frequently if dosage or other therapy
changes are necessary [see Warnings and Precautions (5.8)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
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Risk Summary
Ribavirin is contraindicated for use in pregnant women and in men whose female partners are pregnant
[see Contraindications (4)]. Based on animal data, ribavirin use in pregnancy may be associated with birth
defects. Data from the Ribavirin Pregnancy Registry are insufficient to identify a drug-associated risk
of birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Ribavirin is known to
accumulate in intracellular components from where it is cleared very slowly. In animal studies, ribavirin
exposure was shown to have teratogenic and/or embryocidal effects (see Data).
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated
background risk of major birth defects and miscarriage for the indicated population is unknown. In the
U.S. general population, the estimated background risk of major birth defects and miscarriage is 2 to 4%
and 15 to 20%, respectively.
Data
Human Data
Available data from the Ribavirin Pregnancy Registry on 88 live births from pregnancies in women
directly exposed and 98 live births from pregnancies in women indirectly exposed (by a male partner) to
ribavirin during pregnancy or during the 6 months prior to pregnancy show a higher rate of birth defects
(9.09% and 6.12%, respectively) compared to a background birth defect rate of 2.72% in the
Metropolitan Atlanta Congenital Defects Program (MACDP) birth defects surveillance system. No
pattern of birth defects can be identified from these reports. The miscarriage rate was approximately
21%. The current sample size is insufficient for reaching definitive conclusions based on statistical
analysis. Trends suggesting a common etiology or relationship with ribavirin exposure were not
observed. Methodologic limitations of the Ribavirin Pregnancy Registry include the use of MACDP as
the external comparator group. Limitations of using an external comparator include differences in
methodology and populations, as well as confounding due to the underlying disease and comorbidities.
Animal Data
Embryotoxicity/teratogenicity studies with ribavirin were conducted in rats (oral doses of 0.3, 1 and 10
mg/kg on Gestation Days 6 to 15) and rabbits (oral dose of 0.1, 0.3 and 1 mg/kg on Gestation Days 6 to
18). Ribavirin demonstrated significant embryocidal and teratogenic effects at doses well below the
recommended human dose in all animal species in which adequate studies have been conducted.
Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The
incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of
fetuses and offspring was reduced [see Contraindications (4) and Warnings and Precautions (5.1)].
8.2 Lactation
Risk Summary
There are no data on the presence of ribavirin in human milk or the effects on the breastfed infant or
milk production. The developmental and health benefits of breastfeeding should be considered along
with the mother’s clinical need for ribavirin and any potential adverse effects on the breastfed infant
from ribavirin or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential
Ribavirin may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations
(8.1)].
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Pregnancy Testing
Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained
immediately prior to planned initiation of treatment. Patients should have periodic pregnancy tests during
treatment and during the 6-month period after treatment has been stopped [see Warnings and Precautions
(5.1)].
Contraception
Females of reproductive potential should use effective contraception during treatment and for 6 months
post-therapy based on a multiple-dose half-life (t
) of ribavirin of 12 days (e.g., 15 half-lives for
ribavirin clearance from the body).
Male patients and their female partners should use effective contraception during treatment with
ribavirin and for the 6-month post-therapy period [see Warnings and Precautions (5.1)].
Infertility
Based on animal data, ribavirin may impair male fertility. In animal studies, these effects were mostly
reversible within a few months after drug cessation [see Nonclinical Toxicology (13.1)].    
8.4 Pediatric Use
Safety and effectiveness of ribavirin in combination with PegIntron has not been established in pediatric
patients below the age of 3 years. For treatment with ribavirin/INTRON A, evidence of disease
progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response,
HCV genotype and viral load should be considered when deciding to treat a pediatric patient. The
benefits of treatment should be weighed against the observed safety findings.
Long-term follow-up data in pediatric subjects indicates that ribavirin in combination with PegIntron or
with INTRON A may induce a growth inhibition that results in reduced height in some patients
[see Warnings and Precautions (5.9) and Adverse Reactions (6.1)].
Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily
adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-
up [see Warnings and Precautions (5.10)]. As in adult patients, pediatric patients experienced other
psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia
[see Warnings and Precautions (5.2)].  
8.5 Geriatric Use
Clinical trials of ribavirin combination therapy did not include sufficient numbers of subjects aged 65
and over to determine if they respond differently from younger subjects.
Ribavirin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly patients often have decreased
renal function, care should be taken in dose selection. Renal function should be monitored and dosage
adjustments made accordingly. Ribavirin should not be used in patients with creatinine clearance less
than 50 mL/min [see Contraindications (4)].
1/2
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In general, ribavirin capsules should be administered to elderly patients cautiously, starting at the lower
end of the dosing range, reflecting the greater frequency of decreased hepatic and cardiac function, and
of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency
of anemia (67%) than younger patients (28%) [see Warnings and Precautions (5.2)].  
8.6 Organ Transplant Recipients
The safety and efficacy of INTRON A and PegIntron alone or in combination with ribavirin for the
treatment of hepatitis C in liver or other organ transplant recipients have not been established. In a small
(n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving
interferon alpha and ribavirin combination therapy was more frequent than expected from the center’s
previous experience with renal allograft recipients not receiving combination therapy. The relationship
of the renal failure to renal allograft rejection is not clear.
8.7 HIV or HBV Co-infection
The safety and efficacy of PegIntron/ribavirin and INTRON A/ribavirin for the treatment of patients
with HCV co-infected with HIV or HBV have not been established.
10 OVERDOSAGE
There is limited experience with overdosage. Acute ingestion of up to 20 g of ribavirin capsules,
INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times
the recommended doses have been reported. Primary effects that have been observed are increased
incidence and severity of the adverse reactions related to the therapeutic use of INTRON A and
ribavirin. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction
have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing
recommendations.
There is no specific antidote for INTRON A or ribavirin overdose, and hemodialysis and peritoneal
dialysis are not effective for treatment of overdose of these agents.  
11 DESCRIPTION
Ribavirin, is a synthetic nucleoside analogue (purine analogue). The chemical name of ribavirin is 1-β-
D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula (see Figure
1).
Figure 1: Structural Formula
Ribavirin USP is a white, crystalline powder. It is freely soluble in water and slightly soluble in
anhydrous alcohol. The molecular formula is C H
N O  and the molecular weight is 244.21.
Ribavirin capsules USP consist of a white to off-white granular powder in a white, opaque, gelatin
capsule. Each capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose,
8
12
4
5
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lactose monohydrate, povidone-K 30, and magnesium stearate. The capsule shell consists of titanium
dioxide, sodium lauryl sulfate, and gelatin. The capsule is printed with edible ink containing black iron
oxide.
Meets USP dissolution test 2.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ribavirin is an anti-HCV agent [see Microbiology (12.4)].  
12.3 Pharmacokinetics
Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 11. Ribavirin
was rapidly and extensively absorbed following oral administration. However, due to first-pass
metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between
dose and AUC  (AUC from time zero to last measurable concentration) following single doses of 200
to 1200 mg ribavirin. The relationship between dose and C
was curvilinear, tending to asymptote
above single doses of 400 to 600 mg.
Upon multiple oral dosing, based on AUC
, a 6-fold accumulation of ribavirin was observed in
plasma. Following oral dosing with 600 mg twice daily, steady-state was reached by approximately 4
weeks, with mean steady-state plasma concentrations of 2200 ng/mL (37%). Upon discontinuation of
dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from
nonplasma compartments.
Effect of Antacid on Absorption of Ribavirin: Coadministration of ribavirin capsules with an antacid
containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUC .
The clinical relevance of results from this single-dose study is unknown.
Table 11: Mean (% CV) Pharmacokinetic Parameters for Ribavirin When Administered
Individually to Adults
N=11.
Data obtained from a single-dose pharmacokinetic study using 
C labeled ribavirin; N=5. 
N=6.
Parameter 
Ribavirin 
Single-Dose 
600 mg 
Oral Solution (N=14) 
Single-Dose 
600 mg Capsules 
(N=12)
Multiple-Dose 
600 mg 
Capsules 
 twice daily 
(N=12)
   T
 (hr) 
1.00 (34)
1.7 (46)*
3 (60)
   C
 (ng/mL) 
872 (42)
782 (37)
3680 (85)
   AUC  (ng·hr/mL)
14,098 (38)
13,400 (48)
228,000 (25)
   T
 (hr) 
 
43.6 (47)
298 (30)
   Apparent Volume of
Distribution (L) 
 
2825 (9)  
 
   Apparent Clearance (L/hr) 
 
38.2 (40)
 
   Absolute Bioavailability 
 
64% (44)  
 
tf
max 
12hr
tf
* 
†  
14
‡  
max
max
tf
1/2
†
‡
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Tissue Distribution:  Ribavirin transport into nonplasma compartments has been most extensively studied
in red blood cells and has been identified to be primarily via an e -type equilibrative nucleoside
transporter. This type of transporter is present on virtually all cell types and may account for the
extensive volume of distribution. Ribavirin does not bind to plasma proteins.
Metabolism and Excretion:  Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation
pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis
to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole
carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 
C-ribavirin,
approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in
336 hours. Unchanged ribavirin accounted for 17% of the administered dose.
Special Populations:
Renal Dysfunction
The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of
ribavirin to non-HCV-infected subjects with varying degrees of renal dysfunction. The mean AUC
value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when
compared to control subjects (creatinine clearance greater than 90 mL/min). In subjects with creatinine
clearance values between 30 to 60 mL/min, AUC  was twofold greater when compared to control
subjects. The increased AUC  appears to be due to reduction of renal and nonrenal clearance in these
subjects. Phase 3 efficacy trials included subjects with creatinine clearance values greater than 50
mL/min. The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with
renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine
clearance less than 50 mL/min should not be treated with ribavirin [see Contraindications (4)].
Hepatic Dysfunction
The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean
AUC  values were not significantly different in subjects with mild, moderate, or severe hepatic
dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the
mean C
 values increased with severity of hepatic dysfunction and was twofold greater in subjects
with severe hepatic dysfunction when compared to control subjects.
Elderly Patients
Pharmacokinetic evaluations in elderly subjects have not been performed.
Gender
There were no clinically significant pharmacokinetic differences noted in a single-dose trial of 18 male
and 18 female subjects.
Pediatric Patients
Multiple-dose pharmacokinetic properties for ribavirin capsules and INTRON A in pediatric subjects
with chronic hepatitis C between 5 and 16 years of age are summarized in Table 12. The
pharmacokinetics of ribavirin and INTRON A (dose-normalized) are similar in adults and pediatric
subjects.
Complete pharmacokinetic characteristics of ribavirin oral solution have not been determined in
pediatric subjects. Ribavirin C
 values were similar following administration of ribavirin oral
s
14
tf
tf
tf
tf
max
min
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solution or ribavirin capsules during 48 weeks of therapy in pediatric subjects (3 to 16 years of age).
Table 12: Mean (% CV) Multiple-dose Pharmacokinetic Parameters for INTRON A and
Ribavirin Capsules When Administered to Pediatric Subjects with Chronic Hepatitis C
AUC
 (ng·hr/mL) for ribavirin; AUC
 (IU·hr/mL) for INTRON A.
ND=not done.
Parameter 
Ribavirin 
 15 mg/kg/day 
as 2 divided doses 
(N=17) 
INTRON A 3 MIU/m  
three times weekly 
(N=54) 
   T
 (hr) 
1.9 (83)
5.9 (36)
   C
(ng/mL) 
3275 (25)
51 (48)
   AUC* 
29,774 (26)
622 (48)
   Apparent Clearance L/hr/kg 
0.27 (27)
ND  
Note: numbers in parenthesis indicate % coefficient of variation.
A clinical trial in pediatric subjects with chronic hepatitis C between 3 and 17 years of age was
conducted in which pharmacokinetics for PegIntron and ribavirin (capsules and oral solution) were
evaluated. In pediatric subjects receiving body surface area-adjusted dosing of PegIntron at 60
mcg/m /week, the log transformed ratio estimate of exposure during the dosing interval was predicted
to be 58% [90% CI: 141%, 177%] higher than observed in adults receiving 1.5 mcg/kg/week. The
pharmacokinetics of ribavirin (dose-normalized) in this trial were similar to those reported in a prior
study of ribavirin in combination with INTRON A in pediatric subjects and in adults.
Effect of Food on Absorption of Ribavirin
Both AUC  and C
 increased by 70% when ribavirin capsules were administered with a high-fat meal
(841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study
[see Dosage and Administration (2)].
12.4 Microbiology
Mechanism of Action
The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully
understood. Ribavirin has direct antiviral activity in cell culture against many RNA viruses. Ribavirin
increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate
inhibits HCV polymerase in a biochemical reaction.
Antiviral Activity in Cell Culture
The antiviral activity of ribavirin in the HCV replicon is not well understood and has not been defined
because of the cellular toxicity of ribavirin. Direct antiviral activity has been observed in cell culture
of other RNA viruses. The anti-HCV activity of interferon was demonstrated in cell culture using self-
replicating HCV RNA (HCV replicon cells) or HCV infection.
Resistance
HCV genotypes show wide variability in their response to pegylated recombinant human
interferon/ribavirin therapy. Genetic changes associated with the variable response have not been
identified.
* 
12
0-24
† 
2
max
max 
†
2
tf
max
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Cross-resistance
There is no reported cross-resistance between pegylated/non-pegylated interferons and ribavirin.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic
p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on
body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended
human daily dose). Ribavirin was noncarcinogenic when administered for 2 years to rats at doses up to
40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg
adult).
Mutagenesis
Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity
assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was
observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of
1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum
recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. A dominant lethal assay
in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male
gametes.
Impairment of Fertility
In studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular
degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day,
based on body surface area adjustment for a 60-kg adult; 0.1 to 0.8 times the maximum human 24-hour
dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of
treatment, recovery from ribavirin-induced testicular toxicity was mostly apparent within 1 or 2
spermatogenesis cycles.
13.2 Animal Toxicology and Pharmacology
Long-term studies in the mouse and rat [18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day,
respectively (estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively,
based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times the maximum
human 24-hour dose of ribavirin)] have demonstrated a relationship between chronic ribavirin exposure
and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal
degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.
In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25, and 50 mg/kg/day,
drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma
concentrations at the human therapeutic dose) between study Days 13 and 48. Rat pups dosed from
postnatal Days 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses,
which was subsequently manifested as slight decreases in body weight, crown-rump length, and bone
length. These effects showed evidence of reversibility, and no histopathological effects on bone were
observed. No ribavirin effects were observed regarding neurobehavioral or reproductive
development.  
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14 CLINICAL STUDIES
Clinical Study 1 evaluated PegIntron monotherapy. See PegIntron labeling for information about this
trial.
14.1 Ribavirin/PegIntron Combination Therapy
Adult Subjects
Study 2
A randomized trial compared treatment with two PegIntron/ribavirin regimens [PegIntron 1.5 mcg/kg
subcutaneously once weekly/ribavirin 800 mg orally daily (in divided doses); PegIntron 1.5 mcg/kg
subcutaneously once weekly for 4 weeks then 0.5 mcg/kg subcutaneously once weekly for 44
weeks/ribavirin 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU
subcutaneously three times weekly/ribavirin 1000 or 1200 mg orally daily (in divided doses)] in 1,530
adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for
24 weeks post-treatment. Eligible subjects had compensated liver disease, detectable HCV-RNA,
elevated ALT, and liver histopathology consistent with chronic hepatitis.
Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table
13). The response rate to the PegIntron 1.5 mcg/kg and ribavirin 800 mg dose was higher than the
response rate to INTRON A/ribavirin (see Table 13). The response rate to PegIntron 1.5→0.5
mcg/kg/ribavirin was essentially the same as the response to INTRON A/ ribavirin (data not shown).
Table 13: Rates of Response to Combination Treatment – Study 2
* Serum HCV-RNA was measured with a research-based quantitative polymerase chain reaction assay
by a central laboratory.
 Difference in overall treatment response (PegIntron/ribavirin vs. INTRON A/ribavirin) is 6% with
95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at
baseline. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.
 
PegIntron 1.5 mcg/kg once weekly
Ribavirin 800 mg once daily 
INTRON A 3 MIU three times weekly
Ribavirin 1000/1200 mg once daily 
   Overall response*,  
52% (264/511)
46% (231/505)
   Genotype 1
41% (141/348)
33% (112/343)
   Genotype 2 to 6
75% (123/163)
73% (119/162)
Subjects with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (1.5
mcg/kg)/ribavirin (800 mg) compared to subjects with other viral genotypes. Subjects with both poor
prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a
response rate of 29% (71/247) with INTRON A/ ribavirin combination therapy.
Subjects with lower body weight tended to have higher adverse-reaction rates [see Adverse Reactions
(6.1)] and higher response rates than subjects with higher body weights. Differences in response rates
between treatment arms did not substantially vary with body weight.
Treatment response rates with PegIntron/ribavirin combination therapy were 49% in men and 56% in
women. Response rates were lower in African American and Hispanic subjects and higher in Asians
compared to Caucasians. Although African Americans had a higher proportion of poor prognostic
†
†
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factors compared to Caucasians, the number of non-Caucasians studied (11% of the total) was
insufficient to allow meaningful conclusions about differences in response rates after adjusting for
prognostic factors in this trial.
Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline,
approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction
in inflammation.
Study 3
In a large United States community-based trial, 4,913 subjects with chronic hepatitis C were randomized
to receive PegIntron 1.5 mcg/kg subcutaneously once weekly in combination with a ribavirin dose of
800 to 1400 mg (weight-based dosing [WBD]) or 800 mg (flat) orally daily (in divided doses) for 24 or
48 weeks based on genotype. Response to treatment was defined as undetectable HCV-RNA (based on
an assay with a lower limit of detection of 125 IU/mL) at 24 weeks post-treatment.
Treatment with PegIntron 1.5 mcg/kg and ribavirin 800 to 1400 mg resulted in a higher sustained
virologic response compared to PegIntron in combination with a flat 800 mg daily dose of ribavirin.
Subjects weighing greater than 105 kg obtained the greatest benefit with WBD, although a modest
benefit was also observed in subjects weighing greater than 85 to 105 kg (see Table 14). The benefit of
WBD in subjects weighing greater than 85 kg was observed with HCV genotypes 1 to 3. Insufficient
data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an
increased incidence of anemia [see Adverse Reactions (6.1)].
Table 14: SVR Rate by Treatment and Baseline Weight - Study 3
* P=0.01, primary efficacy comparison (based on data from subjects weighing 65 kg or higher at
baseline and utilizing a logistic regression analysis that includes treatment [WBD or Flat], genotype and
presence/absence of advanced fibrosis, in the model).
Treatment Group 
Subject Baseline Weight 
<65 kg 
(<143 lb) 
65 to 85 kg 
(143 to 188 lb) 
>85 to 105 kg 
(>188 to 231 lb) 
>105 kg 
(>231 lb) 
   WBD*
50% (173/348)
45% (449/994)
42% (351/835)
47% (138/292)
   Flat
51% (173/342)
44% (443/1011)
39% (318/819)
33% (91/272)
A total of 1,552 subjects weighing greater than 65 kg in Study 3 had genotype 2 or 3 and were
randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment
duration.
Study 4
A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two
PegIntron/ribavirin regimens [PegIntron 1.5 mcg/kg and 1 mcg/kg subcutaneously once weekly both in
combination with ribavirin 800 to 1400 mg PO daily (in two divided doses)] and Pegasys 180 mcg
subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in two divided
doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. In this trial, lack of early
virologic response (undetectable HCV-RNA or greater than or equal to 2 log
 reduction from
baseline) by treatment Week 12 was the criterion for discontinuation of treatment. SVR was defined as
undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 IU/mL) at 24
weeks post-treatment (see Table 15).
10
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Table 15: SVR Rate by Treatment – Study 4
% (number) of Subjects 
PegIntron 
1.5 mcg/kg/Ribavirin 
PegIntron 
1 mcg/kg/Ribavirin 
Pegasys 
180 mcg/Copegus 
40 (406/1019)
38 (386/1016)
41 (423/1035)
Overall SVR rates were similar among the three treatment groups. Regardless of treatment group, SVR
rates were lower in subjects with poor prognostic factors. Subjects with poor prognostic factors
randomized to PegIntron (1.5 mcg/kg)/ribavirin or Pegasys/Copegus, however, achieved higher SVR
rates compared to similar subjects randomized to PegIntron 1 mcg/kg/ribavirin. For the PegIntron 1.5
mcg/kg and ribavirin dose, SVR rates for subjects with and without the following prognostic factors
were as follows: cirrhosis (10% vs. 42%), normal ALT levels (32% vs. 42%), baseline viral load
greater than 600,000 IU/mL (35% vs. 61%), 40 years of age and older (38% vs. 50%), and African
American race (23% vs. 44%). In subjects with undetectable HCV-RNA at treatment Week 12 who
received PegIntron (1.5 mcg/kg)/ribavirin, the SVR rate was 81% (328/407).
Study 5 - Ribavirin/PegIntron Combination Therapy in Prior Treatment Failures
In a noncomparative trial, 2,293 subjects with moderate to severe fibrosis who failed previous treatment
with combination alpha interferon/ribavirin were re-treated with PegIntron, 1.5 mcg/kg subcutaneously,
once weekly, in combination with weight adjusted ribavirin. Eligible subjects included prior
nonresponders (subjects who were HCV-RNA positive at the end of a minimum 12 weeks of treatment)
and prior relapsers (subjects who were HCV-RNA negative at the end of a minimum 12 weeks of
treatment and subsequently relapsed after post-treatment follow-up). Subjects who were negative at
Week 12 were treated for 48 weeks and followed for 24 weeks post-treatment. Response to treatment
was defined as undetectable HCV-RNA at 24 weeks post-treatment (measured using a research-based
test, limit of detection 125 IU/mL). The overall response rate was 22% (497/2293) (99% CI: 19.5, 23.9).
Subjects with the following characteristics were less likely to benefit from re-treatment: previous
nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and
genotype 1 infection.
The re-treatment sustained virologic response rates by baseline characteristics are summarized in Table
16.
Table 16: SVR Rates by Baseline Characteristics of Prior Treatment Failures - Study 5
HCV 
Genotype/Metavir
Fibrosis Score 
Overall SVR by Previous Response and Treatment
Nonresponder 
Relapser 
interferon
alfa/ribavirin 
% (number of
subjects) 
peginterferon (2a
and 2b
combined)/ribavirin 
% (number of
subjects) 
interferon
alfa/ribavirin 
% (number of
subjects) 
peginterferon (2a and
2b combined)/ribavirin
% (number of
subjects) 
Overall
18 (158/903)
6 (30/476)
43 (130/300)
35 (113/344)
HCV 1
13 (98/761)
4 (19/431)
32 (67/208)
23 (56/243)
F2
18 (36/202)
6 (7/117)
42 (33/79)
32 (23/72)
F3
16 (38/233)
4 (4/112)
28 (16/58)
21 (14/67)
F4
7 (24/325)
4 (8/202)
26 (18/70)
18 (19/104)
HCV 2/3
49 (53/109)
36 (10/28)
67 (54/81)
57 (52/92)
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F2
68 (23/34)
56 (5/9)
76 (19/25)
61 (11/18)
F3
39 (11/28)
38 (3/8)
67 (18/27)
62 (18/29)
F4
40 (19/47)
18 (2/11)
59 (17/29)
51 (23/45)
HCV 4
17 (5/29)
7 (1/15)
88 (7/8)
50 (4/8)
Achievement of an undetectable HCV-RNA at treatment Week 12 was a strong predictor of SVR. In this
trial, 1,470 (64%) subjects did not achieve an undetectable HCV-RNA at treatment Week 12, and were
offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823
(36%) subjects who were HCV-RNA undetectable at treatment Week 12, those infected with genotype 1
had an SVR of 48% (245/507), with a range of responses by fibrosis scores (F4-F2) of 39 to 55%.
Subjects infected with genotype 2/3 who were HCV-RNA undetectable at treatment Week 12 had an
overall SVR of 70% (196/281), with a range of responses by fibrosis scores (F4-F2) of 60 to 83%.
For all genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving
SVR.
Pediatric Subjects
Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and
detectable HCV-RNA were treated with ribavirin 15 mg/kg per day and PegIntron 60 mcg/m once
weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be
followed for 24 weeks post-treatment. A total of 107 subjects received treatment, of which 52% were
female, 89% were Caucasian, and 67% were infected with HCV Genotype 1. Subjects infected with
Genotypes 1, 4 or Genotype 3 with HCV-RNA greater than or equal to 600,000 IU/mL received 48
weeks of therapy while those infected with Genotype 2 or Genotype 3 with HCV-RNA less than
600,000 IU/mL received 24 weeks of therapy. The trial results are summarized in Table 17.
Table 17: Sustained Virologic Response Rates by Genotype and Assigned Treatment Duration –
Pediatric Trial
 Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.
 N=number of responders/number of subjects with given genotype and assigned treatment duration. 
 Subjects with genotype 3 low viral load (less than 600,000 IU/mL) were to receive 24 weeks of
treatment while those with genotype 3 and high viral load were to receive 48 weeks of treatment.
                    Genotype
All Subjects 
N=107 
24 Weeks 
48 Weeks 
Virologic Response 
N
 (%) 
Virologic Response 
N
 (%) 
All  
26/27 (96.3)
44/80 (55.0)
1
-
38/72 (52.8)
2
14/15 (93.3)
-
3
12/12 (100)
2/3 (66.7)
4
-
4/5 (80.0)
14.2 Ribavirin/INTRON A Combination Therapy
Adult Subjects
2 
*
†
‡
*,†
*,†
‡
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Previously Untreated Subjects
 
Adults with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central
laboratory using a research-based RT-PCR assay) who were previously untreated with alpha interferon
therapy were enrolled into two multicenter, double-blind trials (U.S. and international) and randomized to
receive ribavirin capsules 1200 mg/day (1000 mg/day for subjects weighing less than or equal to 75 kg)
and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 or 48 weeks followed by
24 weeks of off-therapy follow-up. The international trial did not contain a 24-week INTRON A and
placebo treatment arm. The U.S. trial enrolled 912 subjects who, at baseline, were 67% male, 89%
Caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The international trial,
conducted in Europe, Israel, Canada, and Australia, enrolled 799 subjects (65% male, 95% Caucasian,
mean Knodell score 6.8, and 58% genotype 1).
Trial results are summarized in Table 18.
Table 18: Virologic and Histologic Responses: Previously Untreated Subjects
* Number (%) of subjects. 
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment
and during follow-up period. 
Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score
(I+II+III) improvement of greater than or equal to 2 points.
 
U.S. Trial 
International Trial 
24 weeks of treatment 
48 weeks of
treatment 
24 weeks
of
treatment 
48 weeks of
treatment 
INTRON
A/Ribavirin(N=228)
INTRON
A/Placebo
(N=231) 
INTRON
A/Ribavirin
(N=228) 
INTRON
A/Placebo
(N=225) 
INTRON
A/Ribavirin
(N=265) 
INTRON
A/Ribavirin
(N=268) 
INTRON
A/Placebo
(N=266) 
Virologic 
Response 
    Responder  
65 (29)
13 (6)
85 (37)
27 (12)
86 (32)
113 (42)
46 (17)
    Nonresponder
147 (64)
194 (84)
110 (48)
168 (75)
158 (60)
120 (45)
196 (74)
    Missing Data 
16 (7)
24 (10)
33 (14)
30 (13)
21 (8)
35 (13)
24 (9)
Histologic 
 Response 
    Improvement
102 (45)
77 (33)
96 (42)
65 (29)
103 (39)
102 (38)
69 (26)
    No
improvement 
77 (34)
99 (43)
61 (27)
93 (41)
85 (32)
58 (22)
111 (41)
    Missing Data 
49 (21)
55 (24)
71 (31)
67 (30)
77 (29)
108 (40)
86 (32)
Of subjects who had not achieved HCV-RNA below the limit of detection of the research-based assay
by Week 24 of ribavirin/INTRON A treatment, less than 5% responded to an additional 24 weeks of
combination treatment.
Among subjects with HCV Genotype 1 treated with ribavirin/INTRON A therapy who achieved HCV-
RNA below the detection limit of the research-based assay by 24 weeks, those randomized to 48 weeks
of treatment had higher virologic responses compared to those in the 24-week treatment group. There
was no observed increase in response rates for subjects with HCV non-genotype 1 randomized to
ribavirin/INTRON A therapy for 48 weeks compared to 24 weeks.
*
†
‡
†
‡
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Relapse Subjects
Subjects with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central
laboratory using a research-based RT-PCR assay) who had relapsed following one or two courses of
interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-
blind trials (U.S. and international) and randomized to receive ribavirin 1200 mg/day (1000 mg/day for
subjects weighing ≤75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24
weeks followed by 24 weeks of off-therapy follow-up. The U.S. trial enrolled 153 subjects who, at
baseline, were 67% male, 92% Caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58%
genotype 1. The international trial, conducted in Europe, Israel, Canada, and Australia, enrolled 192
subjects (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1). Trial results are
summarized in Table 19.
Table 19: Virologic and Histologic Responses: Relapse Subjects*
 Number (%) of subjects. 
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of
treatment and during follow-up period. 
Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score
(I+II+III) improvement of greater than or equal to 2 points.
U.S. Trial 
International Trial 
INTRON A/
Ribavirin 
(N=77)
INTRON A/
Placebo 
(N=76)
INTRON A/
Ribavirin 
(N=96)
INTRON A/
Placebo 
(N=96)
Virologic Response 
    Responder  
33 (43)
3 (4)
46 (48)
5 (5)
    Nonresponder 
36 (47)
66 (87)
45 (47)
91 (95)
    Missing Data 
8 (10)
7 (9)
5 (5)
0 (0)
Histologic Response 
    Improvement  
38 (49)
27 (36)
49 (51)
30 (31)
    No improvement 
23 (30)
37 (49)
29 (30)
44 (46)
    Missing Data 
16 (21)
12 (16)
18 (19)
22 (23)
Virologic and histologic responses were similar among male and female subjects in both the previously
untreated and relapse trials.
Pediatric Subjects
Pediatric subjects 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA
(assessed by a central laboratory using a research-based RT-PCR assay) were treated with ribavirin 15
mg/kg per day and INTRON A 3 MIU/m three times weekly for 48 weeks followed by 24 weeks of
off-therapy follow-up. A total of 118 subjects received treatment, of which 57% were male, 80%
Caucasian, and 78% genotype 1. Subjects less than 5 years of age received ribavirin oral solution and
those 5 years of age or older received either ribavirin oral solution or capsules.
Trial results are summarized in Table 20.
Table 20: Virologic Response: Previously Untreated Pediatric Subjects*
 
INTRON A 3 MIU/m  three times
weekly/Ribavirin  15 mg/kg/day 
*
† 
‡
†
‡
2 
2
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 Number (%) of subjects.
Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of
treatment and during follow-up period.
   Overall Response  (N=118) 
54 (46)
   Genotype 1 (N=92) 
33 (36)
   Genotype non-1 (N=26) 
21 (81)
Subjects with viral genotype 1, regardless of viral load, had a lower response rate to INTRON
A/ribavirin combination therapy compared to subjects with genotype non-1, 36% vs. 81%. Subjects with
both poor prognostic factors (genotype 1 and high viral load) had a response rate of 26% (13/50).
16 HOW SUPPLIED/STORAGE AND HANDLING
Ribavirin Capsules USP, 200 mg are white/white, size ‘1’ hard gelatin capsule filled with white to
off-white granular powder and imprinted with ‘E’ on white cap and ‘81’ on white body with black ink.
            Bottles of 42                            NDC 65862-290-42
            Bottles of 56                            NDC 65862-290-56
            Bottles of 70                            NDC 65862-290-70
            Bottles of 84                            NDC 65862-290-84
            Bottles of 180                          NDC 65862-290-18
            Bottles of 500                          NDC 65862-290-05
 
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Anemia
The most common adverse experience occurring with ribavirin capsules is anemia, which may be
severe [see Warnings and Precautions (5.2) and Adverse Reactions (6)]. Advise patients that laboratory
evaluations are required prior to starting therapy and periodically thereafter [see Dosage and
Administration (2.4)]. Advise patients to be well hydrated, especially during the initial stages of
treatment.
Embryo-Fetal Toxicity
Inform females of reproductive potential and pregnant women that ribavirin capsules may cause birth
defects, miscarriage, and stillbirth. Advise females of reproductive potential that they must have a
pregnancy test prior to initiating treatment and periodically during therapy. Advise females of
reproductive potential and male patients with female partners of reproductive potential to use effective
contraception during treatment with ribavirin and for 6 months post therapy. Advise patients to notify the
physician immediately in the event of a pregnancy [see Contraindications (4), Warnings and Precautions
(5.1), and Use in Specific Populations (8.1, 8.3)].
Missed Dose
*
†  
†
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Inform patients that in the event a dose is missed, the missed dose should be taken as soon as possible
during the same day. Patients should not double the next dose. Advise patients to contact their healthcare
provider if they have questions.  
Dental and Periodontal Disorders
Advise patients to brush their teeth thoroughly twice daily and have regular dental examinations. If
vomiting occurs, advise patients to rinse out their mouth thoroughly afterwards [see Warnings and
Precautions (5.7)].
The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo
Pharma Limited.
Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides
MEDICATION GUIDE
Ribavirin Capsules USP
(rye'' ba vye' rin)
 
What is the most important information I should know about ribavirin capsules?
1.  Ribavirin capsules may cause birth defects, miscarriage or death of your unborn baby. Do not
take ribavirin capsules if you or your sexual partner is pregnant or plan to become pregnant. Do
not become pregnant during treatment or within 6 months after stopping treatment with ribavirin
capsules. You must use effective birth control during treatment with ribavirin capsules and for 6 months
after stopping treatment.
Females must have a pregnancy test before starting ribavirin capsules, during treatment with ribavirin
capsules, and for 6 months after the last dose of ribavirin capsules.
If you or your female sexual partner becomes pregnant during treatment with ribavirin
capsules or within 6 months after you stop taking ribavirin capsules, tell your healthcare
provider right away.
2.  Ribavirin capsules may cause a significant drop in your red blood cell count and cause anemia
in some cases. Anemia has been associated with worsening of heart problems, and in rare cases
can cause a heart attack and death. Tell your healthcare provider if you have ever had any heart
problems. Ribavirin capsules may not be right for you. Get medical help right away if you experience
chest pain.
3.  Do not take ribavirin capsules alone to treat chronic hepatitis C infection. Ribavirin capsules
should be used in combination with either interferon alfa-2b or peginterferon alfa-2b to treat chronic
hepatitis C infection.
What are ribavirin capsules?   
Ribavirin capsules are a medicine used with either interferon alfa-2b or peginterferon alfa-2b to treat
chronic (lasting a long time) hepatitis C infection in people 3 years and older with liver disease.
It is not known if ribavirin capsules use for longer than 1 year is safe and will work.
It is not known if ribavirin capsules use in children younger than 3 years old is safe and will work.
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Who should not take ribavirin capsules?
See “What is the most important information I should know about ribavirin capsules?”
Do not take ribavirin capsules if you have:
ever had serious allergic reactions to the ingredients in ribavirin capsules. See the end of this
Medication Guide for a complete list of ingredients.
certain types of hepatitis (autoimmune hepatitis).
certain blood disorders (hemoglobinopathies).
severe kidney disease.
taken or currently take didanosine.
Talk to your healthcare provider before taking ribavirin capsules if you have any of these conditions.
What should I tell my healthcare provider before taking ribavirin capsules?
Before you take ribavirin capsules, tell your healthcare provider if you have or ever had:
treatment for hepatitis C that did not work for you
breathing problems. Ribavirin capsules may cause or worsen breathing problems you already have.
vision problems. Ribavirin capsules may cause eye problems or worsen eye problems you already
have. You should have an eye exam before you start treatment with ribavirin capsules.
certain blood disorders such as anemia (low red blood cell count)
high blood pressure, heart problems, or have had a heart attack. Your healthcare provider should
check your blood and heart before you start treatment with ribavirin capsules.
thyroid problems
liver problems other than hepatitis C infection
human immunodeficiency virus (HIV) or any immunity problems
mental health problems, including depression and thoughts of hurting yourself or others
kidney problems
an organ transplant
diabetes. Ribavirin capsules may make your diabetes worse or harder to treat.
any other medical condition
are breastfeeding. It is not known if ribavirin passes into your breast milk. You and your healthcare
provider should decide if you will take ribavirin capsules or breastfeed. 
Tell your healthcare provider about all the medicines you take, including prescription medicines,
vitamins, and herbal supplements. Ribavirin capsules may affect the way other medicines work.
Especially tell your healthcare provider if you take didanosine or a medicine that contains
azathioprine.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when
you get a new medicine.
How should I take ribavirin capsules?
Take ribavirin capsules exactly as your healthcare provider tells you. Your healthcare provider will
tell you how much ribavirin capsules to take and when to take them.
Take ribavirin capsules with food.
Take ribavirin capsules whole. Do not open, break, or crush ribavirin capsules before swallowing.
If you cannot swallow ribavirin capsules whole, tell your healthcare provider.
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If you miss a dose of ribavirin capsules, take the missed dose as soon as possible during the same
day. Do not double the next dose. If you have questions about what to do, call your healthcare
provider.
If you take too much ribavirin, call your healthcare provider or go to the nearest hospital emergency
room right away.
What are the possible side effects of ribavirin capsules?
Ribavirin capsules may cause serious side effects, including:
See “What is the most important information I should know about ribavirin capsules?”
Swelling and irritation of your pancreas (pancreatitis). Symptoms may include: stomach pain,
nausea, vomiting, or diarrhea.
Serious breathing problems. Difficulty breathing may be a sign of a serious lung infection
(pneumonia) that can lead to death.
Serious eye problems that may lead to vision loss or blindness.
Dental problems. Brush your teeth well 2 times each day. Get regular dental exams. If you vomit at
any time during treatment with ribavirin capsules, rinse out your mouth well.
Severe blood disorders. You may have an increased risk of developing severe blood disorders
when ribavirin capsules is used in combination with pegylated alpha interferons and azathioprine.
Your healthcare provider should do blood tests during your treatment with ribavirin capsules in
combination with pegylated alpha interferon and azathioprine to check you for these problems.
Growth problems in children. Weight loss and slowed growth are common in children during
combination treatment with ribavirin capsules and peginterferon alfa-2b or interferon alfa-2b. Most
children will go through a growth spurt and gain weight after treatment stops. Some children may not
reach the height that they were expected to have before treatment. Talk to your healthcare provider
if you are concerned about your child’s growth during treatment with ribavirin capsules and
peginterferon alfa-2b or with ribavirin capsules and interferon alfa-2b.
Severe depression.
Thoughts of hurting yourself or others, and suicide attempts. Adults and children who take
ribavirin capsules, especially teenagers, are more likely to have suicidal thoughts or attempt to hurt
themselves while taking ribavirin capsules. Call your healthcare provider right away or go to the
nearest hospital emergency room if you have new or worse depression or thoughts about hurting
yourself or others or dying.
The most common side effects of ribavirin capsules in adults include:
flu-like symptoms - feeling tired or weak, headache, shaking chills along with high temperature
(fever), nausea, and muscle aches
mood changes, feeling irritable
The most common side effects of ribavirin capsules in children include:
fever
headache
a decrease in blood cells that fight infection (neutropenia)
tiredness
decreased appetite
vomiting
These are not all the possible side effects of ribavirin capsules. For more information ask your
healthcare provider or pharmacist.
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Call your healthcare provider if you have any side effect that bothers you or that does not go away, and
for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ribavirin capsules?
Store ribavirin capsules between 15° to 30°C (59° to 86°F).
Keep ribavirin capsules and all medicines out of the reach of children.
General information about the safe and effective use of ribavirin capsules.
It is not known if treatment with ribavirin capsules will cure hepatitis C virus infections or prevent
cirrhosis, liver failure, or liver cancer that can be caused by hepatitis C virus infections. It is not known
if taking ribavirin capsules will prevent you from infecting another person with the hepatitis C virus.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not
use ribavirin capsules for a condition for which it was not prescribed. Do not give ribavirin capsules to
other people, even if they have the same symptoms that you have. They may harm them.
You can ask your pharmacist or healthcare provider for information about ribavirin capsules that is
written for health professionals.
What are the ingredients in ribavirin capsules?
Active ingredient: ribavirin
Inactive ingredients: microcrystalline cellulose, lactose monohydrate, povidone-K 30, and magnesium
stearate. The capsule shell consists of titanium dioxide, sodium lauryl sulfate, and gelatin. The capsule
is printed with edible ink containing black iron oxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.
Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides
Distributed by:
Aurobindo Pharma USA, Inc. 
279 Princeton-Hightstown Road
East Windsor, NJ 08520   
Manufactured by: 
Aurobindo Pharma Limited 
Hyderabad-500 038, India
Revised: 02/2020
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 200 mg (500 Capsules Bottle)
NDC 65862-290-05 
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Rx only 
Ribavirin Capsules USP 
200 mg 
PHARMACIST: Dispense the accompanying 
Medication Guide to each patient.  
AUROBINDO     500 Capsules 
 
 
RIBAVIRIN  
ribavirin capsule
Product Information
Product T ype
HUMAN PRESCRIPTION DRUG
Item Code (Source)
NDC:65862-290
Route of Administration
ORAL
Active Ingredient/Active Moiety
Ingredient Name
Basis of Strength
Strength
RIBAVIRIN (UNII: 49717AWG6K) (RIBAVIRIN - UNII:49717AWG6K)
RIBAVIRIN
200 mg
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Aurobindo Pharma Limited
Inactive Ingredients
Ingredient Name
Strength
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
 
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
 
POVIDONE K30 (UNII: U725QWY32X)
 
MAGNESIUM STEARATE (UNII: 70097M6I30)
 
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
 
SODIUM LAURYL SULFATE (UNII: 368GB5141J)
 
GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
 
FERROSOFERRIC OXIDE (UNII: XM0M87F357)
 
Product Characteristics
Color
WHITE
Score
no score
Shape
CAPSULE
Size
19mm
Flavor
Imprint Code
E;81
Contains
    
Packaging
#
Item Code
Package Description
Marketing Start Date
Marketing End Date
1 NDC:65862-290-42
42 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
2 NDC:65862-290-56
56 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
3 NDC:65862-290-70
70 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
4 NDC:65862-290-84
84 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
5 NDC:65862-290-18
180 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
6 NDC:65862-290-05
500 in 1 BOTTLE; Type 0: Not a Combination Product
09/17/2009
Marketing Information
Marketing Category
Application Number or Monograph Citation
Marketing Start Date
Marketing End Date
ANDA
ANDA079117
09/17/2009
Labeler - Aurobindo Pharma Limited (650082092)
Establishment
Name
Address
ID/FEI
Business Operations
Aurobindo Pharma Limited
918917642
ANALYSIS(65862-290) , MANUFACTURE(65862-290)
 
Revised: 2/2020
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 1 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in 
hospitalized adults with coronavirus-19 (COVID-19) 
 
Study No: CCB-CRISIS-01 
Version Date:  01 May 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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 2 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 16 
3.1 Background ................................................................................................................ 16 
3.2 Coronavirus-19 (COVID-19) ..................................................................................... 16 
3.2.1 Coronavirus Biology .................................................................................................... 16 
3.3 Host Nucleotide Synthesis ......................................................................................... 16 
3.4 Dihydroorotate dehydrogenase (DHODH) ................................................................ 16 
3.5 Brequinar .................................................................................................................... 17 
3.6 Rationale for the Planned Trial .................................................................................. 17 
3.6.1 Brequinar Dose Selection ............................................................................................. 18 
3.6.2 Risk/Benefit of Brequinar ............................................................................................ 18 
3.7 Risks Associated with Participation in the Clinical Study ......................................... 18 
3.8 Possible Interactions with Concomitant Medical Treatments .................................... 19 
3.8.1 CYP Interactions .......................................................................................................... 19 
3.9 Steps to be Taken to Control or Mitigate Risks ......................................................... 19 
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 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 01MAY2020 
 
7.4 Inclusion of Women and Minorities........................................................................... 25 
8 STUDY TREATMENTS .................................................................................................... 26 
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 Hospital Discharge Prior to Study Day 15 ................................................................. 27 
8.5 Concomitant Medication/Treatment .......................................................................... 27 
8.6 Treatment Compliance ............................................................................................... 28 
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 ........................................................................................... 29 
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 ....................................................................................................... 34 
9.6 Compliance with Study Procedures ........................................................................... 34 
9.7 Early Withdrawal from the Study .............................................................................. 34 
9.8 Early Termination of the Study .................................................................................. 35 
10 ADVERSE EVENT REPORTING..................................................................................... 36 
10.1 Classification of Causality ......................................................................................... 37 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 01MAY2020 
 
10.2 Classification of Severity ........................................................................................... 38 
10.3 Serious Adverse Event (SAE) Reporting ................................................................... 38 
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 39 
10.5 Pregnancies................................................................................................................. 40 
10.6 Safety Monitoring for Hematologic Toxicities .......................................................... 40 
10.7 Data Safety Monitoring Board ................................................................................... 42 
11 STATISTICAL CONSIDERATIONS................................................................................ 43 
11.1 Study Populations for Analysis .................................................................................. 43 
11.2 Safety Analyses .......................................................................................................... 43 
11.3 Efficacy Analyses ....................................................................................................... 43 
11.4 DHO and Brequinar Concentration Levels ................................................................ 43 
11.5 Sample Size Considerations ....................................................................................... 43 
11.6 Randomization ........................................................................................................... 43 
11.7 Pooling of Study Centers............................................................................................ 43 
11.8 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 
13.4 Audit ........................................................................................................................... 48 
13.5 Confidentiality ............................................................................................................ 49 
13.6 Finance ....................................................................................................................... 49 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 5 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
14 REFERENCES ................................................................................................................... 50 
15 APPENDICES .................................................................................................................... 52 
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events .................................................. 52 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 53 
15.3 Appendix C: National Early Warning Score (NEWS2) ............................................. 54 
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment Guidance. ..... 55 
 
 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 6 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 7 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
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 
EHR 
Electronic health record 
ESR 
Erythrocyte Sedimentation Rate 
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 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 8 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
Abbreviation 
Definition 
WOCBP 
Women of childbearing potential 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 10 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
procedures are presented in detail in the procedures section, see below. Subjects 
will be followed through Day 15. Mortality will be assessed at Day 29. 
See below for instructions regarding hospital discharge prior to Day 15. 
Hematology and chemistry results and study information such as NEWS2 criteria 
are to be collected using the available EHR data as much as possible to avoid extra 
procedures for the study. 
Sample Size: 
Approximately 24 subjects will be randomized to either standard of care or 
standard of care plus brequinar in a 1:2 ratio (approximately 8 assigned to standard 
of care and 16 subjects on brequinar).  
Number of Sites: 
1 - 8 
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 and at least one of the following co-morbidities by 
subject history or present in the institution’s electronic health record: 
hypertension, diabetes, chronic kidney disease, chronic obstructive 
pulmonary disease (COPD) or asthma, cardiovascular disease (coronary 
artery disease or congestive heart failure), liver cirrhosis, age > 65, BMI > 
30.  
3. If discharged from the hospital prior to Study Day 15 or if follow up is 
needed for study drug-related adverse event, willing to go to an outpatient 
laboratory for a laboratory sample as well as a contact (phone call or other 
digital media) on Study Days 7 and 15 and contact only on Day 29. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time 
polymerase chain reaction (RT-PCR) or other FDA-cleared commercial or 
public health assay. 
5. Life expectancy > 48h in the opinion of the investigator. 
6. Hospitalized (in patient with expected duration ≥ 24 hours) 
7. 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 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. 
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they have assessments through Day 15, whether conducted in the hospital or 
contacted via phone or other digital media. 
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of informed consent through Day 
15. After Day 15, collect/record only Serious Adverse Events (SAEs) or those 
judged by the Investigator or designated person to be related to study drug, 
including but not limited to potential hematologic toxicities. Post-randomization 
adverse events will be those with an onset after the date and time of randomization. 
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, safety 
laboratory data, and NEWS2 Assessments.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of post randomization adverse events, defined as AEs 
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, NEWS2 
Criteria, and other clinical measures will be summarized using appropriate 
descriptive statistics. 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 01MAY2020 
 
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:  
Sharon Levy, MD 
Title: 
Prosoft Clinical 
Telephone No.: 
M: (610) 316-9764 
O: (484) 320-2062 
E-mail: 
s.levy@prosoftclinical.com 
Sharon.levy27@gmail.com 
 
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PROTOCOL VERSION DATE: 01MAY2020 
 
3 
INTRODUCTION 
3.1 Background 
3.2 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]).  
3.2.1 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]). 
3.3  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.  
3.4  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.  
 
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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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]).    
3.5  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]). 
3.6  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 CRISIS trial will study standard of care (SOC) and SOC with 5 days of DHODH inhibition. 
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, 
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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.  
3.6.1 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 
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 reassuring the safety of 
this regimen (see Brequinar IB [5]).  
3.6.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive database exists with more than 800 cancer 
patients 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. Brequinar has 
also been utilized at lower doses than used in the cancer studies in 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. While no DHODHi has been tested to date in the clinic for 
infection with SARS-CoV-2 and no brequinar safety information is available in treatment of this 
disease, DHODHi therapy in the context of trials for patients with cancer has the expected safety 
side-effects of mucositis and bone marrow suppression. 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 mucositis and only 1 (2.6%) episode of mild thrombocytopenia. The 100 mg per day dose 
proposed for administration in this study should be safe and well tolerated.  
The possible 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. As discussed above, inhibition of DHODH is expected to reduce the ability 
of the virus to replicate and it is for this reason that study CCB-CRISIS-01 will administer 
brequinar to patients with COVID-19. 
 
3.7 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of brequinar in patients with refractory 
solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis have 
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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.  
COVID-19 patients are at higher risk of complications and poor outcomes when their infection is 
combined with comorbidities including hypertension, diabetes, chronic kidney disease, chronic 
obstructive pulmonary disease (COPD) or asthma, cardiovascular disease (coronary artery disease 
or congestive heart failure), liver cirrhosis, age > 65, and BMI > 30 [15]. Therefore, participants 
in this protocol must have at least one of these comorbidities in order to justify that the risks of 
potential and known toxicities associated with brequinar are outweighed by the potential benefits 
in this higher risk population. 
In addition to ensuring a higher risk population, a comprehensive safety monitoring plan will be 
utilized in this study to assess the ongoing safety and well-being of participants (see Section 10.6).  
3.8 Possible Interactions with Concomitant Medical Treatments 
While not previously tested in patients with viral infections, brequinar has been administered to 
subjects taking a variety of concomitant medications that are typical in severely ill cancer patients. 
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. Brequinar has also been used concomitantly with antibiotics, antifungals and other 
critical care medications. 
 
There is no experience with brequinar for treatment of SARS-CoV-2 and other severe viral 
infections and no formal interaction studies have been conducted.  
3.8.1 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).  
3.9 Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated in a hospital setting by highly experienced infectious disease or other 
critical care specialists and other qualified staff familiar with the treatment of severe viral 
infections and their complications.  
Subjects in the Brequinar Treatment Group 
If the subject is in the brequinar treatment group and is being discharged prior to completing the 
study, ensure a hematology/chemistry sample is obtained prior to discharge on the day of 
discharge. The subject is to return to the research facility for the Days 7 and 15 visits if able and 
permitted. If unable or not permitted to return to the research facility due to COVID-19 restrictions, 
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the remaining visit activities except for the lab draw will be conducted by phone or other digital 
media. The lab draw will be performed by an outpatient laboratory at a designated facility. Lab 
draws for any outpatient visits for the Day 7 and 15 visits are limited to safety labs (hematology 
and chemistry). Additional outpatient laboratory or study visits are to be conducted as needed for 
follow up of adverse events including hematologic toxicities. 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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5 
TRIAL DESIGN 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care per institutional guidelines for treatment of patients with 
SARS-CoV-2 infection. In addition to standard of care, the brequinar group will receive brequinar 
100 mg once daily for 5 days.    
The Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance is provided in 
Appendix D Section 15.4. This guidance provides an example of standard of care instructions for 
treatment of COVID-19. The guidance is provided as informational only, it is not required that this 
guidance be used for treatment as standards of care may differ between institutions. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Study procedures are presented in 
detail in Section 8. Subjects will be followed through Day 15, with mortality assessed via a phone 
call/other digital media acceptable to institution on Day 29. 
If the subject is being discharged prior to Day 7, see Section 8.4. 
It is understood that some assessments may not be conducted if the subject is unable to return to 
the clinic after discharge due to restricted travel. If an assessment is missed due to after hospital 
discharge, e.g., samples or blood draws, this will not be counted as a protocol deviation. Any of 
the study visits may be conducted via telephone if the subject has been discharged from the hospital 
and is not permitted to or is unable to return to the hospital/clinic for these visits. 
Information is to be collected using the electronic health record (EHR) whenever possible. It is not 
required to perform study-specific laboratory assessments, NEWS 2 assessments, etc. separately 
for study purposes. 
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7 
TRIAL POPULATION 
7.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 24 subjects have completed the study. Subjects will be randomized to either 
standard of care or standard of care plus brequinar or in a 1:2: ratio (approximately 8 subjects 
assigned to standard of care alone and approximately 16 subjects on standard of care plus 
brequinar).  
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 and at least one of the following co-morbidities by subject history 
or present in the institution’s electronic health record: hypertension, diabetes, chronic 
kidney disease, chronic obstructive pulmonary disease (COPD) or asthma, cardiovascular 
disease (coronary artery disease or congestive heart failure), liver cirrhosis, age > 65, BMI 
> 30.  
3. If discharged from the hospital prior to Study Day 15 or if follow up is needed for study 
drug-related adverse event, willing to go to an outpatient laboratory to obtain a laboratory 
sample as well as a contact (phone call or other digital media) on Study Days 7 and 15 and 
contact only on Day 29.  
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase 
chain reaction (RT-PCR) or other Food and Drug Administration (FDA)-cleared 
commercial or public health assay. 
5. Life expectancy > 48h in the opinion of the investigator. 
6. Hospitalized (in patient with expected duration ≥ 24 hours) 
7. 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 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. 
8. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of brequinar.  
9. ≤ 10 days since first COVID-19 symptom as determined by treating clinician. 
10. Platelets ≥100,000 cell/mm3. 
7.3 Exclusion Criteria 
1. In intensive care unit (ICU) or equivalent level of care or expected to require ICU level of 
care within next 24 hours. 
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2. 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. 
3. Active malignancy other than squamous cell carcinoma; anticancer treatment such as 
chemotherapy or radiation therapy within the past month. 
4. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy 
test. 
5. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide), tacrolimus, 
sirolimus, or pre-existing prednisone at higher than 20 mg daily (ongoing or within 2 weeks 
of study entry). 
7.4 Inclusion of Women and Minorities 
Adult men and women of all races and ethnic groups are eligible for this trial. 
 
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8 
STUDY TREATMENTS 
8.1 Description of Study Medications 
8.1.1 Brequinar 
Brequinar will be supplied as 100 mg capsules. Dosing will be a single 5-day course of brequinar 
100 mg once daily for 5 doses. The initial brequinar dose (Day 1) should be administered as soon 
as possible based on study drug availability from the investigational pharmacy. 
8.2 Treatment Administration 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 
infection. Subjects will be randomly assigned in a 1:2 ratio to standard of care alone or standard 
of care plus brequinar. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE).  
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 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 (Study 785-001 [16], 785-003 [17], and 785-005 [18]) with five 
consecutive days of intravenous (IV) brequinar dosing and 168 subjects, there were no toxic 
deaths. For subjects from these three studies who were treated with a dose of 100 mg or below  
(as will be dosed in CCB-CRISIS-01), 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 [19], 785-031 [20] , and 785-034 [21]), 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 15 (or longer if needed to follow up 
study drug-related adverse events). Mortality is assessed via a phone call or other digital media at 
Day 29. 
After treatment, participants will be monitored through at least Study Day 15 (or longer if needed 
to follow study drug-related AEs/SAEs). Participants may discontinue from the study by 
withdrawing consent at any time or for any reason as presented in Section 9.7. 
8.4 Hospital Discharge Prior to Study Day 15 
For subjects in the brequinar treatment group, if the subject is discharged from the hospital prior 
to Day 5 the subject is to take a final dose on the day of discharge. 
If the subject is discharged from the hospital on Days 2 or 4 or 6, ensure hematology/chemistry 
sample has been obtained prior to discharge and collect these results on the appropriate EDC page. 
Following discharge, the subject is to return to the research facility for the Days 7 and 15 visits if 
able and permitted.  
If discharge occurs on Days 10, 11, or 12, ensure a hematology/chemistry sample has been 
obtained prior to discharge and record these results on the appropriate EDC page. Following 
discharge, the subject is to return to the research facility for the Day 15 visit if able and permitted. 
If discharge occurs on Days 13, 14 or 15, complete the Day 15 Final Visit activities. No further 
visits are required unless follow up is needed for a study drug-related AE or an SAE; the Day 29 
mortality assessment is still to take place. 
If the subject is unable or not permitted to return for planned study visits, the visit activities will 
be conducted by contacting the subject (phone or other digital media) except for the lab draw. The 
lab draw will be completed at an outpatient laboratory.  
Study completion or the reason for study discontinuation will be recorded in the source document 
and the eCRF. A subject is considered completed the study if they have assessments through Day 
15, whether conducted in the hospital or contacted via phone or other digital media. 
8.5 Concomitant Medication/Treatment 
Record the name, 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. The use of other DHODH inhibitors is not permitted 
during the study including leflunomide or teriflunomide (see Section 8.8).  
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8.6 Treatment Compliance 
Compliance will be assessed by reviewing the subject’s EHR and other 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  
Each brequinar bottle/dispensing container for subject use will be labeled with at least the 
following information: 
For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: Brequinar 100 mg capsules 
For oral use only. Take with approximately 8 ounces water. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.7.3 Blinding and Randomization 
The trial will be conducted in an open-label manner with random assignment to standard of care 
or standard of care plus brequinar. The brequinar capsules will be provided to each participating 
institution in bulk to be dispensed by the institution’s pharmacist for each subject. Randomization 
assignments will be provided by the sponsor. 
8.7.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment will be known for 
each subject. 
Expectedness will be determined by establishing whether the 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.   
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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, used and discarded.  It must 
be clear from the records whether the subject received study medication or was assigned to 
standard of care. 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. 
8.8 Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide), 
tacrolimus, sirolimus, or pre-existing prednisone at higher than 20 mg daily (ongoing or within 2 
weeks of study entry). 
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 telephone or other digital media. Study information is to be 
collected from the EHR as much as possible such as NEWS2 Assessments, height, weight, 
hematology/chemistry, from Progress Notes for AEs, and from medication records for new or 
changed concomitant medications. Visits to an outpatient laboratory post hospital discharge may 
be required if subjects are not able or permitted to return for follow up study visits.  
 
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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), 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.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures. Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be subject to review by the Sponsor; a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. 
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 
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 265 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 266 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 267 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 268 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 36 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
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 15. After Day 
15, collect/record only Serious Adverse Events (SAEs) or those judged 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.   
Any serious adverse events (SAEs) experienced after 30 days post the last dose of study drug 
should only be reported to the sponsor if the investigator suspects a causal relationship to the 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, or require therapy. 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the appropriate electronic data capture form.  
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 
Clinical Study Report 
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CONFIDENTIAL
03 May 2021
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
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03 May 2021
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Clinical Study Report 
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CONFIDENTIAL
03 May 2021
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 40 of 55 
PROTOCOL VERSION DATE: 01MAY2020 
 
The Sponsor is to 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 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to 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 knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must 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.   
10.5 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 the Sponsor Contact 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 pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as 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-
up with 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. 
10.6 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 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 01MAY2020 
 
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 analyses will be based on the ITT population, which is defined as all randomized subjects.   
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, NEWS2 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 
NEWS2 Assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will be assessed in terms of mortality, hospitalization status and duration, NEWS2 score, 
viral load (plasma and nasopharyngeal), and inflammatory markers. 
11.4 DHO and Brequinar Concentration Levels 
DHO and brequinar concentrations levels will be summarized using descriptive statistics. 
11.5 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 24 
subjects are planned to be entered in this trial.  Additional subjects may be enrolled following data 
review. 
11.6 Randomization 
A randomization scheme will be provided by the Sponsor to ensure subjects are randomly assigned 
to SOC or SOC + brequinar in a 1:2 ratio.  
11.7 Pooling of Study Centers 
Not applicable to this small, early phase study. 
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11.8 Interim Analysis 
No interim analysis is planned for this trial. 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 01MAY2020 
 
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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 01MAY2020 
 
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) 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. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the 
assessment of acute-illness severity in the NHS. Updated report of a working party. 
London: RCP, 2017. 
15. Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K, and the 
Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. 
JAMA. April 22, 2020. https://jama.doi:10:1001/jama.2020.6775. 
16. Study DUP 785-001 Clinical Study Report (on file with Clear Creek) 
17. Study DUP 785-003 Clinical Study Report (on file with Clear Creek) 
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18. Study DUP 785-005 Clinical Study Report (on file with Clear Creek) 
19. Study DUP 785-022 Clinical Study Report (on file with Clear Creek) 
20. Study DUP 785-031 Clinical Study Report (on file with Clear Creek) 
21. Study DUP 785-034 Clinical Study Report (on file with Clear Creek) 
 
 
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15 APPENDICES 
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events 
CCB-CRISIS-01  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2 - D7 
(± 8 hours) 
Final Visit  
D15 
(± 2 days) 
F/U  
Phone 
Call 
2 weeks/ 
Survival 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
AE/Concomitant Medications  
X 
X 
D7 
X 
 
Medical history / History of current illness 
X 
 
 
 
 
Demographics, collect Height and weight 
X 
 
 
 
 
Check for Physical Exam abnormalities 
X 
 
 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
Hematology/Chemistry 
X 
X (pre-dose) 
 D7 
X 
 
Inflammatory Markers* 
 
X (pre-dose) 
D3, D5, D7 
X 
 
DHO/brequinar PK Sample Collection & Processing 
 
X (pre-dose) 
D3, D5, D7 
X (DHO 
only) 
 
Swab collection for nasopharyngeal viral load 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Clinical SARS-CoV-2 testing RT-PCR 
X 
 
 
 
 
Hospital Status 
 
 
D3, D5, D7 
X 
 
NEWS2 Assessments 
 
X 
D3, D5, D7 
X 
 
Dispense Study Medication if assigned to brequinar 
 
X 
D2 – 5 
 
 
Drug Accountability 
 
 
D7 
 
 
Survival Assessment Day 29 
 
 
 
 
X 
Collect information from available electronic health record (EHR), Progress Notes, and medication 
records; a special visit by research staff is not to be performed. Hematology, Results for Chemistry 
and available inflammatory markers analyzed locally are to be obtained from the EHR; do not 
draw another set of labs. Missed samples due to hospital staff too busy or for technical reasons 
unable to obtain samples will not be counted as protocol deviations. 
Note that any visits other than Screening/Day 1 may be conducted via telephone or digital media. 
Missed samples/assessments when phone visits occur will not be counted as protocol deviations. 
*Inflammatory markers are to be collected from the EHR when available; otherwise process and 
ship samples to the central laboratory per the Laboratory Manual. DHO and brequinar samples 
will also be sent to the central laboratory. 
Note that if the subject is discharged before Day 15, ensure safety laboratory samples for 
hematology and chemistry are obtained prior to discharge and on an outpatient basis per Section 
8.4. 
 
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15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-01 
STUDY TITLE:  The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in hospitalized adults with 
coronavirus-19 (COVID-19). 
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: __________________ 
 
Site Address: 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
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15.3 Appendix C: National Early Warning Score (NEWS2)  
Use SpO2 Scale 2 if target range is 88 – 92%, e.g., in hypercapnic respiratory failure. 
National Early Warning System Score (NEWS) 2  Royal College of Physicians 2017 [14] 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05JUNE2020 FINAL 
 
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in 
hospitalized adults with coronavirus-19 (COVID-19) 
 
Study No: CCB-CRISIS-01 
Version Date:  05 JUNE 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 .............................................................................................................. 18 
3.1 Background ................................................................................................................ 18 
3.2 Coronavirus-19 (COVID-19) ..................................................................................... 18 
3.2.1 Coronavirus Biology .................................................................................................... 18 
3.3 Host Nucleotide Synthesis ......................................................................................... 18 
3.4 Dihydroorotate dehydrogenase (DHODH) ................................................................ 18 
3.5 Brequinar .................................................................................................................... 19 
3.6 Rationale for the Planned Trial .................................................................................. 19 
3.6.1 Brequinar Dose Selection ............................................................................................. 20 
3.6.2 Risk/Benefit of Brequinar ............................................................................................ 20 
3.7 Risks Associated with Participation in the Clinical Study ......................................... 20 
3.8 Possible Interactions with Concomitant Medical Treatments .................................... 21 
3.8.1 CYP Interactions .......................................................................................................... 21 
3.9 Steps to be Taken to Control or Mitigate Risks ......................................................... 21 
4 TRIAL OBJECTIVES ........................................................................................................ 23 
4.1 Primary Objective ...................................................................................................... 23 
4.2 Secondary Objectives ................................................................................................. 23 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 23 
5 TRIAL DESIGN ................................................................................................................. 24 
6 TRIAL ENDPOINTS.......................................................................................................... 25 
6.1 Primary Endpoint ....................................................................................................... 25 
6.2 Secondary Endpoints .................................................................................................. 25 
6.3 EXPLORATORY Endpoints ..................................................................................... 25 
7 TRIAL POPULATION ....................................................................................................... 26 
7.1 Number of Subjects .................................................................................................... 26 
7.2 Inclusion criteria ......................................................................................................... 26 
7.3 Exclusion Criteria ....................................................................................................... 27 
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7.4 Inclusion of Women and Minorities........................................................................... 28 
8 STUDY TREATMENTS .................................................................................................... 29 
8.1 Description of Study Medications .............................................................................. 29 
8.1.1 Brequinar ...................................................................................................................... 29 
8.2 Treatment Administration .......................................................................................... 29 
8.2.1 Safety/Tolerability ........................................................................................................ 29 
8.3 Study Discontinuation ................................................................................................ 30 
8.4 Stopping Criteria ........................................................................................................ 30 
8.4.1 Individual Stopping Criteria ......................................................................................... 30 
8.4.2 Study-Level Stopping Criteria...................................................................................... 30 
8.5 Hospital Discharge Prior to Study Day 15 ................................................................. 30 
8.6 Concomitant Medication/Treatment .......................................................................... 31 
8.7 Treatment Compliance ............................................................................................... 31 
8.8 Storage, Stability, Labeling and Packaging ............................................................... 31 
8.8.1 Storage and Stability .................................................................................................... 31 
8.8.2 Labeling and Packaging ............................................................................................... 31 
8.8.3 Blinding and Randomization ........................................................................................ 32 
8.8.4 Unblinding/Expectedness ............................................................................................. 32 
8.8.5 Study Drug Accountability ........................................................................................... 32 
8.9 Prohibited Medications .............................................................................................. 33 
8.10 Study Adjustments Due to COVID-19....................................................................... 33 
9 CONDUCT OF THE TRIAL.............................................................................................. 34 
9.1 Ethical and Regulatory Considerations ...................................................................... 34 
9.2 Informed Consent ....................................................................................................... 34 
9.3 Institutional Review Board......................................................................................... 35 
9.4 Schedule of Events ..................................................................................................... 35 
9.5 Study Conduct ............................................................................................................ 36 
9.5.1 Unscheduled Visits ....................................................................................................... 38 
9.6 Compliance with Study Procedures ........................................................................... 38 
9.7 Early Withdrawal from the Study .............................................................................. 38 
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9.8 Early Termination of the Study .................................................................................. 39 
10 ADVERSE EVENT REPORTING..................................................................................... 40 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 41 
10.2 Infection Follow Up ................................................................................................... 41 
10.3 Classification of Causality ......................................................................................... 41 
10.4 Classification of Severity ........................................................................................... 42 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 42 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 44 
10.7 Pregnancies................................................................................................................. 44 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 45 
10.9 Data Safety Monitoring Board ................................................................................... 46 
10.9.1 
DSMB Safety Review Schedule ............................................................................. 46 
11 STATISTICAL CONSIDERATIONS................................................................................ 47 
11.1 Study Populations for Analysis .................................................................................. 47 
11.2 Safety Analyses .......................................................................................................... 47 
11.3 Efficacy Analyses ....................................................................................................... 47 
11.4 DHO and Brequinar Concentration Levels ................................................................ 47 
11.5 Sample Size Considerations ....................................................................................... 47 
11.6 Randomization ........................................................................................................... 47 
11.7 Pooling of Study Centers............................................................................................ 47 
11.8 Interim Analysis ......................................................................................................... 48 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 49 
12.1 Investigator’s Performance ........................................................................................ 49 
12.2 Confidentiality ............................................................................................................ 49 
12.3 Source Documentation ............................................................................................... 49 
12.4 Data Collection ........................................................................................................... 50 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 50 
12.6 Non-Protocol Research .............................................................................................. 51 
12.7 Publication .................................................................................................................. 51 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 52 
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13.1 General ....................................................................................................................... 52 
13.2 Indemnity ................................................................................................................... 52 
13.3 Data Monitoring ......................................................................................................... 52 
13.4 Audit ........................................................................................................................... 52 
13.5 Confidentiality ............................................................................................................ 53 
13.6 Finance ....................................................................................................................... 53 
14 REFERENCES ................................................................................................................... 54 
15 APPENDICES .................................................................................................................... 56 
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events .................................................. 56 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 57 
15.3 Appendix C: National Early Warning Score (NEWS2) ............................................. 58 
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment Guidance. ..... 59 
 
 
 
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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.
 ............................................... 18 
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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 
DSMB 
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 
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Abbreviation 
Definition 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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2 
SYNOPSIS  
CCB-CRISIS-01 SYNOPSIS  
IND 
149291 
Title 
The CRISIS Study: A randomized open-label study assessing the safety and anti-
coronavirus response of suppression of host nucleotide synthesis in hospitalized 
adults with coronavirus-19 (COVID-19) 
Protocol 
CCB-CRISIS-01 
Rationale 
Brequinar is a potent DHODH inhibitor that has been studied in more than 1,000 
cancer, psoriasis, and organ transplant patients. 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. 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 primary dose-limiting adverse effects have included 
thrombocytopenia and mucositis. 
The CRISIS trial will study standard of care (SOC) and SOC with 5 days of 
DHODH inhibition. 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. 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. Brequinar has not been previously tested as an anti-
viral. 
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:2 ratio to either standard of care (SOC) alone, 
or SOC + brequinar. 
Brequinar is available as 100 mg oral capsules. Five once daily doses of brequinar 
100 mg are to be administered on Study Days 1 – 5 for those assigned to the SOC 
+ brequinar group.  
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 298 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 11 of 59 
PROTOCOL VERSION DATE: 05JUNE2020 FINAL 
 
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 and at least one of the following co-morbidities by 
subject history or present in the institution’s electronic health record: 
hypertension, diabetes, chronic kidney disease, chronic obstructive 
pulmonary disease (COPD) or asthma, cardiovascular disease (coronary 
artery disease or congestive heart failure), liver cirrhosis, age > 65, BMI > 
30.  
3. If discharged from the hospital prior to Study Day 15 or if follow up is 
needed for study drug-related adverse event, willing to go to an outpatient 
laboratory for a laboratory sample as well as a contact (phone call or other 
digital media) on Study Days 7 and 15 and contact only on Day 29. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time 
polymerase chain reaction (RT-PCR) or other FDA-cleared commercial or 
public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating 
physician immediately. Men treated or enrolled on this protocol must also 
agree to use adequate contraception for the duration of study participation, 
and for 90 days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study 
drug administration until 90 days after the last dose of brequinar. 
8. ≤ 10 days since first COVID-19 symptom as determined by treating 
clinician. 
9. COVID-19 symptoms of severity mild (fever, cough, sore throat, malaise, 
headache, muscle pain, gastrointestinal symptoms, without shortness of 
breath or dyspnea), moderate (any symptom of mild illness or shortness of 
breath with exertion), or severe (any symptom of moderate illness or 
shortness of breath at rest, or respiratory distress). 
10. COVID-19 signs of severity mild (no clinical signs), moderate (respiratory 
rate ≥ 20 breaths per minute, saturation of oxygen (SpO2) > 93% on room 
air at sea level, heart rate ≥ 90 beats per minute) or severe (respiratory rate 
≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at 
sea level or PaO2/FiO2 < 300) 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 299 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 12 of 59 
PROTOCOL VERSION DATE: 05JUNE2020 FINAL 
 
Exclusion 
Criteria: 
1. Any physical examination findings and/or history of any illness that, in the 
opinion of the study investigator, might confound the results of the study 
or pose an additional risk to the patient 
2. Active malignancy other than squamous cell carcinoma; anticancer 
treatment such as chemotherapy or radiation therapy within the past month. 
3. Nursing women or women of childbearing potential (WOCBP) with a 
positive pregnancy test. 
4. Treatment 
with 
another 
DHODH 
inhibitor 
(e.g., 
leflunomide, 
teriflunomide), tacrolimus, sirolimus, or pre-existing prednisone at higher 
than 20 mg daily (ongoing or within 2 weeks of study entry). 
5. Platelets ≤150,000 cell/mm3. 
6. Hemoglobin < 12 gm/dL 
7. Absolute neutrophil count < 1500 cells/mm3 
8. Renal dysfunction, i.e., creatinine clearance < 50 mL/min 
9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN 
10. History of bleeding disorders or recent surgery in the six weeks preceding 
enrollment 
11. Concomitant use of agents known to cause thrombocytopenia 
12. Concomitant use of corticosteroids, regardless of dose; or use of 
corticosteroids at any dose in the two weeks preceding enrollment. 
13. History of gastrointestinal ulcer, or history of gastrointestinal bleeding. 
14. History of hepatitis B and/or C infection, active liver disease and/or 
cirrhosis. 
15. History of known cardiovascular disease including unstable angina, 
myocardial infarction, uncontrolled arrythmias, and heart failure. 
16. Baseline COVID-19 severity characterized as “Critical” based on the FDA 
Guidance “COVID-19: Developing Drugs and Biological Products for the 
Treatment or Prevention (https://www.fda.gov/media/137926/download). 
Evidence of critical illness defined by at least one of the following: 
1. Respiratory failure based on resource utilization requiring at least 
one of the following: 
1. Endotracheal intubation and mechanical ventilation, oxygen 
delivered by high-flow nasal cannula (heated, humidified 
oxygen delivered via reinforced nasal cannula at flow rates 
> 20 L/min with fraction of delivered oxygen ≥ 0.5), 
noninvasive positive pressure ventilation, ECMO, or 
clinical diagnosis of respiratory failure (i.e., clinical need 
for one of the preceding therapies, but preceding therapies 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 300 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 301 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 302 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 303 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 16 of 59 
PROTOCOL VERSION DATE: 05JUNE2020 FINAL 
 
If discharge occurs on Days 10, 11, or 12, ensure a hematology/chemistry sample 
has been obtained prior to discharge and record these results on the appropriate 
EDC page. Following discharge, the subject is to return to the research facility for 
the Day 15 visit if able and permitted. 
If discharge occurs on Days 13, 14 or 15, complete the Day 15 Final Visit activities. 
No further visits are required unless follow up is needed for a study drug-related 
AE or an SAE; the Day 29 mortality assessment is still to take place. 
If the subject is unable or not permitted to return for planned study visits, the visit 
activities will be conducted by contacting the subject (phone or other digital media) 
except for the lab draw. The hematology/chemistry sample will be obtained via 
outpatient laboratory.  
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF. A subject is considered completed the study if 
they have assessments through Day 15, whether conducted in the hospital or 
contacted via phone or other digital media. 
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of informed consent through Day 
15. After Day 15, collect/record only Serious Adverse Events (SAEs) or those 
judged by the Investigator or designated person to be related to study drug, 
including but not limited to potential hematologic toxicities. Post-randomization 
adverse events will be those with an onset after the date and time of randomization. 
Subjects who develop Grade 3 or 4 toxicities are to be re-evaluated every 2 days, 
as feasible, until the toxicity returns to Grade ≤ 2 severity. 
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, safety 
laboratory data, and NEWS2 Assessments.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of post randomization adverse events, defined as AEs 
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, NEWS2 
Criteria, and other clinical measures will be summarized using appropriate 
descriptive statistics. 
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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:  
Sharon Levy, MD 
Title: 
Prosoft Clinical 
Telephone No.: 
M: (610) 316-9764 
O: (484) 320-2062 
E-mail: 
s.levy@prosoftclinical.com 
Sharon.levy27@gmail.com 
 
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3 
INTRODUCTION 
3.1 Background 
3.2 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]).  
3.2.1 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]). 
3.3  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.  
3.4  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. 
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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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]).    
3.5  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]). 
3.6  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 CRISIS trial will study standard of care (SOC) and SOC with 5 days of DHODH inhibition. 
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, 
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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.  
3.6.1 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 
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 reassuring the safety of 
this regimen (see Brequinar IB [5]).  
3.6.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive database exists with more than 800 cancer 
patients 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. Brequinar has 
also been utilized at lower doses than used in the cancer studies in 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. While no DHODHi has been tested to date in the clinic for 
infection with SARS-CoV-2 and no brequinar safety information is available in treatment of this 
disease, DHODHi therapy in the context of trials for patients with cancer has the expected safety 
side-effects of mucositis and bone marrow suppression. 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 mucositis and only 1 (2.6%) episode of mild thrombocytopenia. The 100 mg per day dose 
proposed for administration in this study should be safe and well tolerated.  
The possible 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. As discussed above, inhibition of DHODH is expected to reduce the ability 
of the virus to replicate and it is for this reason that study CCB-CRISIS-01 will administer 
brequinar to patients with COVID-19. 
 
3.7 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of brequinar in patients with refractory 
solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis have 
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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.  
COVID-19 patients are at higher risk of complications and poor outcomes when their infection is 
combined with comorbidities including hypertension, diabetes, chronic kidney disease, chronic 
obstructive pulmonary disease (COPD) or asthma, cardiovascular disease (coronary artery disease 
or congestive heart failure), liver cirrhosis, age > 65, and BMI > 30 [15]. Therefore, participants 
in this protocol must have at least one of these comorbidities in order to justify that the risks of 
potential and known toxicities associated with brequinar are outweighed by the potential benefits 
in this higher risk population. 
In addition to ensuring a higher risk population, 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).  
3.8 Possible Interactions with Concomitant Medical Treatments 
While not previously tested in patients with viral infections, brequinar has been administered to 
subjects taking a variety of concomitant medications that are typical in severely ill cancer patients. 
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. Brequinar has also been used concomitantly with antibiotics, antifungals and other 
critical care medications. 
 
There is no experience with brequinar for treatment of SARS-CoV-2 and other severe viral 
infections and no formal interaction studies have been conducted.  
3.8.1 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).  
3.9 Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated in a hospital setting by highly experienced infectious disease or other 
critical care specialists and other qualified staff familiar with the treatment of severe viral 
infections and their complications.  
Subjects in the Brequinar Treatment Group 
If the subject is in the brequinar treatment group and is being discharged prior to completing the 
study, ensure a hematology/chemistry sample is obtained prior to discharge on the day of 
discharge. The subject is to return to the research facility for the Days 7 and 15 visits if able and 
permitted. If unable or not permitted to return to the research facility due to COVID-19 restrictions, 
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the remaining visit activities except for the lab draw will be conducted by phone or other digital 
media. The lab draw will be performed by an outpatient laboratory at a designated facility. Lab 
draws for any outpatient visits for the Day 7 and 15 visits are limited to safety labs (hematology 
and chemistry). Additional outpatient laboratory or study visits are to be conducted as needed for 
follow up of adverse events including hematologic toxicities. 
 
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5 
TRIAL DESIGN 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care per institutional guidelines for treatment of patients with 
SARS-CoV-2 infection. In addition to standard of care, the brequinar group will receive brequinar 
100 mg once daily for 5 days.    
The Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance is provided in 
Appendix D Section 15.4. This guidance provides an example of standard of care instructions for 
treatment of COVID-19. The guidance is provided as informational only, it is not required that this 
guidance be used for treatment as standards of care may differ between institutions. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Study procedures are presented in 
detail in Section 8. Subjects will be followed through Day 15, with mortality assessed via a phone 
call/other digital media acceptable to institution on Day 29. 
If the subject is being discharged prior to Day 7, see Section 8.5. 
It is understood that some assessments may not be conducted if the subject is unable to return to 
the clinic after discharge due to restricted travel. If an assessment is missed due to after hospital 
discharge, e.g., samples or blood draws, this will not be counted as a protocol deviation. Any of 
the study visits may be conducted via telephone if the subject has been discharged from the hospital 
and is not permitted to or is unable to return to the hospital/clinic for these visits. 
Information is to be collected using the electronic health record (EHR) whenever possible. It is not 
required to perform study-specific laboratory assessments, NEWS 2 assessments, etc. separately 
for study purposes. 
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7 
TRIAL POPULATION 
7.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 24 subjects have completed the study. Subjects will be randomized to either 
standard of care or standard of care plus brequinar or in a 1:2: ratio (approximately 8 subjects 
assigned to standard of care alone and approximately 16 subjects on standard of care plus 
brequinar).  
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 and at least one of the following co-morbidities by subject history 
or present in the institution’s electronic health record: hypertension, diabetes, chronic 
kidney disease, chronic obstructive pulmonary disease (COPD) or asthma, cardiovascular 
disease (coronary artery disease or congestive heart failure), liver cirrhosis, age > 65, BMI 
> 30.  
3. If discharged from the hospital prior to Study Day 15 or if follow up is needed for study 
drug-related adverse event, willing to go to an outpatient laboratory to obtain a laboratory 
sample as well as a contact (phone call or other digital media) on Study Days 7 and 15 and 
contact only on Day 29.  
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase 
chain reaction (RT-PCR) or other Food and Drug Administration (FDA)-cleared 
commercial or public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men treated or enrolled on this protocol must also agree to 
use adequate contraception for the duration of study participation and for 90 days after 
completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of brequinar.  
8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician. 
9. COVID-19 symptoms of severity mild (fever, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnea), 
moderate (any symptom of mild illness or shortness of breath with exertion), or severe 
(any symptom of moderate illness or shortness of breath at rest, or respiratory distress). 
[22]. 
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10. COVID-19 signs of severity mild (no clinical signs), moderate (respiratory rate ≥ 20 
breaths per minute, saturation of oxygen (SpO2) > 93% on room air at sea level, heart rate 
≥ 90 beats per minute) or severe (respiratory rate ≥ 30 per minute, heart rate ≥ 125 per 
minute, SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300) [22]. 
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. Active malignancy other than squamous cell carcinoma; anticancer treatment such as 
chemotherapy or radiation therapy within the past month. 
3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy 
test. 
4. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide), tacrolimus, 
sirolimus, or pre-existing prednisone at higher than 20 mg daily (ongoing or within 2 weeks 
of study entry). 
5. Platelets ≤150,000 cell/mm3. 
6. Hemoglobin < 12 gm/dL 
7. Absolute neutrophil count < 1500 cells/mm3 
8. Renal dysfunction, i.e., creatinine clearance < 50 mL/min 
9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN 
10. History of bleeding disorders or recent surgery in the six weeks preceding enrollment 
11. Concomitant use of agents known to cause thrombocytopenia 
12. Concomitant use of corticosteroids, regardless of dose; or use of corticosteroids at any dose 
in the two weeks preceding enrollment. 
13. History of gastrointestinal ulcer, or history of gastrointestinal bleeding. 
14. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis. 
15. History of known cardiovascular disease including unstable angina, myocardial infarction, 
uncontrolled arrythmias, and heart failure. 
16. Baseline COVID-19 severity characterized as “Critical” based on the FDA Guidance 
“COVID-19: Developing Drugs and Biological Products for the Treatment or Prevention 
(https://www.fda.gov/media/137926/download). Evidence of critical illness defined by at 
least one of the following: 
a. Respiratory failure based on resource utilization requiring at least one of the 
following: 
i. Endotracheal intubation and mechanical ventilation, oxygen delivered by 
high-flow nasal cannula (heated, humidified oxygen delivered via 
reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered 
oxygen ≥ 0.5), noninvasive positive pressure ventilation, ECMO, or clinical 
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diagnosis of respiratory failure (i.e., clinical need for one of the preceding 
therapies, but preceding therapies may not be able to be administered in 
setting of resource limitation) 
b. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure 
< 60 mm Hg or requiring vasopressors) 
c. Multi-organ dysfunction/failure. See [22].  
7.4 Inclusion of Women and Minorities 
Adult men and women of all races and ethnic groups are eligible for this trial. 
 
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8 
STUDY TREATMENTS 
8.1 Description of Study Medications 
8.1.1 Brequinar 
Brequinar will be supplied as 100 mg capsules. Dosing will be a single 5-day course of brequinar 
100 mg once daily for 5 doses. The initial brequinar dose (Day 1) should be administered as soon 
as possible based on study drug availability from the investigational pharmacy. 
8.2 Treatment Administration 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 
infection. Subjects will be randomly assigned in a 1:2 ratio to standard of care alone or standard 
of care plus brequinar. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE).  
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 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 (Study 785-001 [16], 785-003 [17], and 785-005 [18]) with five 
consecutive days of intravenous (IV) brequinar dosing and 168 subjects, there were no toxic 
deaths. For subjects from these three studies who were treated with a dose of 100 mg or below  
(as will be dosed in CCB-CRISIS-01), 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 [19], 785-031 [20] , and 785-034 [21]), 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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If discharge occurs on Days 10, 11, or 12, ensure a hematology/chemistry sample has been 
obtained prior to discharge and record these results on the appropriate EDC page. Following 
discharge, the subject is to return to the research facility for the Day 15 visit if able and permitted. 
If discharge occurs on Days 13, 14 or 15, complete the Day 15 Final Visit activities. No further 
visits are required unless follow up is needed for a study drug-related AE or an SAE; the Day 29 
mortality assessment is still to take place. 
If the subject is unable or not permitted to return for planned study visits, the visit activities will 
be conducted by contacting the subject (phone or other digital media) except for the lab draw. The 
lab draw will be completed at an outpatient laboratory when feasible.  
Study completion or the reason for study discontinuation will be recorded in the source document 
and the eCRF. A subject is considered completed the study if they have assessments through Day 
15, whether conducted in the hospital or contacted via phone or other digital media. 
8.6 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 8.9.  
8.7 Treatment Compliance 
Compliance will be assessed by reviewing the subject’s EHR and other study records as 
appropriate. 
8.8 Storage, Stability, Labeling and Packaging 
8.8.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.8.2 Labeling and Packaging  
Each brequinar bottle/dispensing container for subject use will be labeled with at least the 
following information: 
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For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: Brequinar 100 mg capsules 
For oral use only. Take with approximately 8 ounces water. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.8.3 Blinding and Randomization 
The trial will be conducted in an open-label manner with random assignment to standard of care 
or standard of care plus brequinar. The brequinar capsules will be provided to each participating 
institution in bulk to be dispensed by the institution’s pharmacist for each subject. Randomization 
assignments will be provided by the sponsor. 
8.8.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment will be known for 
each subject. 
Expectedness will be determined by establishing whether the 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.   
8.8.5 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, used and discarded.  It must 
be clear from the records whether the subject received study medication or was assigned to 
standard of care. 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.   
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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. 
8.9 Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide), 
tacrolimus, sirolimus, or pre-existing prednisone at higher than 20 mg daily (ongoing or within 2 
weeks of study entry). Treatment is prohibited with agents known to cause thrombocytopenia. 
Concomitant use of corticosteroids, regardless of dose or use or corticosteroids at any dose in the 
two weeks preceding enrollment is also prohibited. 
8.10 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 telephone or other digital media. Study information is to be 
collected from the EHR as much as possible such as NEWS2 Assessments, height, weight, 
hematology/chemistry, from Progress Notes for AEs, and from medication records for new or 
changed concomitant medications. Visits to an outpatient laboratory post hospital discharge may 
be required if subjects are not able or permitted to return for follow up study visits.  
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). Remdesivir may be used in this clinical trial as a component of standard of care 
of patients hospitalized with severe disease in settings where remdesivir is available via the 
Emergency Use Authorization (EUA). 
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), 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.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures. Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be subject to review by the Sponsor; a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. 
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 
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 326 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 327 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 40 of 59 
PROTOCOL VERSION DATE: 05JUNE2020 FINAL 
 
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 15. After Day 
15, collect/record only Serious Adverse Events (SAEs) or those judged 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.   
Any serious adverse events (SAEs) experienced after 30 days post the last dose of study drug 
should only be reported to the sponsor if the investigator suspects a causal relationship to the 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, or require therapy. 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the appropriate electronic data capture form.  
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 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 328 of 582


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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05JUNE2020 FINAL 
 
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 Medical Monitor 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 is to 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 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to 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 knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must 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 the Sponsor Contact 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 pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
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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-
up with 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 selecting a relatively brief 5-day exposure and a low brequinar dose, all 
subjects in the clinical trial will initially be hospitalized as in-patients and will be under the care 
of highly qualified infectious disease, critical care, and associated medical personnel. As is 
standard of care for moderately to severely ill in-patients, daily samples will be obtained for 
hematology assessments including complete blood count with full differential (WBC, RBC, 
hemoglobin, hematocrit, platelet count, absolute neutrophils, absolute lymphocytes, absolute 
monocytes, absolute eosinophils, and absolute basophils). Any clinically significant out-of-range 
laboratory values will be assessed by hospital staff in a timely manner and treatment needs 
addressed as appropriate. 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 Clear Creek Medical Monitor 
will assess the available hematology data on a weekly 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, the Sponsor, and the Medical Monitor. In 
addition, the Data Safety Monitoring Board 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. 
Subjects who are discharged from the hospital before Day 7 will have follow up contacts with 
study staff (phone calls or other digital media) on Days 7, 15 and 29. Early discharge subjects in 
the brequinar treatment group will also have samples for safety labs (hematology and chemistry) 
obtained either at the research facility or at an outpatient laboratory on Study Days 7 ± 2 and 15 ± 
2. The safety laboratory results are to be initially assessed in real time by the Principal Investigator 
or designated person and the Medical Monitor. 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-hospital assessments and phone call visits will specifically ask about possible hematologic 
toxicity including any evidence of the list below. Early discharge 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. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05JUNE2020 FINAL 
 
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 analyses will be based on the ITT population, which is defined as all randomized subjects.   
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, NEWS2 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 
NEWS2 Assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will be assessed in terms of mortality, hospitalization status and duration, NEWS2 score, 
viral load (plasma and nasopharyngeal), and inflammatory markers. 
11.4 DHO and Brequinar Concentration Levels 
DHO and brequinar concentrations levels will be summarized using descriptive statistics. 
11.5 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 24 
subjects are planned to be entered in this trial.  Additional subjects may be enrolled following data 
review. 
11.6 Randomization 
A randomization scheme will be provided by the Sponsor to ensure subjects are randomly assigned 
to SOC or SOC + brequinar in a 1:2 ratio.  
11.7 Pooling of Study Centers 
Not applicable to this small, early phase study. 
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11.8 Interim Analysis 
No interim analysis is planned for this trial. 
 
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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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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) 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. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the 
assessment of acute-illness severity in the NHS. Updated report of a working party. 
London: RCP, 2017. 
15. Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K, and the 
Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. 
JAMA. April 22, 2020. https://jama.doi:10:1001/jama.2020.6775. 
16. Study DUP 785-001 Clinical Study Report (on file with Clear Creek) 
17. Study DUP 785-003 Clinical Study Report (on file with Clear Creek) 
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18. Study DUP 785-005 Clinical Study Report (on file with Clear Creek) 
19. Study DUP 785-022 Clinical Study Report (on file with Clear Creek) 
20. Study DUP 785-031 Clinical Study Report (on file with Clear Creek) 
21. Study DUP 785-034 Clinical Study Report (on file with Clear Creek) 
22. 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-01 Schedule of Events 
CCB-CRISIS-01  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2 - D7 
(± 8 hours) 
Final Visit  
D15 
(± 2 days) 
F/U  
Phone 
Call 
2 weeks/ 
Survival 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
AE/Concomitant Medications (daily until discharge) 
X 
X 
D1-7 
X 
 
Medical history / History of current illness 
X 
 
 
 
 
Demographics, collect Height and weight 
X 
 
 
 
 
Check for Physical Exam abnormalities 
X 
 
 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
Hematology/Chemistry 
X 
X (pre-dose) 
 D1-7 
X 
 
Inflammatory Markers* 
 
X (pre-dose) 
D3, D5, D7 
X 
 
DHO/brequinar PK Sample Collection & Processing 
 
X (pre-dose) 
D3, D5, D7 
X (DHO only) 
 
Swab collection for nasopharyngeal viral load 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Clinical SARS-CoV-2 testing RT-PCR 
X 
 
 
 
 
Hospital Status 
 
 
D3, D5, D7 
X 
 
NEWS2 Assessments 
 
X 
D3, D5, D7 
X 
 
Dispense Study Medication if assigned to brequinar 
 
X 
D2 – 5 
 
 
Drug Accountability 
 
 
D7 
 
 
Survival Assessment Day 29 
 
 
 
 
X 
Collect information from available electronic health record (EHR), Progress Notes, and medication 
records; a special visit by research staff is not to be performed. Results for Hematology, Chemistry 
and available inflammatory markers analyzed locally are to be obtained from the EHR; do not 
draw another set of labs. Missed samples due to hospital staff too busy or for technical reasons 
unable to obtain samples will not be counted as protocol deviations. Record urinalysis results if 
urinalysis is clinically indicated and results are available in the EHR. 
Note that any visits other than Screening/Day 1 may be conducted via telephone or digital media. 
Missed samples/assessments when phone visits occur will not be counted as protocol deviations. 
*Inflammatory markers are to be collected from the EHR when available; otherwise process and 
ship samples to the central laboratory per the Laboratory Manual. DHO and brequinar samples 
will also be sent to the central laboratory. 
Note that if the subject is discharged before Day 15, ensure safety laboratory samples for 
hematology and chemistry are obtained prior to discharge and on an outpatient basis when feasible 
per Section 8.5. 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05JUNE2020 FINAL 
 
15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-01 
STUDY TITLE:  The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in hospitalized adults with 
coronavirus-19 (COVID-19). 
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: __________________ 
 
Site Address: 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
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15.3 Appendix C: National Early Warning Score (NEWS2)  
Use SpO2 Scale 2 if target range is 88 – 92%, e.g., in hypercapnic respiratory failure. 
National Early Warning System Score (NEWS) 2 Royal College of Physicians 2017 [14]. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 1 of 59 
PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in 
hospitalized adults with coronavirus-19 (COVID-19) 
 
Study No: CCB-CRISIS-01 
Version Date:  06 JULY 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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 18 
3.1 Background ................................................................................................................ 18 
3.2 Coronavirus-19 (COVID-19) ..................................................................................... 18 
3.2.1 Coronavirus Biology .................................................................................................... 18 
3.3 Host Nucleotide Synthesis ......................................................................................... 18 
3.4 Dihydroorotate dehydrogenase (DHODH) ................................................................ 18 
3.5 Brequinar .................................................................................................................... 19 
3.6 Rationale for the Planned Trial .................................................................................. 19 
3.6.1 Brequinar Dose Selection ............................................................................................. 20 
3.6.2 Risk/Benefit of Brequinar ............................................................................................ 20 
3.7 Risks Associated with Participation in the Clinical Study ......................................... 20 
3.8 Possible Interactions with Concomitant Medical Treatments .................................... 21 
3.8.1 CYP Interactions .......................................................................................................... 21 
3.9 Steps to be Taken to Control or Mitigate Risks ......................................................... 21 
4 TRIAL OBJECTIVES ........................................................................................................ 23 
4.1 Primary Objective ...................................................................................................... 23 
4.2 Secondary Objectives ................................................................................................. 23 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 23 
5 TRIAL DESIGN ................................................................................................................. 24 
6 TRIAL ENDPOINTS.......................................................................................................... 25 
6.1 Primary Endpoint ....................................................................................................... 25 
6.2 Secondary Endpoints .................................................................................................. 25 
6.3 EXPLORATORY Endpoints ..................................................................................... 25 
7 TRIAL POPULATION ....................................................................................................... 26 
7.1 Number of Subjects .................................................................................................... 26 
7.2 Inclusion criteria ......................................................................................................... 26 
7.3 Exclusion Criteria ....................................................................................................... 27 
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7.4 Inclusion of Women and Minorities........................................................................... 28 
8 STUDY TREATMENTS .................................................................................................... 29 
8.1 Description of Study Medications .............................................................................. 29 
8.1.1 Brequinar ...................................................................................................................... 29 
8.2 Treatment Administration .......................................................................................... 29 
8.2.1 Safety/Tolerability ........................................................................................................ 29 
8.3 Study Discontinuation ................................................................................................ 30 
8.4 Stopping Criteria ........................................................................................................ 30 
8.4.1 Individual Stopping Criteria ......................................................................................... 30 
8.4.2 Study-Level Stopping Criteria...................................................................................... 30 
8.5 Hospital Discharge Prior to Study Day 15 ................................................................. 30 
8.6 Concomitant Medication/Treatment .......................................................................... 31 
8.7 Treatment Compliance ............................................................................................... 31 
8.8 Storage, Stability, Labeling and Packaging ............................................................... 31 
8.8.1 Storage and Stability .................................................................................................... 31 
8.8.2 Labeling and Packaging ............................................................................................... 31 
8.8.3 Blinding and Randomization ........................................................................................ 32 
8.8.4 Unblinding/Expectedness ............................................................................................. 32 
8.8.5 Study Drug Accountability ........................................................................................... 32 
8.9 Prohibited Medications .............................................................................................. 33 
8.10 Study Adjustments Due to COVID-19....................................................................... 33 
9 CONDUCT OF THE TRIAL.............................................................................................. 34 
9.1 Ethical and Regulatory Considerations ...................................................................... 34 
9.2 Informed Consent ....................................................................................................... 34 
9.3 Institutional Review Board......................................................................................... 35 
9.4 Schedule of Events ..................................................................................................... 35 
9.5 Study Conduct ............................................................................................................ 36 
9.5.1 Unscheduled Visits ....................................................................................................... 38 
9.6 Compliance with Study Procedures ........................................................................... 38 
9.7 Early Withdrawal from the Study .............................................................................. 38 
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9.8 Early Termination of the Study .................................................................................. 39 
10 ADVERSE EVENT REPORTING..................................................................................... 40 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 41 
10.2 Infection Follow Up ................................................................................................... 41 
10.3 Classification of Causality ......................................................................................... 41 
10.4 Classification of Severity ........................................................................................... 42 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 42 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 44 
10.7 Pregnancies................................................................................................................. 44 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 45 
10.9 Data Safety Monitoring Board ................................................................................... 46 
10.9.1 
DSMB Safety Review Schedule ............................................................................. 46 
11 STATISTICAL CONSIDERATIONS................................................................................ 47 
11.1 Study Populations for Analysis .................................................................................. 47 
11.2 Safety Analyses .......................................................................................................... 47 
11.3 Efficacy Analyses ....................................................................................................... 47 
11.4 DHO and Brequinar Concentration Levels ................................................................ 47 
11.5 Sample Size Considerations ....................................................................................... 47 
11.6 Randomization ........................................................................................................... 47 
11.7 Pooling of Study Centers............................................................................................ 47 
11.8 Interim Analysis ......................................................................................................... 48 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 49 
12.1 Investigator’s Performance ........................................................................................ 49 
12.2 Confidentiality ............................................................................................................ 49 
12.3 Source Documentation ............................................................................................... 49 
12.4 Data Collection ........................................................................................................... 50 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 50 
12.6 Non-Protocol Research .............................................................................................. 51 
12.7 Publication .................................................................................................................. 51 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 52 
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13.1 General ....................................................................................................................... 52 
13.2 Indemnity ................................................................................................................... 52 
13.3 Data Monitoring ......................................................................................................... 52 
13.4 Audit ........................................................................................................................... 52 
13.5 Confidentiality ............................................................................................................ 53 
13.6 Finance ....................................................................................................................... 53 
14 REFERENCES ................................................................................................................... 54 
15 APPENDICES .................................................................................................................... 56 
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events .................................................. 56 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 57 
15.3 Appendix C: National Early Warning Score (NEWS2) ............................................. 58 
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment Guidance. ..... 59 
 
 
 
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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. ............................................... 18 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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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 
DSMB 
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 
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Abbreviation 
Definition 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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2 
SYNOPSIS  
CCB-CRISIS-01 SYNOPSIS  
IND 
149291 
Title 
The CRISIS Study: A randomized open-label study assessing the safety and anti-
coronavirus response of suppression of host nucleotide synthesis in hospitalized 
adults with coronavirus-19 (COVID-19) 
Protocol 
CCB-CRISIS-01 
Rationale 
Brequinar is a potent DHODH inhibitor that has been studied in more than 1,000 
cancer, psoriasis, and organ transplant patients. 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. 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 primary dose-limiting adverse effects have included 
thrombocytopenia and mucositis. 
The CRISIS trial will study standard of care (SOC) and SOC with 5 days of 
DHODH inhibition. 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. 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. Brequinar has not been previously tested as an anti-
viral. 
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:2 ratio to either standard of care (SOC) alone, 
or SOC + brequinar. 
Brequinar is available as 100 mg oral capsules. Five once daily doses of brequinar 
100 mg are to be administered on Study Days 1 – 5 for those assigned to the SOC 
+ brequinar group.  
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PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
Inclusion 
Criteria: 
 
1. Willing and able to provide informed consent for the trial, written, 
electronic, verbal or other method deemed acceptable by the institution and 
IRB.  
2. 18 years of age or older.  
3. If discharged from the hospital prior to Study Day 15 or if follow up is 
needed for study drug-related adverse event, willing to go to an outpatient 
laboratory for a laboratory sample as well as a contact (phone call or other 
digital media) on Study Days 7 and 15 and contact only on Day 29. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time 
polymerase chain reaction (RT-PCR) or other FDA-cleared commercial or 
public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating 
physician immediately. Men and women treated or enrolled on this protocol 
must also agree to use adequate contraception for the duration of study 
participation, and for 90 days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study 
drug administration until 90 days after the last dose of brequinar. 
8. ≤ 10 days since first COVID-19 symptom as determined by treating 
clinician. 
9. COVID-19 symptoms of severity mild (fever, cough, sore throat, malaise, 
headache, muscle pain, gastrointestinal symptoms, without shortness of 
breath or dyspnea), moderate (any symptom of mild illness or shortness of 
breath with exertion), or severe (any symptom of moderate illness or 
shortness of breath at rest, or respiratory distress). 
10. COVID-19 signs of severity mild (no clinical signs), moderate (respiratory 
rate ≥ 20 breaths per minute, saturation of oxygen (SpO2) > 93% on room 
air at sea level, heart rate ≥ 90 beats per minute) or severe (respiratory rate 
≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at 
sea level or PaO2/FiO2 < 300) 
Exclusion 
Criteria: 
1. Any physical examination findings and/or history of any illness that, in the 
opinion of the study investigator, might confound the results of the study 
or pose an additional risk to the patient 
2. Active malignancy other than squamous cell carcinoma; anticancer 
treatment such as chemotherapy or radiation therapy within the past month. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
3. Nursing women or women of childbearing potential (WOCBP) with a 
positive pregnancy test. 
4. Treatment 
with 
another 
DHODH 
inhibitor 
(e.g., 
leflunomide, 
teriflunomide), tacrolimus, sirolimus. 
5. Platelets ≤150,000 cell/mm3. 
6. Hemoglobin < 12 gm/dL 
7. Absolute neutrophil count < 1500 cells/mm3 
8. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN 
10. History of bleeding disorders or recent surgery in the six weeks preceding 
enrollment 
11. Concomitant use of agents known to cause bone marrow suppression 
leading to thrombocytopenia 
12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding. 
13. History of hepatitis B and/or C infection, active liver disease and/or 
cirrhosis. 
14. Heart failure, current uncontrolled cardiovascular disease, including 
unstable angina, uncontrolled arrhythmias, major adverse cardiac event 
within 6 months (e.g. stroke, myocardial infarction, hospitalization due to 
heart failure, or revascularization procedure). 
15. Baseline COVID-19 severity characterized as “Critical” based on the FDA 
Guidance “COVID-19: Developing Drugs and Biological Products for the 
Treatment or Prevention (https://www.fda.gov/media/137926/download). 
Evidence of critical illness defined by at least one of the following: 
1. Respiratory failure based on resource utilization requiring at least 
one of the following: 
1. Endotracheal intubation and mechanical ventilation, oxygen 
delivered by high-flow nasal cannula (heated, humidified 
oxygen delivered via reinforced nasal cannula at flow rates 
> 20 L/min with fraction of delivered oxygen ≥ 0.5), 
noninvasive positive pressure ventilation, ECMO, or 
clinical diagnosis of respiratory failure (i.e., clinical need 
for one of the preceding therapies, but preceding therapies 
may not be able to be administered in setting of resource 
limitation) 
2. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic 
blood pressure < 60 mm Hg or requiring vasopressors) 
16. Multi-organ dysfunction/failure. 
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03 May 2021
Appendix 16.1.1
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CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 16 of 59 
PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
If the subject is unable or not permitted to return for planned study visits, the visit 
activities will be conducted by contacting the subject (phone or other digital media) 
except for the lab draw. The hematology/chemistry sample will be obtained via 
outpatient laboratory.  
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF. A subject is considered completed the study if 
they have assessments through Day 15, whether conducted in the hospital or 
contacted via phone or other digital media. 
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of informed consent through Day 
15. After Day 15, collect/record only Serious Adverse Events (SAEs) or those 
judged by the Investigator or designated person to be related to study drug, 
including but not limited to potential hematologic toxicities. Post-randomization 
adverse events will be those with an onset after the date and time of randomization. 
Subjects who develop Grade 3 or 4 toxicities are to be re-evaluated every 2 days, 
as feasible, until the toxicity returns to Grade ≤ 2 severity. 
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, safety 
laboratory data, and NEWS2 Assessments.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of post randomization adverse events, defined as AEs 
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, NEWS2 
Criteria, and other clinical measures will be summarized using appropriate 
descriptive statistics. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
Page 17 of 59 
PROTOCOL VERSION DATE: 06JULY2020 FINAL 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Title: 
Address: 
Telephone No.: 
Fax No.: 
E-mail: 
Barbara Powers, MSN, Ph.D. 
Clinical Operations 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
484-686-0545 
617-863-2082 
bpowers@clearcreekbio.com  
MEDICAL MONITOR 
Name:  
Sharon Levy, MD 
Title: 
Prosoft Clinical 
Telephone No.: 
M: (610) 316-9764 
O: (484) 320-2062 
E-mail: 
s.levy@prosoftclinical.com
Sharon.levy27@gmail.com 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 18 of 59 
PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
3 
INTRODUCTION 
3.1 Background 
3.2 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]).  
3.2.1 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]). 
3.3  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.  
3.4  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.  
 
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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PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
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]).    
3.5  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]). 
3.6  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 CRISIS trial will study standard of care (SOC) and SOC with 5 days of DHODH inhibition. 
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, 
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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.  
3.6.1 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 
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 reassuring the safety of 
this regimen (see Brequinar IB [5]).  
3.6.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive database exists with more than 800 cancer 
patients 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. Brequinar has 
also been utilized at lower doses than used in the cancer studies in 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. While no DHODHi has been tested to date in the clinic for 
infection with SARS-CoV-2 and no brequinar safety information is available in treatment of this 
disease, DHODHi therapy in the context of trials for patients with cancer has the expected safety 
side-effects of mucositis and bone marrow suppression. 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 mucositis and only 1 (2.6%) episode of mild thrombocytopenia. The 100 mg per day dose 
proposed for administration in this study should be safe and well tolerated.  
The possible 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. As discussed above, inhibition of DHODH is expected to reduce the ability 
of the virus to replicate and it is for this reason that study CCB-CRISIS-01 will administer 
brequinar to patients with COVID-19. 
 
3.7 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of brequinar in patients with refractory 
solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis have 
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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.  
COVID-19 patients are at higher risk of complications and poor outcomes when their infection is 
combined with comorbidities including hypertension, diabetes, chronic kidney disease, chronic 
obstructive pulmonary disease (COPD) or asthma, cardiovascular disease (coronary artery disease 
or congestive heart failure), liver cirrhosis, age > 65, and BMI > 30 [15]. Therefore, participants 
in this protocol must have at least one of these comorbidities in order to justify that the risks of 
potential and known toxicities associated with brequinar are outweighed by the potential benefits 
in this higher risk population. 
In addition to ensuring a higher risk population, 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).  
3.8 Possible Interactions with Concomitant Medical Treatments 
While not previously tested in patients with viral infections, brequinar has been administered to 
subjects taking a variety of concomitant medications that are typical in severely ill cancer patients. 
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. Brequinar has also been used concomitantly with antibiotics, antifungals and other 
critical care medications. 
 
There is no experience with brequinar for treatment of SARS-CoV-2 and other severe viral 
infections and no formal interaction studies have been conducted.  
3.8.1 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).  
3.9 Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated in a hospital setting by highly experienced infectious disease or other 
critical care specialists and other qualified staff familiar with the treatment of severe viral 
infections and their complications.  
Subjects in the Brequinar Treatment Group 
If the subject is in the brequinar treatment group and is being discharged prior to completing the 
study, ensure a hematology/chemistry sample is obtained prior to discharge on the day of 
discharge. The subject is to return to the research facility for the Days 7 and 15 visits if able and 
permitted. If unable or not permitted to return to the research facility due to COVID-19 restrictions, 
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the remaining visit activities except for the lab draw will be conducted by phone or other digital 
media. The lab draw will be performed by an outpatient laboratory at a designated facility. Lab 
draws for any outpatient visits for the Day 7 and 15 visits are limited to safety labs (hematology 
and chemistry). Additional outpatient laboratory or study visits are to be conducted as needed for 
follow up of adverse events including hematologic toxicities. 
 
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5 
TRIAL DESIGN 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care per institutional guidelines for treatment of patients with 
SARS-CoV-2 infection. In addition to standard of care, the brequinar group will receive brequinar 
100 mg once daily for 5 days.    
The Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance is provided in 
Appendix D Section 15.4. This guidance provides an example of standard of care instructions for 
treatment of COVID-19. The guidance is provided as informational only, it is not required that this 
guidance be used for treatment as standards of care may differ between institutions. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Study procedures are presented in 
detail in Section 8. Subjects will be followed through Day 15, with mortality assessed via a phone 
call/other digital media acceptable to institution on Day 29. 
If the subject is being discharged prior to Day 7, see Section 8.5. 
It is understood that some assessments may not be conducted if the subject is unable to return to 
the clinic after discharge due to restricted travel. If an assessment is missed due to after hospital 
discharge, e.g., samples or blood draws, this will not be counted as a protocol deviation. Any of 
the study visits may be conducted via telephone if the subject has been discharged from the hospital 
and is not permitted to or is unable to return to the hospital/clinic for these visits. 
Information is to be collected using the electronic health record (EHR) whenever possible. It is not 
required to perform study-specific laboratory assessments, NEWS 2 assessments, etc. separately 
for study purposes. 
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7 
TRIAL POPULATION 
7.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 24 subjects have completed the study. Subjects will be randomized to either 
standard of care or standard of care plus brequinar or in a 1:2: ratio (approximately 8 subjects 
assigned to standard of care alone and approximately 16 subjects on standard of care plus 
brequinar).  
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. If discharged from the hospital prior to Study Day 15 or if follow up is needed for study 
drug-related adverse event, willing to go to an outpatient laboratory to obtain a laboratory 
sample as well as a contact (phone call or other digital media) on Study Days 7 and 15 and 
contact only on Day 29.  
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase 
chain reaction (RT-PCR) or other Food and Drug Administration (FDA)-cleared 
commercial or public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men and women treated or enrolled on this protocol must 
also agree to use adequate contraception for the duration of study participation and for 90 
days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of brequinar.  
8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician. 
9. COVID-19 symptoms of severity mild (fever, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnea), 
moderate (any symptom of mild illness or shortness of breath with exertion), or severe 
(any symptom of moderate illness or shortness of breath at rest, or respiratory distress). 
[22]. 
10. COVID-19 signs of severity mild (no clinical signs), moderate (respiratory rate ≥ 20 
breaths per minute, saturation of oxygen (SpO2) > 93% on room air at sea level, heart rate 
≥ 90 beats per minute) or severe (respiratory rate ≥ 30 per minute, heart rate ≥ 125 per 
minute, SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300) [22]. 
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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. Active malignancy other than squamous cell carcinoma; anticancer treatment such as
chemotherapy or radiation therapy within the past month.
3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy
test.
4. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide), tacrolimus,
sirolimus.
5. Platelets ≤150,000 cell/mm3.
6. Hemoglobin < 12 gm/dL
7. Absolute neutrophil count < 1500 cells/mm3
8. Renal dysfunction, i.e., creatinine clearance < 30 mL/min
9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN
10. History of bleeding disorders or recent surgery in the six weeks preceding enrollment
11. Concomitant use of agents known to cause bone marrow suppression leading to
thrombocytopenia
12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding.
13. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis.
14. Heart failure, current uncontrolled cardiovascular disease, including unstable angina,
uncontrolled arrhythmias, major adverse cardiac event within 6 months (e.g. stroke,
myocardial infarction, hospitalization due to heart failure, or revascularization procedure).
15. Baseline COVID-19 severity characterized as “Critical” based on the FDA Guidance 
“COVID-19: Developing Drugs and Biological Products for the Treatment or Prevention 
(https://www.fda.gov/media/137926/download). Evidence of critical illness defined by at 
least one of the following:
a.
Respiratory failure based on resource utilization requiring at least one of the
following:
i. Endotracheal intubation and mechanical ventilation, oxygen delivered by
high-flow nasal cannula (heated, humidified oxygen delivered via
reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered
oxygen ≥ 0.5), noninvasive positive pressure ventilation, ECMO, or clinical
diagnosis of respiratory failure (i.e., clinical need for one of the preceding
therapies, but preceding therapies may not be able to be administered in
setting of resource limitation)
b. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure
< 60 mm Hg or requiring vasopressors)
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16. Multi-organ dysfunction/failure. See [22].  
7.4 Inclusion of Women and Minorities 
Adult men and women of all races and ethnic groups are eligible for this trial. 
 
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8 
STUDY TREATMENTS 
8.1 Description of Study Medications 
8.1.1 Brequinar 
Brequinar will be supplied as 100 mg capsules. Dosing will be a single 5-day course of brequinar 
100 mg once daily for 5 doses. The initial brequinar dose (Day 1) should be administered as soon 
as possible based on study drug availability from the investigational pharmacy. 
8.2 Treatment Administration 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 
infection. Subjects will be randomly assigned in a 1:2 ratio to standard of care alone or standard 
of care plus brequinar. The brequinar dosing interval should be 24h ± 6h. Therefore, a subject 
being discharged less than 18 hours after the previous brequinar dose should not dose on the day 
of discharge. If possible, the subject should wait to be discharged until reaching at least 18 hours 
after the previous dose, then dose and be discharged. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE).  
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 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 (Study 785-001 [16], 785-003 [17], and 785-005 [18]) with five 
consecutive days of intravenous (IV) brequinar dosing and 168 subjects, there were no toxic 
deaths. For subjects from these three studies who were treated with a dose of 100 mg or below  
(as will be dosed in CCB-CRISIS-01), 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 [19], 785-031 [20] , and 785-034 [21]), 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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PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
Following discharge, the subject is to return to the research facility for the Days 7 and 15 visits if 
able and permitted.  
If discharge occurs on Days 10, 11, or 12, ensure a hematology/chemistry sample has been 
obtained prior to discharge and record these results on the appropriate EDC page. Following 
discharge, the subject is to return to the research facility for the Day 15 visit if able and permitted. 
If discharge occurs on Days 13, 14 or 15, complete the Day 15 Final Visit activities. No further 
visits are required unless follow up is needed for a study drug-related AE or an SAE; the Day 29 
mortality assessment is still to take place. 
If the subject is unable or not permitted to return for planned study visits, the visit activities will 
be conducted by contacting the subject (phone or other digital media) except for the lab draw. The 
lab draw will be completed at an outpatient laboratory when feasible.  
Study completion or the reason for study discontinuation will be recorded in the source document 
and the eCRF. A subject is considered completed the study if they have assessments through Day 
15, whether conducted in the hospital or contacted via phone or other digital media. 
8.6 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 8.9.  
8.7 Treatment Compliance 
Compliance will be assessed by reviewing the subject’s EHR and other study records as 
appropriate. 
8.8 Storage, Stability, Labeling and Packaging 
8.8.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.8.2 Labeling and Packaging  
Each brequinar bottle/dispensing container for subject use will be labeled with at least the 
following information: 
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For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: Brequinar 100 mg capsules 
For oral use only. Take with approximately 8 ounces water. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.8.3 Blinding and Randomization 
The trial will be conducted in an open-label manner with random assignment to standard of care 
or standard of care plus brequinar. The brequinar capsules will be provided to each participating 
institution in bulk to be dispensed by the institution’s pharmacist for each subject. Randomization 
assignments will be provided by the sponsor. 
8.8.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment will be known for 
each subject. 
Expectedness will be determined by establishing whether the 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.   
8.8.5 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, used and discarded.  It must 
be clear from the records whether the subject received study medication or was assigned to 
standard of care. 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.   
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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. 
8.9 Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide), 
tacrolimus, sirolimus. Treatment is prohibited with agents known to cause bone marrow 
suppression leading to thrombocytopenia.  
8.10 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 telephone or other digital media. Study information is to be 
collected from the EHR as much as possible such as NEWS2 Assessments, height, weight, 
hematology/chemistry, from Progress Notes for AEs, and from medication records for new or 
changed concomitant medications. Visits to an outpatient laboratory post hospital discharge may 
be required if subjects are not able or permitted to return for follow up study visits.  
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). Remdesivir may be used in this clinical trial as a component of standard of care 
of patients hospitalized with severe disease in settings where remdesivir is available via the 
Emergency Use Authorization (EUA). 
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), 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.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures. Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be subject to review by the Sponsor; a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. 
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 
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 385 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 386 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 40 of 59 
PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
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 15. After Day 
15, collect/record only Serious Adverse Events (SAEs) or those judged 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.   
Any serious adverse events (SAEs) experienced after 30 days post the last dose of study drug 
should only be reported to the sponsor if the investigator suspects a causal relationship to the 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, or require therapy. 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the appropriate electronic data capture form.  
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 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 387 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 388 of 582


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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
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 Medical Monitor 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 is to 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 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to 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 knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must 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 the Sponsor Contact 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 pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
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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-
up with 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 selecting a relatively brief 5-day exposure and a low brequinar dose, all 
subjects in the clinical trial will initially be hospitalized as in-patients and will be under the care 
of highly qualified infectious disease, critical care, and associated medical personnel. As is 
standard of care for moderately to severely ill in-patients, daily samples will be obtained for 
hematology assessments including complete blood count with full differential (WBC, RBC, 
hemoglobin, hematocrit, platelet count, absolute neutrophils, absolute lymphocytes, absolute 
monocytes, absolute eosinophils, and absolute basophils). Any clinically significant out-of-range 
laboratory values will be assessed by hospital staff in a timely manner and treatment needs 
addressed as appropriate. 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 Clear Creek Medical Monitor 
will assess the available hematology data on a weekly 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, the Sponsor, and the Medical Monitor. In 
addition, the Data Safety Monitoring Board 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. 
Subjects who are discharged from the hospital before Day 7 will have follow up contacts with 
study staff (phone calls or other digital media) on Days 7, 15 and 29. Early discharge subjects in 
the brequinar treatment group will also have samples for safety labs (hematology and chemistry) 
obtained either at the research facility or at an outpatient laboratory on Study Days 7 ± 2 and 15 ± 
2. The safety laboratory results are to be initially assessed in real time by the Principal Investigator 
or designated person and the Medical Monitor. 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-hospital assessments and phone call visits will specifically ask about possible hematologic 
toxicity including any evidence of the list below. Early discharge 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. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
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 analyses will be based on the ITT population, which is defined as all randomized subjects.   
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, NEWS2 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 
NEWS2 Assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will be assessed in terms of mortality, hospitalization status and duration, NEWS2 score, 
viral load (plasma and nasopharyngeal), and inflammatory markers. 
11.4 DHO and Brequinar Concentration Levels 
DHO and brequinar concentrations levels will be summarized using descriptive statistics. 
11.5 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 24 
subjects are planned to be entered in this trial.  Additional subjects may be enrolled following data 
review. 
11.6 Randomization 
A randomization scheme will be provided by the Sponsor to ensure subjects are randomly assigned 
to SOC or SOC + brequinar in a 1:2 ratio.  
11.7 Pooling of Study Centers 
Not applicable to this small, early phase study. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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11.8 Interim Analysis 
No interim analysis is planned for this trial. 
 
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Clinical Study Report 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 06JULY2020 FINAL 
 
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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
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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) 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. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the
assessment of acute-illness severity in the NHS. Updated report of a working party.
London: RCP, 2017.
15. Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K, and the 
Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. 
JAMA. April 22, 2020. https://jama.doi:10:1001/jama.2020.6775.
16. Study DUP 785-001 Clinical Study Report (on file with Clear Creek)
17. Study DUP 785-003 Clinical Study Report (on file with Clear Creek)
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18. Study DUP 785-005 Clinical Study Report (on file with Clear Creek)
19. Study DUP 785-022 Clinical Study Report (on file with Clear Creek)
20. Study DUP 785-031 Clinical Study Report (on file with Clear Creek)
21. Study DUP 785-034 Clinical Study Report (on file with Clear Creek)
22. 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-01 Schedule of Events 
CCB-CRISIS-01  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2 - D7 
(± 8 hours) 
Final Visit  
D15 
(± 2 days) 
F/U  
Phone 
Call 
2 weeks/ 
Survival 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
AE/Concomitant Medications (daily until discharge) 
X 
X 
D1-7 
X 
 
Medical history / History of current illness 
X 
 
 
 
 
Demographics, collect Height and weight 
X 
 
 
 
 
Check for Physical Exam abnormalities 
X 
 
 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
Hematology/Chemistry 
X 
X (pre-dose) 
 D1-7 
X 
 
Inflammatory Markers* 
 
X (pre-dose) 
D3, D5, D7 
X 
 
DHO/brequinar PK Sample Collection & Processing 
 
X (pre-dose) 
D3, D5, D7 
X (DHO only) 
 
Swab collection for nasopharyngeal viral load 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Clinical SARS-CoV-2 testing RT-PCR 
X 
 
 
 
 
Hospital Status 
 
 
D3, D5, D7 
X 
 
NEWS2 Assessments 
 
X 
D3, D5, D7 
X 
 
Dispense Study Medication if assigned to brequinar 
 
X 
D2 – 5 
 
 
Drug Accountability 
 
 
D7 
 
 
Survival Assessment Day 29 
 
 
 
 
X 
Collect information from available electronic health record (EHR), Progress Notes, and medication 
records; a special visit by research staff is not to be performed. Results for Hematology, Chemistry 
and available inflammatory markers analyzed locally are to be obtained from the EHR; do not 
draw another set of labs. Missed samples due to hospital staff too busy or for technical reasons 
unable to obtain samples will not be counted as protocol deviations. Record urinalysis results if 
urinalysis is clinically indicated and results are available in the EHR. 
Note that any visits other than Screening/Day 1 may be conducted via telephone or digital media. 
Missed samples/assessments when phone visits occur will not be counted as protocol deviations. 
*Inflammatory markers are to be collected from the EHR when available; otherwise process and 
ship samples to the central laboratory per the Laboratory Manual. DHO and brequinar samples 
will also be sent to the central laboratory. 
Note that if the subject is discharged before Day 15, ensure safety laboratory samples for 
hematology and chemistry are obtained prior to discharge and on an outpatient basis when feasible 
per Section 8.5. 
 
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15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-01 
STUDY TITLE:  The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in hospitalized adults with 
coronavirus-19 (COVID-19). 
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: __________________ 
 
Site Address: 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
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15.3 Appendix C: National Early Warning Score (NEWS2)  
Use SpO2 Scale 2 if target range is 88 – 92%, e.g., in hypercapnic respiratory failure. 
National Early Warning System Score (NEWS) 2 Royal College of Physicians 2017 [14]. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 1 of 60 
PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in 
hospitalized adults with coronavirus-19 (COVID-19) 
 
Study No: CCB-CRISIS-01 
Version Date:  31 JULY 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 .............................................................................................................. 19 
3.1 Background ................................................................................................................ 19 
3.2 Coronavirus-19 (COVID-19) ..................................................................................... 19 
3.2.1 Coronavirus Biology .................................................................................................... 19 
3.3 Host Nucleotide Synthesis ......................................................................................... 19 
3.4 Dihydroorotate dehydrogenase (DHODH) ................................................................ 19 
3.5 Brequinar .................................................................................................................... 20 
3.6 Rationale for the Planned Trial .................................................................................. 20 
3.6.1 Brequinar Dose Selection ............................................................................................. 21 
3.6.2 Risk/Benefit of Brequinar ............................................................................................ 21 
3.7 Risks Associated with Participation in the Clinical Study ......................................... 21 
3.8 Possible Interactions with Concomitant Medical Treatments .................................... 22 
3.8.1 CYP Interactions .......................................................................................................... 22 
3.9 Steps to be Taken to Control or Mitigate Risks ......................................................... 22 
4 TRIAL OBJECTIVES ........................................................................................................ 24 
4.1 Primary Objective ...................................................................................................... 24 
4.2 Secondary Objectives ................................................................................................. 24 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 24 
5 TRIAL DESIGN ................................................................................................................. 25 
6 TRIAL ENDPOINTS.......................................................................................................... 26 
6.1 Primary Endpoint ....................................................................................................... 26 
6.2 Secondary Endpoints .................................................................................................. 26 
6.3 EXPLORATORY Endpoints ..................................................................................... 26 
7 TRIAL POPULATION ....................................................................................................... 27 
7.1 Number of Subjects .................................................................................................... 27 
7.2 Inclusion criteria ......................................................................................................... 27 
7.3 Exclusion Criteria ....................................................................................................... 28 
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7.4 Inclusion of Women and Minorities........................................................................... 29 
8 STUDY TREATMENTS .................................................................................................... 30 
8.1 Description of Study Medications .............................................................................. 30 
8.1.1 Brequinar ...................................................................................................................... 30 
8.2 Treatment Administration .......................................................................................... 30 
8.2.1 Safety/Tolerability ........................................................................................................ 30 
8.3 Study Discontinuation ................................................................................................ 31 
8.4 Stopping Criteria ........................................................................................................ 31 
8.4.1 Individual Stopping Criteria ......................................................................................... 31 
8.4.2 Study-Level Stopping Criteria...................................................................................... 31 
8.5 Hospital Discharge Prior to Study Day 15 ................................................................. 31 
8.6 Concomitant Medication/Treatment .......................................................................... 32 
8.7 Treatment Compliance ............................................................................................... 32 
8.8 Storage, Stability, Labeling and Packaging ............................................................... 32 
8.8.1 Storage and Stability .................................................................................................... 32 
8.8.2 Labeling and Packaging ............................................................................................... 32 
8.8.3 Blinding and Randomization ........................................................................................ 33 
8.8.4 Unblinding/Expectedness ............................................................................................. 33 
8.8.5 Study Drug Accountability ........................................................................................... 33 
8.9 Prohibited Medications .............................................................................................. 34 
8.10 Study Adjustments Due to COVID-19....................................................................... 34 
9 CONDUCT OF THE TRIAL.............................................................................................. 35 
9.1 Ethical and Regulatory Considerations ...................................................................... 35 
9.2 Informed Consent ....................................................................................................... 35 
9.3 Institutional Review Board......................................................................................... 36 
9.4 Schedule of Events ..................................................................................................... 36 
9.5 Study Conduct ............................................................................................................ 37 
9.5.1 Unscheduled Visits ....................................................................................................... 39 
9.6 Compliance with Study Procedures ........................................................................... 39 
9.7 Early Withdrawal from the Study .............................................................................. 39 
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9.8 Early Termination of the Study .................................................................................. 40 
10 ADVERSE EVENT REPORTING..................................................................................... 41 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 42 
10.2 Infection Follow Up ................................................................................................... 42 
10.3 Classification of Causality ......................................................................................... 42 
10.4 Classification of Severity ........................................................................................... 43 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 43 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 45 
10.7 Pregnancies................................................................................................................. 45 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 46 
10.9 Data Safety Monitoring Board ................................................................................... 47 
10.9.1 
DSMB Safety Review Schedule ............................................................................. 47 
11 STATISTICAL CONSIDERATIONS................................................................................ 48 
11.1 Study Populations for Analysis .................................................................................. 48 
11.2 Safety Analyses .......................................................................................................... 48 
11.3 Efficacy Analyses ....................................................................................................... 48 
11.4 DHO and Brequinar Concentration Levels ................................................................ 48 
11.5 Sample Size Considerations ....................................................................................... 48 
11.6 Randomization ........................................................................................................... 48 
11.7 Pooling of Study Centers............................................................................................ 48 
11.8 Interim Analysis ......................................................................................................... 49 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 50 
12.1 Investigator’s Performance ........................................................................................ 50 
12.2 Confidentiality ............................................................................................................ 50 
12.3 Source Documentation ............................................................................................... 50 
12.4 Data Collection ........................................................................................................... 51 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 51 
12.6 Non-Protocol Research .............................................................................................. 52 
12.7 Publication .................................................................................................................. 52 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 53 
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13.1 General ....................................................................................................................... 53 
13.2 Indemnity ................................................................................................................... 53 
13.3 Data Monitoring ......................................................................................................... 53 
13.4 Audit ........................................................................................................................... 53 
13.5 Confidentiality ............................................................................................................ 54 
13.6 Finance ....................................................................................................................... 54 
14 REFERENCES ................................................................................................................... 55 
15 APPENDICES .................................................................................................................... 57 
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events .................................................. 57 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 58 
15.3 Appendix C: National Early Warning Score (NEWS2) ............................................. 59 
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment Guidance. ..... 60 
 
 
 
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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. ............................................... 19 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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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 
DSMB 
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 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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Abbreviation 
Definition 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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2 
SYNOPSIS  
CCB-CRISIS-01 SYNOPSIS  
IND 
149291 
Title 
The CRISIS Study: A randomized open-label study assessing the safety and anti-
coronavirus response of suppression of host nucleotide synthesis in hospitalized 
adults with coronavirus-19 (COVID-19) 
Protocol 
CCB-CRISIS-01 
Rationale 
Brequinar is a potent DHODH inhibitor that has been studied in more than 1,000 
cancer, psoriasis, and organ transplant patients. 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. 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 primary dose-limiting adverse effects have included 
thrombocytopenia and mucositis. 
The CRISIS trial will study standard of care (SOC) and SOC with 5 days of 
DHODH inhibition. 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. 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. Brequinar has not been previously tested as an anti-
viral. 
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:2 ratio to either standard of care (SOC) alone, 
or SOC + brequinar. 
Brequinar is available as 100 mg oral capsules. Five once daily doses of brequinar 
100 mg are to be administered on Study Days 1 – 5 for those assigned to the SOC 
+ brequinar group.  
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
Inclusion 
Criteria: 
 
1. Willing and able to provide informed consent for the trial, written, 
electronic, verbal or other method deemed acceptable by the institution and 
IRB.  
2. 18 years of age or older.  
3. If discharged from the hospital prior to Study Day 15 or if follow up is 
needed for study drug-related adverse event, willing to go to an outpatient  
facility if feasible or be in contact with the study team (phone call or other 
digital media) for remaining study assessments. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time 
polymerase chain reaction (RT-PCR) or other FDA-cleared commercial or 
public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating 
physician immediately. Men and women treated or enrolled on this protocol 
must also agree to use adequate contraception for the duration of study 
participation, and for 90 days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study 
drug administration until 90 days after the last dose of brequinar. 
8. ≤ 10 days since first COVID-19 symptom as determined by treating 
clinician. 
9. COVID-19 symptoms of severity mild (fever, cough, sore throat, malaise, 
headache, muscle pain, gastrointestinal symptoms, without shortness of 
breath or dyspnea), moderate (any symptom of mild illness or shortness of 
breath with exertion), or severe (any symptom of moderate illness or 
shortness of breath at rest, or respiratory distress). 
10. COVID-19 signs of severity mild (no clinical signs), moderate (respiratory 
rate ≥ 20 breaths per minute, saturation of oxygen (SpO2) > 93% on room 
air at sea level, heart rate ≥ 90 beats per minute) or severe (respiratory rate 
≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at 
sea level or PaO2/FiO2 < 300) 
Exclusion 
Criteria: 
1. Any physical examination findings and/or history of any illness that, in the 
opinion of the study investigator, might confound the results of the study 
or pose an additional risk to the patient 
2. Active malignancy other than squamous cell carcinoma; anticancer 
treatment such as chemotherapy or radiation therapy within the past month. 
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PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
3. Nursing women or women of childbearing potential (WOCBP) with a 
positive pregnancy test. 
4. Treatment 
with 
another 
DHODH 
inhibitor 
(e.g., 
leflunomide, 
teriflunomide), tacrolimus, sirolimus. 
5. Platelets ≤150,000 cell/mm3. 
6. Hemoglobin < 12 gm/dL 
7. Absolute neutrophil count < 1500 cells/mm3 
8. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN 
10. History of bleeding disorders or recent surgery in the six weeks preceding 
enrollment 
11. Concomitant use of agents known to cause bone marrow suppression 
leading to thrombocytopenia 
12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding. 
13. History of hepatitis B and/or C infection, active liver disease and/or 
cirrhosis. 
14. Heart failure, current uncontrolled cardiovascular disease, including 
unstable angina, uncontrolled arrhythmias, major adverse cardiac event 
within 6 months (e.g. stroke, myocardial infarction, hospitalization due to 
heart failure, or revascularization procedure). 
15. Baseline COVID-19 severity characterized as “Critical” based on the FDA 
Guidance “COVID-19: Developing Drugs and Biological Products for the 
Treatment or Prevention (https://www.fda.gov/media/137926/download). 
Evidence of critical illness defined by at least one of the following: 
1. Respiratory failure based on resource utilization requiring at least 
one of the following: 
1. Endotracheal intubation and mechanical ventilation, oxygen 
delivered by high-flow nasal cannula (heated, humidified 
oxygen delivered via reinforced nasal cannula at flow rates 
> 20 L/min with fraction of delivered oxygen ≥ 0.5), 
noninvasive positive pressure ventilation, ECMO, or 
clinical diagnosis of respiratory failure (i.e., clinical need 
for one of the preceding therapies, but preceding therapies 
may not be able to be administered in setting of resource 
limitation) 
2. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic 
blood pressure < 60 mm Hg or requiring vasopressors) 
16. Multi-organ dysfunction/failure. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
For all subjects, if discharge occurs on Days 10, 11, or 12, ensure a 
hematology/chemistry sample has been obtained on the day of discharge and 
record these results on the appropriate EDC page. Following discharge, the subject 
is to return to the research or out-patient lab collection facility for the Day 15 visit 
if feasible. Out-patient lab results are to be entered into the EDC and reviewed by 
a member of the study team. 
If discharge occurs on Days 13, 14 or 15, complete the Day 15 Final Visit activities 
prior to discharge. No further visits are required unless follow up is needed for a 
study drug-related AE or an SAE; the Day 29 mortality assessment is still to take 
place. 
If the subject is unable or not permitted to return for planned study visits, the visit 
activities will be conducted by contacting the subject (phone or other digital media) 
except for the lab draw. The hematology/chemistry sample will be obtained via 
outpatient laboratory, if feasible and the results entered into the EDC and reviewed 
by the study team.  
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF. A subject is considered completed the study if 
they have assessments through Day 15, whether conducted in the hospital or 
contacted via phone or other digital media. 
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of informed consent through Day 
15. After Day 15, collect/record only Serious Adverse Events (SAEs) or those 
judged by the Investigator or designated person to be related to study drug, 
including but not limited to potential hematologic toxicities. Post-randomization 
adverse events will be those with an onset after the date and time of randomization. 
Subjects who develop Grade 3 or 4 toxicities are to be re-evaluated every 2 days, 
as feasible, until the toxicity returns to Grade ≤ 2 severity. 
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, safety 
laboratory data, and NEWS2 Assessments.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of post randomization adverse events, defined as AEs 
occurring after randomization will be tabulated by Medical Dictionary for 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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Regulatory Activities (MedDRA) preferred term and system organ class, and by 
severity and relationship to study treatment. All laboratory results, NEWS2 
Criteria, and other clinical measures will be summarized using appropriate 
descriptive statistics. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
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:  
Sharon Levy, MD 
Title: 
Prosoft Clinical 
Telephone No.: 
M: (610) 316-9764 
O: (484) 320-2062 
E-mail: 
s.levy@prosoftclinical.com 
Sharon.levy27@gmail.com 
 
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PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
3 
INTRODUCTION 
3.1 Background 
3.2 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]).  
3.2.1 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]). 
3.3  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.  
3.4  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.  
 
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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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]).    
3.5  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]). 
3.6  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 CRISIS trial will study standard of care (SOC) and SOC with 5 days of DHODH inhibition. 
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, 
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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.  
3.6.1 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 
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 reassuring the safety of 
this regimen (see Brequinar IB [5]).  
3.6.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive database exists with more than 800 cancer 
patients 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. Brequinar has 
also been utilized at lower doses than used in the cancer studies in 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. While no DHODHi has been tested to date in the clinic for 
infection with SARS-CoV-2 and no brequinar safety information is available in treatment of this 
disease, DHODHi therapy in the context of trials for patients with cancer has the expected safety 
side-effects of mucositis and bone marrow suppression. 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 mucositis and only 1 (2.6%) episode of mild thrombocytopenia. The 100 mg per day dose 
proposed for administration in this study should be safe and well tolerated.  
The possible 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. As discussed above, inhibition of DHODH is expected to reduce the ability 
of the virus to replicate and it is for this reason that study CCB-CRISIS-01 will administer 
brequinar to patients with COVID-19. 
 
3.7 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of brequinar in patients with refractory 
solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis have 
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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.  
COVID-19 patients are at higher risk of complications and poor outcomes when their infection is 
combined with comorbidities including hypertension, diabetes, chronic kidney disease, chronic 
obstructive pulmonary disease (COPD) or asthma, cardiovascular disease (coronary artery disease 
or congestive heart failure), liver cirrhosis, age > 65, and BMI > 30 [15]. It is likely that participants 
in this protocol who are sick enough to be hospitalized will have at least one of these comorbidities. 
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).  
3.8 Possible Interactions with Concomitant Medical Treatments 
While not previously tested in patients with viral infections, brequinar has been administered to 
subjects taking a variety of concomitant medications that are typical in severely ill cancer patients. 
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. Brequinar has also been used concomitantly with antibiotics, antifungals and other 
critical care medications. 
 
There is no experience with brequinar for treatment of SARS-CoV-2 and other severe viral 
infections and no formal interaction studies have been conducted.  
3.8.1 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).  
3.9 Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated in the hospital setting by highly experienced infectious disease or other 
critical care specialists and other qualified staff familiar with the treatment of severe viral 
infections and their complications. Subjects will be followed for study purposes through at least 
Day 15 even if improved enough to be discharged from the hospital. 
Subjects in the Brequinar Treatment Group 
If the subject is in the brequinar treatment group and is being discharged prior to completing the 
study, ensure a hematology/chemistry sample is obtained prior to discharge on the day of 
discharge. The subject is to return to the research or out-patient facility for the Days 7 and 15 visits 
if able and permitted. If unable or not permitted to return to the research facility due to COVID-
19 restrictions, the remaining visit activities except for the lab draw will be conducted by phone 
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or other digital media. The lab draw will be performed by an outpatient laboratory at a designated 
facility. Lab draws for any outpatient visits for the Day 7 and 15 visits are limited to safety labs 
(hematology and chemistry). Additional outpatient laboratory or study visits are to be conducted 
as needed for follow up of adverse events including hematologic toxicities. 
 
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5 
TRIAL DESIGN 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care per institutional guidelines for treatment of patients with 
SARS-CoV-2 infection. In addition to standard of care, the brequinar group will receive brequinar 
100 mg once daily for 5 days.    
The Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance is provided in 
Appendix D Section 15.4. This guidance provides an example of standard of care instructions for 
treatment of COVID-19. The guidance is provided as informational only, it is not required that this 
guidance be used for treatment as standards of care may differ between institutions. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Study procedures are presented in 
detail in Section 8. Subjects will be followed through Day 15, with mortality assessed via a phone 
call/other digital media acceptable to institution on Day 29. 
If the subject is being discharged prior to Day 7, see Section 8.5. 
It is understood that some assessments may not be conducted if the subject is unable to return to 
the clinic after discharge due to restricted travel. If an assessment is missed due to after hospital 
discharge, e.g., samples or blood draws, this will not be counted as a protocol deviation. Any of 
the study visits may be conducted via telephone if the subject has been discharged from the hospital 
and is not permitted to or is unable to return to the hospital/clinic for these visits. 
Information is to be collected using the electronic health record (EHR) whenever possible. It is not 
required to perform study-specific laboratory assessments, NEWS 2 assessments, etc. separately 
for study purposes. 
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7 
TRIAL POPULATION 
7.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 24 subjects have completed the study. Subjects will be randomized to either 
standard of care or standard of care plus brequinar or in a 1:2: ratio (approximately 8 subjects 
assigned to standard of care alone and approximately 16 subjects on standard of care plus 
brequinar).  
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. If discharged from the hospital prior to Study Day 15 or if follow up is needed for study 
drug-related adverse event, willing to go to an outpatient  facility if feasible or be in contact 
with the study team (phone call or other digital media) for remaining study assessments. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase 
chain reaction (RT-PCR) or other Food and Drug Administration (FDA)-cleared 
commercial or public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men and women treated or enrolled on this protocol must 
also agree to use adequate contraception for the duration of study participation and for 90 
days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of brequinar.  
8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician. 
9. COVID-19 symptoms of severity mild (fever, cough, sore throat, malaise, headache, 
muscle pain, gastrointestinal symptoms, without shortness of breath or dyspnea), 
moderate (any symptom of mild illness or shortness of breath with exertion), or severe 
(any symptom of moderate illness or shortness of breath at rest, or respiratory distress). 
[22]. 
10. COVID-19 signs of severity mild (no clinical signs), moderate (respiratory rate ≥ 20 
breaths per minute, saturation of oxygen (SpO2) > 93% on room air at sea level, heart rate 
≥ 90 beats per minute) or severe (respiratory rate ≥ 30 per minute, heart rate ≥ 125 per 
minute, SpO2 ≤ 93% on room air at sea level or PaO2/FiO2 < 300) [22]. 
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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. Active malignancy other than squamous cell carcinoma; anticancer treatment such as
chemotherapy or radiation therapy within the past month.
3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy
test.
4. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide), tacrolimus,
sirolimus.
5. Platelets ≤150,000 cell/mm3.
6. Hemoglobin < 12 gm/dL
7. Absolute neutrophil count < 1500 cells/mm3
8. Renal dysfunction, i.e., creatinine clearance < 30 mL/min
9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN
10. History of bleeding disorders or recent surgery in the six weeks preceding enrollment
11. Concomitant use of agents known to cause bone marrow suppression leading to
thrombocytopenia
12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding.
13. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis.
14. Heart failure, current uncontrolled cardiovascular disease, including unstable angina,
uncontrolled arrhythmias, major adverse cardiac event within 6 months (e.g. stroke,
myocardial infarction, hospitalization due to heart failure, or revascularization procedure).
15. Baseline COVID-19 severity characterized as “Critical” based on the FDA Guidance 
“COVID-19: Developing Drugs and Biological Products for the Treatment or Prevention 
(https://www.fda.gov/media/137926/download). Evidence of critical illness defined by at 
least one of the following:
a.
Respiratory failure based on resource utilization requiring at least one of the
following:
i. Endotracheal intubation and mechanical ventilation, oxygen delivered by
high-flow nasal cannula (heated, humidified oxygen delivered via
reinforced nasal cannula at flow rates > 20 L/min with fraction of delivered
oxygen ≥ 0.5), noninvasive positive pressure ventilation, ECMO, or clinical
diagnosis of respiratory failure (i.e., clinical need for one of the preceding
therapies, but preceding therapies may not be able to be administered in
setting of resource limitation)
b. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood pressure
< 60 mm Hg or requiring vasopressors)
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16. Multi-organ dysfunction/failure. See [22].  
7.4 Inclusion of Women and Minorities 
Adult men and women of all races and ethnic groups are eligible for this trial. 
 
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8 
STUDY TREATMENTS 
8.1 Description of Study Medications 
8.1.1 Brequinar 
Brequinar will be supplied as 100 mg capsules. Dosing will be a single 5-day course of brequinar 
100 mg once daily for 5 doses. The initial brequinar dose (Day 1) should be administered as soon 
as possible based on study drug availability from the investigational pharmacy. At least the first 
dose of study medication is to be taken in the hospital. Subjects in the brequinar group discharged 
before Day 5 will be dispensed brequinar to take at home daily until all 5 doses have been taken. 
8.2 Treatment Administration 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 
infection. Subjects will be randomly assigned in a 1:2 ratio to standard of care alone or standard 
of care plus brequinar. The brequinar dosing interval should be 24h ± 6h. If discharged prior to 
Day 5, the subject may take any remaining doses once a day at home. In this case, the subject is to 
record dosing using a medication diary provided by the study team. The diary information will be 
provided to the study team either verbally or electronically or during an in-person visit. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE).  
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 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 (Study 785-001 [16], 785-003 [17], and 785-005 [18]) with five 
consecutive days of intravenous (IV) brequinar dosing and 168 subjects, there were no toxic 
deaths. For subjects from these three studies who were treated with a dose of 100 mg or below  
(as will be dosed in CCB-CRISIS-01), 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 [19], 785-031 [20] , and 785-034 [21]), the study drug related 
AEs through 21 days (each observed in one subject only) included diarrhea, headache, nausea, 
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For subjects in the brequinar treatment group discharged from the hospital prior to Day 5, the 
subject is to take home the remaining doses of brequinar for daily self-administration. All subjects 
(brequinar and SOC) should have the scheduled assessments, e.g. lab samples and the 
nasopharyngeal swab, on the day of discharge and enter these results on the appropriate EDC page. 
Following discharge, subjects are to return to the research or out-patient lab collection facility for 
the remaining study visits, if feasible. Out-patient lab results are to be entered into the EDC and 
reviewed by a member of the study team. It is important that every effort be made to have subjects 
return at least on Days 7 and 15, if feasible. Subjects in the brequinar group are to record brequinar 
dosing on the medication diary provided by the study team. The study team will arrange for the 
subject to return any unused study medication to the research facility. 
For all subjects, if discharge occurs on Days 10, 11, or 12, ensure a hematology/chemistry sample 
has been obtained on the day of discharge and record these results on the appropriate EDC page. 
Following discharge, the subject is to return to the research or out-patient lab collection facility for 
the Day 15 visit, if feasible. Out-patient lab results are to be entered into the EDC and reviewed 
by a member of the study team. 
If discharge occurs on Days 13, 14 or 15, complete the Day 15 Final Visit activities prior to 
discharge. No further visits are required unless follow up is needed for a study drug-related AE or 
an SAE; the Day 29 mortality assessment is still to take place. 
If the subject is unable or not permitted to return for planned study visits, the visit activities will 
be conducted by contacting the subject (phone or other digital media) except for the lab draw. The 
lab draw will be completed at a research facility or an outpatient laboratory, if feasible, and the 
results entered into the EDC and reviewed by the study team.  
Study completion or the reason for study discontinuation will be recorded in the source document 
and the eCRF. A subject is considered completed the study if they have assessments through Day 
15, whether conducted in the hospital or contacted via phone or other digital media. 
8.6 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 8.9.  
8.7 Treatment Compliance 
Compliance will be assessed by reviewing the subject’s EHR, the study medication diary when 
applicable, and other study records as appropriate. 
8.8 Storage, Stability, Labeling and Packaging 
8.8.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.8.2 Labeling and Packaging  
Each brequinar bottle/dispensing container for subject use will be labeled with at least the 
following information: 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: Brequinar 100 mg capsules 
For oral use only. Take with approximately 8 ounces water. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.8.3 Blinding and Randomization 
The trial will be conducted in an open-label manner with random assignment to standard of care 
or standard of care plus brequinar. The brequinar capsules will be provided to each participating 
institution in bulk to be dispensed by the institution’s pharmacist for each subject. Randomization 
assignments will be provided by the sponsor. 
8.8.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment will be known for 
each subject. 
Expectedness will be determined by establishing whether the 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.   
8.8.5 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, used and discarded.  It must 
be clear from the records whether the subject received study medication or was assigned to 
standard of care. 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.  
Subjects in the brequinar group who are discharged prior to Day 5 will be given a study medication 
diary for recording at home treatment administration.  The diary information will be collected by 
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the study team either verbally or electronically or in person during a visit to the research facility. 
Unused study drug at the patient’s home is to be returned to the research facility.  
At the end of the study, any unused study drug in the pharmacy will be returned to the Sponsor for 
destruction or may be destroyed locally; disposition of study drug will be documented. The study 
team will make arrangements for the subject to return any unused study medication to the research 
facility. 
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. 
8.9 Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide), 
tacrolimus, sirolimus. Treatment is prohibited with agents known to cause bone marrow 
suppression leading to thrombocytopenia.  
8.10 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 telephone or other digital media. Study information is to be 
collected from the EHR as much as possible such as NEWS2 Assessments, height, weight, 
hematology/chemistry, from Progress Notes for AEs, and from medication records for new or 
changed concomitant medications. Visits to an outpatient laboratory post hospital discharge may 
be required if subjects are not able or permitted to return to the research facility for follow up study 
visits.  
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). Remdesivir may be used in this clinical trial as a component of standard of care 
of patients hospitalized with severe disease in settings where remdesivir is available via the 
Emergency Use Authorization (EUA) or other FDA approval. 
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), 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.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures. Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be subject to review by the Sponsor; a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. 
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 
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 445 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 446 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 41 of 60 
PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
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 15. After Day 
15, collect/record only Serious Adverse Events (SAEs) or those judged 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.   
Any serious adverse events (SAEs) experienced after 30 days post the last dose of study drug 
should only be reported to the sponsor if the investigator suspects a causal relationship to the 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, or require therapy. 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the appropriate electronic data capture form.  
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 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 447 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 448 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
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 Medical Monitor 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 is to 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 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to 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 knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must 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 the Sponsor Contact 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 pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
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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-
up with 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 selecting a relatively brief 5-day exposure and a low brequinar dose, all 
subjects in the clinical trial will initially be hospitalized as in-patients and will be under the care 
of highly qualified infectious disease, critical care, and associated medical personnel. As is 
standard of care for moderately to severely ill in-patients, daily samples will be obtained for 
hematology assessments including complete blood count with full differential (WBC, RBC, 
hemoglobin, hematocrit, platelet count, absolute neutrophils, absolute lymphocytes, absolute 
monocytes, absolute eosinophils, and absolute basophils). Any clinically significant out-of-range 
laboratory values will be assessed by hospital staff in a timely manner and treatment needs 
addressed as appropriate. 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 Clear Creek Medical Monitor 
will assess the available hematology data on a weekly 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, the Sponsor, and the Medical Monitor. In 
addition, the Data Safety Monitoring Board 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. 
Subjects who are discharged from the hospital before Day 7 will have follow up contacts with 
study staff (phone calls or other digital media) on Days 7, 15 and 29. Early discharge subjects in 
the brequinar treatment group will also have samples for safety labs (hematology and chemistry) 
obtained either at the research facility or at an outpatient laboratory on Study Days 7 ± 2 and 15 ± 
2. The safety laboratory results are to be initially assessed in real time by the Principal Investigator 
or designated person and the Medical Monitor. 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-hospital assessments and phone call visits will specifically ask about possible hematologic 
toxicity including any evidence of the list below. Early discharge 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. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 31JULY2020 FINAL 
 
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 analyses will be based on the ITT population, which is defined as all randomized subjects.   
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, NEWS2 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 
NEWS2 Assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will be assessed in terms of mortality, hospitalization status and duration, NEWS2 score, 
viral load (plasma and nasopharyngeal), and inflammatory markers. 
11.4 DHO and Brequinar Concentration Levels 
DHO and brequinar concentrations levels will be summarized using descriptive statistics. 
11.5 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 24 
subjects are planned to be entered in this trial.  Additional subjects may be enrolled following data 
review. 
11.6 Randomization 
A randomization scheme will be provided by the Sponsor to ensure subjects are randomly assigned 
to SOC or SOC + brequinar in a 1:2 ratio.  
11.7 Pooling of Study Centers 
Not applicable to this small, early phase study. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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11.8 Interim Analysis 
No interim analysis is planned for this trial. 
 
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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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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) 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. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the
assessment of acute-illness severity in the NHS. Updated report of a working party.
London: RCP, 2017.
15. Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K, and the 
Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. 
JAMA. April 22, 2020. https://jama.doi:10:1001/jama.2020.6775.
16. Study DUP 785-001 Clinical Study Report (on file with Clear Creek)
17. Study DUP 785-003 Clinical Study Report (on file with Clear Creek)
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18. Study DUP 785-005 Clinical Study Report (on file with Clear Creek)
19. Study DUP 785-022 Clinical Study Report (on file with Clear Creek)
20. Study DUP 785-031 Clinical Study Report (on file with Clear Creek)
21. Study DUP 785-034 Clinical Study Report (on file with Clear Creek)
22. 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-01 Schedule of Events 
CCB-CRISIS-01  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2 - D7 
(± 8 hours) 
Final Visit  
D15 
(± 2 days) 
F/U  
Phone 
Call 
2 weeks/ 
Survival 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
AE/Concomitant Medications (daily until discharge) 
X 
X 
D1-7 
X 
 
Medical history / History of current illness 
X 
 
 
 
 
Demographics, collect Height and weight 
X 
 
 
 
 
Check for Physical Exam abnormalities 
X 
 
 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
Hematology/Chemistry 
X 
X (pre-dose) 
 D1-7 
X 
 
Inflammatory Markers* 
 
X (pre-dose) 
D3, D5, D7 
X 
 
DHO/brequinar PK Sample Collection & Processing 
 
X (pre-dose) 
D3, D5, D7 
X (DHO only) 
 
Swab collection for nasopharyngeal viral load 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Clinical SARS-CoV-2 testing RT-PCR 
X 
 
 
 
 
Hospital Status 
 
 
D3, D5, D7 
X 
 
NEWS2 Assessments 
 
X 
D3, D5, D7 
X 
 
Dispense Study Medication if assigned to brequinar** 
 
X 
D2 – 5 
 
 
Drug Accountability 
 
 
D7 
 
 
Survival Assessment Day 29 
 
 
 
 
X 
Collect information from available electronic health record (EHR), Progress Notes, and medication records; 
a special visit by research staff is not to be performed. Results for Hematology, Chemistry and available 
inflammatory markers analyzed locally are to be obtained from the EHR; do not draw another set of labs. 
Missed samples due to hospital staff too busy or for technical reasons unable to obtain samples will not be 
counted as protocol deviations. Record urinalysis results if urinalysis is clinically indicated and results are 
available in the EHR. Note that if the subject is discharged before Day 15, follow instructions provided in 
Section 8.5. 
Note that any visits other than Screening/Day 1 may be conducted via telephone or digital media. Missed 
samples/assessments when phone visits occur will not be counted as protocol deviations. 
*Inflammatory markers are to be collected from the EHR when available; otherwise process and ship 
samples to the central laboratory per the Laboratory Manual. DHO and brequinar samples will also be sent 
to the central laboratory. 
**If a subject in the brequinar group is discharged prior to Day 5 (has not completed taking brequinar all 5 
days) the subject may be dispensed study medication to take at home on a daily basis. In this instance the 
subject is also to be provided with the study medication diary for drug accountability purposes. 
 
 
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15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-01 
STUDY TITLE:  The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in hospitalized adults with 
coronavirus-19 (COVID-19). 
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: __________________ 
 
Site Address: 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
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15.3 Appendix C: National Early Warning Score (NEWS2)  
Use SpO2 Scale 2 if target range is 88 – 92%, e.g., in hypercapnic respiratory failure. 
National Early Warning System Score (NEWS) 2 Royal College of Physicians 2017 [14]. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in 
hospitalized adults with coronavirus-19 (COVID-19) 
 
Study No: CCB-CRISIS-01 
Version Date:  05 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. 
 
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TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 18 
3.1 Background ................................................................................................................ 18 
3.2 Coronavirus-19 (COVID-19) ..................................................................................... 18 
3.2.1 Coronavirus Biology .................................................................................................... 18 
3.3 Host Nucleotide Synthesis ......................................................................................... 18 
3.4 Dihydroorotate dehydrogenase (DHODH) ................................................................ 18 
3.5 Brequinar .................................................................................................................... 19 
3.6 Rationale for the Planned Trial .................................................................................. 19 
3.6.1 Brequinar Dose Selection ............................................................................................. 20 
3.6.2 Risk/Benefit of Brequinar ............................................................................................ 20 
3.7 Risks Associated with Participation in the Clinical Study ......................................... 20 
3.8 Possible Interactions with Concomitant Medical Treatments .................................... 21 
3.8.1 CYP Interactions .......................................................................................................... 21 
3.9 Steps to be Taken to Control or Mitigate Risks ......................................................... 21 
4 TRIAL OBJECTIVES ........................................................................................................ 23 
4.1 Primary Objective ...................................................................................................... 23 
4.2 Secondary Objectives ................................................................................................. 23 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 23 
5 TRIAL DESIGN ................................................................................................................. 24 
6 TRIAL ENDPOINTS.......................................................................................................... 25 
6.1 Primary Endpoint ....................................................................................................... 25 
6.2 Secondary Endpoints .................................................................................................. 25 
6.3 EXPLORATORY Endpoints ..................................................................................... 25 
7 TRIAL POPULATION ....................................................................................................... 26 
7.1 Number of Subjects .................................................................................................... 26 
7.2 Inclusion criteria ......................................................................................................... 26 
7.3 Exclusion Criteria ....................................................................................................... 26 
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7.4 Inclusion of Women and Minorities........................................................................... 27 
8 STUDY TREATMENTS .................................................................................................... 28 
8.1 Description of Study Medications .............................................................................. 28 
8.1.1 Brequinar ...................................................................................................................... 28 
8.2 Treatment Administration .......................................................................................... 28 
8.2.1 Safety/Tolerability ........................................................................................................ 28 
8.3 Study Discontinuation ................................................................................................ 29 
8.4 Stopping Criteria ........................................................................................................ 29 
8.4.1 Individual Stopping Criteria ......................................................................................... 29 
8.4.2 Study-Level Stopping Criteria...................................................................................... 29 
8.5 Hospital Discharge Prior to Study Day 15 ................................................................. 29 
8.6 Concomitant Medication/Treatment .......................................................................... 30 
8.7 Treatment Compliance ............................................................................................... 30 
8.8 Storage, Stability, Labeling and Packaging ............................................................... 30 
8.8.1 Storage and Stability .................................................................................................... 30 
8.8.2 Labeling and Packaging ............................................................................................... 30 
8.8.3 Blinding and Randomization ........................................................................................ 31 
8.8.4 Unblinding/Expectedness ............................................................................................. 31 
8.8.5 Study Drug Accountability ........................................................................................... 31 
8.9 Prohibited Medications .............................................................................................. 32 
8.10 Study Adjustments Due to COVID-19....................................................................... 32 
9 CONDUCT OF THE TRIAL.............................................................................................. 33 
9.1 Ethical and Regulatory Considerations ...................................................................... 33 
9.2 Informed Consent ....................................................................................................... 33 
9.3 Institutional Review Board......................................................................................... 34 
9.4 Schedule of Events ..................................................................................................... 34 
9.5 Study Conduct ............................................................................................................ 35 
9.5.1 Unscheduled Visits ....................................................................................................... 37 
9.6 Compliance with Study Procedures ........................................................................... 37 
9.7 Early Withdrawal from the Study .............................................................................. 37 
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9.8 Early Termination of the Study .................................................................................. 38 
10 ADVERSE EVENT REPORTING..................................................................................... 39 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 40 
10.2 Infection Follow Up ................................................................................................... 40 
10.3 Classification of Causality ......................................................................................... 40 
10.4 Classification of Severity ........................................................................................... 41 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 41 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 43 
10.7 Pregnancies................................................................................................................. 43 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 44 
10.9 Data Safety Monitoring Board ................................................................................... 45 
10.9.1 
DSMB Safety Review Schedule ............................................................................. 45 
11 STATISTICAL CONSIDERATIONS................................................................................ 46 
11.1 Study Populations for Analysis .................................................................................. 46 
11.2 Safety Analyses .......................................................................................................... 46 
11.3 Efficacy Analyses ....................................................................................................... 46 
11.4 DHO and Brequinar Concentration Levels ................................................................ 46 
11.5 Sample Size Considerations ....................................................................................... 46 
11.6 Randomization ........................................................................................................... 46 
11.7 Pooling of Study Centers............................................................................................ 46 
11.8 Interim Analysis ......................................................................................................... 47 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 48 
12.1 Investigator’s Performance ........................................................................................ 48 
12.2 Confidentiality ............................................................................................................ 48 
12.3 Source Documentation ............................................................................................... 48 
12.4 Data Collection ........................................................................................................... 49 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 49 
12.6 Non-Protocol Research .............................................................................................. 50 
12.7 Publication .................................................................................................................. 50 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 51 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
13.1 General ....................................................................................................................... 51 
13.2 Indemnity ................................................................................................................... 51 
13.3 Data Monitoring ......................................................................................................... 51 
13.4 Audit ........................................................................................................................... 51 
13.5 Confidentiality ............................................................................................................ 52 
13.6 Finance ....................................................................................................................... 52 
14 REFERENCES ................................................................................................................... 53 
15 APPENDICES .................................................................................................................... 55 
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events .................................................. 55 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 56 
15.3 Appendix C: National Early Warning Score (NEWS2) ............................................. 57 
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment Guidance. ..... 58 
 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
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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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
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 
DSMB 
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 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
Abbreviation 
Definition 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
2 
SYNOPSIS  
CCB-CRISIS-01 SYNOPSIS  
IND 
149291 
Title 
The CRISIS Study: A randomized open-label study assessing the safety and anti-
coronavirus response of suppression of host nucleotide synthesis in hospitalized 
adults with coronavirus-19 (COVID-19) 
Protocol 
CCB-CRISIS-01 
Rationale 
Brequinar is a potent DHODH inhibitor that has been studied in more than 1,000 
cancer, psoriasis, and organ transplant patients. 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. 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 primary dose-limiting adverse effects have included 
thrombocytopenia and mucositis. 
The CRISIS trial will study standard of care (SOC) and SOC with 5 days of 
DHODH inhibition. 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. 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. Brequinar has not been previously tested as an anti-
viral. 
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:2 ratio to either standard of care (SOC) alone, 
or SOC + brequinar. 
Brequinar is available as 100 mg oral capsules. Five once daily doses of brequinar 
100 mg are to be administered on Study Days 1 – 5 for those assigned to the SOC 
+ brequinar group.  
Clinical Study Report 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 11 of 58 
PROTOCOL VERSION DATE: 05AUG2020 FINAL 
Inclusion 
Criteria: 
 
1. Willing and able to provide informed consent for the trial, written, 
electronic, verbal or other method deemed acceptable by the institution and 
IRB.  
2. 18 years of age or older.  
3. If discharged from the hospital prior to Study Day 15 or if follow up is 
needed for study drug-related adverse event, willing to go to an outpatient  
facility if feasible or be in contact with the study team (phone call or other 
digital media) for remaining study assessments. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time 
polymerase chain reaction (RT-PCR) or other FDA-cleared commercial or 
public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating 
physician immediately. Men and women treated or enrolled on this protocol 
must also agree to use adequate contraception for the duration of study 
participation, and for 90 days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study 
drug administration until 90 days after the last dose of brequinar. 
8. ≤ 10 days since first COVID-19 symptom as determined by treating 
clinician. 
9. Able to swallow capsules. 
10. At least one COVID-19 symptom including but not limited to fever, cough, 
sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, 
shortness of breath, dyspnea, dysgeusia, or other symptom commonly 
associated with COVID-19. 
Exclusion 
Criteria: 
1. Any physical examination findings and/or history of any illness that, in the 
opinion of the study investigator, might confound the results of the study 
or pose an additional risk to the patient 
2. Active malignancy other than squamous cell carcinoma; anticancer 
treatment such as chemotherapy or radiation therapy within the past month. 
3. Nursing women or women of childbearing potential (WOCBP) with a 
positive pregnancy test. 
4. Treatment 
with 
another 
DHODH 
inhibitor 
(e.g., 
leflunomide, 
teriflunomide), tacrolimus, sirolimus. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
study drug-related AE or an SAE; the Day 29 mortality assessment is still to take 
place. 
If the subject is unable or not permitted to return for planned study visits, the visit 
activities will be conducted by contacting the subject (phone or other digital media) 
except for the lab draw. The hematology/chemistry sample will be obtained via 
outpatient laboratory, if feasible and the results entered into the EDC and reviewed 
by the study team.  
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF. A subject is considered completed the study if 
they have assessments through Day 15, whether conducted in the hospital or 
contacted via phone or other digital media. 
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of informed consent through Day 
15. After Day 15, collect/record only Serious Adverse Events (SAEs) or those 
judged by the Investigator or designated person to be related to study drug, 
including but not limited to potential hematologic toxicities. Post-randomization 
adverse events will be those with an onset after the date and time of randomization. 
Subjects who develop Grade 3 or 4 toxicities are to be re-evaluated every 2 days, 
as feasible, until the toxicity returns to Grade ≤ 2 severity. 
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, safety 
laboratory data, and NEWS2 Assessments.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of post randomization adverse events, defined as AEs 
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, NEWS2 
Criteria, and other clinical measures will be summarized using appropriate 
descriptive statistics. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
Page 17 of 58 
PROTOCOL VERSION DATE: 05AUG2020 FINAL 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Title: 
Address: 
Telephone No.: 
Fax No.: 
E-mail: 
Barbara Powers, MSN, Ph.D. Clinical 
Operations 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th 
Floor, Cambridge, MA 02139 
484-686-0545 
617-863-2082 
bpowers@clearcreekbio.com  
MEDICAL MONITOR 
Name:  
Sharon Levy, MD 
Title: 
Prosoft Clinical 
Telephone No.: 
M: (610) 316-9764 
O: (484) 320-2062 
E-mail: 
s.levy@prosoftclinical.com
Sharon.levy27@gmail.com 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
3 
INTRODUCTION 
3.1 Background 
3.2 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]).  
3.2.1 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]). 
3.3  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.  
3.4  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.  
 
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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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]).    
3.5  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]). 
3.6  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 CRISIS trial will study standard of care (SOC) and SOC with 5 days of DHODH inhibition. 
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, 
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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.  
3.6.1 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 
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 reassuring the safety of 
this regimen (see Brequinar IB [5]).  
3.6.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive database exists with more than 800 cancer 
patients 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. Brequinar has 
also been utilized at lower doses than used in the cancer studies in 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. While no DHODHi has been tested to date in the clinic for 
infection with SARS-CoV-2 and no brequinar safety information is available in treatment of this 
disease, DHODHi therapy in the context of trials for patients with cancer has the expected safety 
side-effects of mucositis and bone marrow suppression. 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 mucositis and only 1 (2.6%) episode of mild thrombocytopenia. The 100 mg per day dose 
proposed for administration in this study should be safe and well tolerated.  
The possible 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. As discussed above, inhibition of DHODH is expected to reduce the ability 
of the virus to replicate and it is for this reason that study CCB-CRISIS-01 will administer 
brequinar to patients with COVID-19. 
 
3.7 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of brequinar in patients with refractory 
solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis have 
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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.  
COVID-19 patients are at higher risk of complications and poor outcomes when their infection is 
combined with comorbidities including hypertension, diabetes, chronic kidney disease, chronic 
obstructive pulmonary disease (COPD) or asthma, cardiovascular disease (coronary artery disease 
or congestive heart failure), liver cirrhosis, age > 65, and BMI > 30 [15]. It is likely that participants 
in this protocol who are sick enough to be hospitalized will have at least one of these comorbidities. 
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).  
3.8 Possible Interactions with Concomitant Medical Treatments 
While not previously tested in patients with viral infections, brequinar has been administered to 
subjects taking a variety of concomitant medications that are typical in severely ill cancer patients. 
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. Brequinar has also been used concomitantly with antibiotics, antifungals and other 
critical care medications. 
 
There is no experience with brequinar for treatment of SARS-CoV-2 and other severe viral 
infections and no formal interaction studies have been conducted.  
3.8.1 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).  
3.9 Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated in the hospital setting by highly experienced infectious disease or other 
critical care specialists and other qualified staff familiar with the treatment of severe viral 
infections and their complications. Subjects will be followed for study purposes through at least 
Day 15 even if improved enough to be discharged from the hospital. 
Subjects in the Brequinar Treatment Group 
If the subject is in the brequinar treatment group and is being discharged prior to completing the 
study, ensure a hematology/chemistry sample is obtained prior to discharge on the day of 
discharge. The subject is to return to the research or out-patient facility for the Days 7 and 15 visits 
if able and permitted. If unable or not permitted to return to the research facility due to COVID-
19 restrictions, the remaining visit activities except for the lab draw will be conducted by phone 
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or other digital media. The lab draw will be performed by an outpatient laboratory at a designated 
facility. Lab draws for any outpatient visits for the Day 7 and 15 visits are limited to safety labs 
(hematology and chemistry). Additional outpatient laboratory or study visits are to be conducted 
as needed for follow up of adverse events including hematologic toxicities. 
 
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5 
TRIAL DESIGN 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care per institutional guidelines for treatment of patients with 
SARS-CoV-2 infection. In addition to standard of care, the brequinar group will receive brequinar 
100 mg once daily for 5 days.    
The Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance is provided in 
Appendix D Section 15.4. This guidance provides an example of standard of care instructions for 
treatment of COVID-19. The guidance is provided as informational only, it is not required that this 
guidance be used for treatment as standards of care may differ between institutions. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Study procedures are presented in 
detail in Section 8. Subjects will be followed through Day 15, with mortality assessed via a phone 
call/other digital media acceptable to institution on Day 29. 
If the subject is being discharged prior to Day 7, see Section 8.5. 
It is understood that some assessments may not be conducted if the subject is unable to return to 
the clinic after discharge due to restricted travel. If an assessment is missed due to after hospital 
discharge, e.g., samples or blood draws, this will not be counted as a protocol deviation. Any of 
the study visits may be conducted via telephone if the subject has been discharged from the hospital 
and is not permitted to or is unable to return to the hospital/clinic for these visits. 
Information is to be collected using the electronic health record (EHR) whenever possible. It is not 
required to perform study-specific laboratory assessments, NEWS 2 assessments, etc. separately 
for study purposes. 
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7 
TRIAL POPULATION 
7.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 24 subjects have completed the study. Subjects will be randomized to either 
standard of care or standard of care plus brequinar or in a 1:2: ratio (approximately 8 subjects 
assigned to standard of care alone and approximately 16 subjects on standard of care plus 
brequinar).  
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. If discharged from the hospital prior to Study Day 15 or if follow up is needed for study 
drug-related adverse event, willing to go to an outpatient  facility if feasible or be in contact 
with the study team (phone call or other digital media) for remaining study assessments. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase 
chain reaction (RT-PCR) or other Food and Drug Administration (FDA)-cleared 
commercial or public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men and women treated or enrolled on this protocol must 
also agree to use adequate contraception for the duration of study participation and for 90 
days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of brequinar.  
8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician. 
9. Able to swallow capsules. 
10. At least one COVID-19 symptom including but not limited to fever, cough, sore throat, 
malaise, headache, muscle pain, gastrointestinal symptoms, shortness of breath, dyspnea, 
dysgeusia, or other symptom commonly associated with COVID-19. [22]. 
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. Active malignancy other than squamous cell carcinoma; anticancer treatment such as 
chemotherapy or radiation therapy within the past month. 
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3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy 
test. 
4. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide), tacrolimus, 
sirolimus. 
5. Platelets ≤150,000 cell/mm3. 
6. Hemoglobin < 10 gm/dL for menstruating women and < 12 gm/dL for all other subjects 
7. Absolute neutrophil count < 1500 cells/mm3 
8. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN 
10. History of bleeding disorders or recent surgery in the six weeks preceding enrollment 
11. Concomitant use of agents known to cause bone marrow suppression leading to 
thrombocytopenia 
12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding. 
13. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis. 
14. Heart failure, current uncontrolled cardiovascular disease, including unstable angina, 
uncontrolled arrhythmias, major adverse cardiac event within 6 months (e.g. stroke, 
myocardial infarction, hospitalization due to heart failure, or revascularization procedure). 
15.  Life expectancy of < 5 days in the judgment of the treating clinician. 
16. Evidence of critical illness defined by at least one of the following: 
a. Respiratory failure requiring at least one of the following: 
i. Endotracheal intubation and mechanical ventilation, noninvasive positive 
pressure ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., 
clinical need for one of the preceding therapies, but preceding therapies may 
not be able to be administered in setting of resource limitation) 
ii. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood 
pressure < 60 mm Hg or requiring vasopressors) 
b. Multi-organ dysfunction/failure. See [22].  
7.4 Inclusion of Women and Minorities 
Adult men and women of all races and ethnic groups are eligible for this trial. 
 
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8 
STUDY TREATMENTS 
8.1 Description of Study Medications 
8.1.1 Brequinar 
Brequinar will be supplied as 100 mg capsules. Dosing will be a single 5-day course of brequinar 
100 mg once daily for 5 doses. The initial brequinar dose (Day 1) should be administered as soon 
as possible based on study drug availability from the investigational pharmacy. At least the first 
dose of study medication is to be taken in the hospital. Subjects in the brequinar group discharged 
before Day 5 will be dispensed brequinar to take at home daily until all 5 doses have been taken. 
8.2 Treatment Administration 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 
infection. Subjects will be randomly assigned in a 1:2 ratio to standard of care alone or standard 
of care plus brequinar. The brequinar dosing interval should be 24h ± 6h. If discharged prior to 
Day 5, the subject may take any remaining doses once a day at home. In this case, the subject is to 
record dosing using a medication diary provided by the study team. The diary information will be 
provided to the study team either verbally or electronically or during an in-person visit. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE).  
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 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 (Study 785-001 [16], 785-003 [17], and 785-005 [18]) with five 
consecutive days of intravenous (IV) brequinar dosing and 168 subjects, there were no toxic 
deaths. For subjects from these three studies who were treated with a dose of 100 mg or below  
(as will be dosed in CCB-CRISIS-01), 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 [19], 785-031 [20] , and 785-034 [21]), the study drug related 
AEs through 21 days (each observed in one subject only) included diarrhea, headache, nausea, 
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For subjects in the brequinar treatment group discharged from the hospital prior to Day 5, the 
subject is to take home the remaining doses of brequinar for daily self-administration. All subjects 
(brequinar and SOC) should have the scheduled assessments, e.g. lab samples and the 
nasopharyngeal swab, on the day of discharge and enter these results on the appropriate EDC page. 
Following discharge, subjects are to return to the research or out-patient lab collection facility for 
the remaining study visits, if feasible. Out-patient lab results are to be entered into the EDC and 
reviewed by a member of the study team. It is important that every effort be made to have subjects 
return at least on Days 7 and 15, if feasible. Subjects in the brequinar group are to record brequinar 
dosing on the medication diary provided by the study team. The study team will arrange for the 
subject to return any unused study medication to the research facility. 
For all subjects, if discharge occurs on Days 10, 11, or 12, ensure a hematology/chemistry sample 
has been obtained on the day of discharge and record these results on the appropriate EDC page. 
Following discharge, the subject is to return to the research or out-patient lab collection facility for 
the Day 15 visit, if feasible. Out-patient lab results are to be entered into the EDC and reviewed 
by a member of the study team. 
If discharge occurs on Days 13, 14 or 15, complete the Day 15 Final Visit activities prior to 
discharge. No further visits are required unless follow up is needed for a study drug-related AE or 
an SAE; the Day 29 mortality assessment is still to take place. 
If the subject is unable or not permitted to return for planned study visits, the visit activities will 
be conducted by contacting the subject (phone or other digital media) except for the lab draw. The 
lab draw will be completed at a research facility or an outpatient laboratory, if feasible, and the 
results entered into the EDC and reviewed by the study team.  
Study completion or the reason for study discontinuation will be recorded in the source document 
and the eCRF. A subject is considered completed the study if they have assessments through Day 
15, whether conducted in the hospital or contacted via phone or other digital media. 
8.6 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 8.9.  
8.7 Treatment Compliance 
Compliance will be assessed by reviewing the subject’s EHR, the study medication diary when 
applicable, and other study records as appropriate. 
8.8 Storage, Stability, Labeling and Packaging 
8.8.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.8.2 Labeling and Packaging  
Each brequinar bottle/dispensing container for subject use will be labeled with at least the 
following information: 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: Brequinar 100 mg capsules 
For oral use only. Take with approximately 8 ounces water. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.8.3 Blinding and Randomization 
The trial will be conducted in an open-label manner with random assignment to standard of care 
or standard of care plus brequinar. The brequinar capsules will be provided to each participating 
institution in bulk to be dispensed by the institution’s pharmacist for each subject. Randomization 
assignments will be provided by the sponsor. 
8.8.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment will be known for 
each subject. 
Expectedness will be determined by establishing whether the 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.   
8.8.5 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, used and discarded.  It must 
be clear from the records whether the subject received study medication or was assigned to 
standard of care. 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.  
Subjects in the brequinar group who are discharged prior to Day 5 will be given a study medication 
diary for recording at home treatment administration.  The diary information will be collected by 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
the study team either verbally or electronically or in person during a visit to the research facility. 
Unused study drug at the patient’s home is to be returned to the research facility.  
At the end of the study, any unused study drug in the pharmacy will be returned to the Sponsor for 
destruction or may be destroyed locally; disposition of study drug will be documented. The study 
team will make arrangements for the subject to return any unused study medication to the research 
facility. 
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. 
8.9 Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide), 
tacrolimus, sirolimus. Treatment is prohibited with agents known to cause bone marrow 
suppression leading to thrombocytopenia.  
8.10 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 telephone or other digital media. Study information is to be 
collected from the EHR as much as possible such as NEWS2 Assessments, height, weight, 
hematology/chemistry, from Progress Notes for AEs, and from medication records for new or 
changed concomitant medications. Visits to an outpatient laboratory post hospital discharge may 
be required if subjects are not able or permitted to return to the research facility for follow up study 
visits.  
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). Remdesivir may be used in this clinical trial as a component of standard of care 
of patients hospitalized with severe disease in settings where remdesivir is available via the 
Emergency Use Authorization (EUA) or other FDA approval. 
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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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
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), 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.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures. Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be subject to review by the Sponsor; a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. 
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 
Clinical Study Report 
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03 May 2021
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Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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CONFIDENTIAL
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 503 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 504 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 39 of 58 
PROTOCOL VERSION DATE: 05AUG2020 FINAL 
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 15. After Day 
15, collect/record only Serious Adverse Events (SAEs) or those judged 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.   
Any serious adverse events (SAEs) experienced after 30 days post the last dose of study drug 
should only be reported to the sponsor if the investigator suspects a causal relationship to the 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, or require therapy. 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the appropriate electronic data capture form.  
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 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 505 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 506 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 507 of 582


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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
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 Medical Monitor 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 is to 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 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to 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 knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must 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 the Sponsor Contact 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 pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
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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-
up with 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 selecting a relatively brief 5-day exposure and a low brequinar dose, all 
subjects in the clinical trial will initially be hospitalized as in-patients and will be under the care 
of highly qualified infectious disease, critical care, and associated medical personnel. As is 
standard of care for moderately to severely ill in-patients, daily samples will be obtained for 
hematology assessments including complete blood count with full differential (WBC, RBC, 
hemoglobin, hematocrit, platelet count, absolute neutrophils, absolute lymphocytes, absolute 
monocytes, absolute eosinophils, and absolute basophils). Any clinically significant out-of-range 
laboratory values will be assessed by hospital staff in a timely manner and treatment needs 
addressed as appropriate. 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 Clear Creek Medical Monitor 
will assess the available hematology data on a weekly 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, the Sponsor, and the Medical Monitor. In 
addition, the Data Safety Monitoring Board 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. 
Subjects who are discharged from the hospital before Day 7 will have follow up contacts with 
study staff (phone calls or other digital media) on Days 7, 15 and 29. Early discharge subjects in 
the brequinar treatment group will also have samples for safety labs (hematology and chemistry) 
obtained either at the research facility or at an outpatient laboratory on Study Days 7 ± 2 and 15 ± 
2. The safety laboratory results are to be initially assessed in real time by the Principal Investigator 
or designated person and the Medical Monitor. 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-hospital assessments and phone call visits will specifically ask about possible hematologic 
toxicity including any evidence of the list below. Early discharge 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. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
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 analyses will be based on the ITT population, which is defined as all randomized subjects.   
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, NEWS2 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 
NEWS2 Assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will be assessed in terms of mortality, hospitalization status and duration, NEWS2 score, 
viral load (plasma and nasopharyngeal), and inflammatory markers. 
11.4 DHO and Brequinar Concentration Levels 
DHO and brequinar concentrations levels will be summarized using descriptive statistics. 
11.5 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 24 
subjects are planned to be entered in this trial.  Additional subjects may be enrolled following data 
review. 
11.6 Randomization 
A randomization scheme will be provided by the Sponsor to ensure subjects are randomly assigned 
to SOC or SOC + brequinar in a 1:2 ratio.  
11.7 Pooling of Study Centers 
Not applicable to this small, early phase study. 
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11.8 Interim Analysis 
No interim analysis is planned for this trial. 
 
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PROTOCOL VERSION DATE: 05AUG2020 FINAL 
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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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) 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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PROTOCOL NUMBER:  CCB-CRISIS-01  
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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. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the
assessment of acute-illness severity in the NHS. Updated report of a working party.
London: RCP, 2017.
15. Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K, and the 
Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. 
JAMA. April 22, 2020. https://jama.doi:10:1001/jama.2020.6775.
16. Study DUP 785-001 Clinical Study Report (on file with Clear Creek)
17. Study DUP 785-003 Clinical Study Report (on file with Clear Creek)
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18. Study DUP 785-005 Clinical Study Report (on file with Clear Creek)
19. Study DUP 785-022 Clinical Study Report (on file with Clear Creek)
20. Study DUP 785-031 Clinical Study Report (on file with Clear Creek)
21. Study DUP 785-034 Clinical Study Report (on file with Clear Creek)
22. 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-01 Schedule of Events 
CCB-CRISIS-01  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2 - D7 
(± 8 hours) 
Final Visit  
D15 
(± 2 days) 
F/U  
Phone 
Call 
2 weeks/ 
Survival 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
AE/Concomitant Medications (daily until discharge) 
X 
X 
D1-7 
X 
 
Medical history / History of current illness 
X 
 
 
 
 
Demographics, collect Height and weight 
X 
 
 
 
 
Check for Physical Exam abnormalities 
X 
 
 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
Hematology/Chemistry 
X 
X (pre-dose) 
 D1-7 
X 
 
Inflammatory Markers* 
 
X (pre-dose) 
D3, D5, D7 
X 
 
DHO/brequinar PK Sample Collection & Processing 
 
X (pre-dose) 
D3, D5, D7 
X (DHO only) 
 
Swab collection for nasopharyngeal viral load 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Clinical SARS-CoV-2 testing RT-PCR 
X 
 
 
 
 
Hospital Status 
 
 
D3, D5, D7 
X 
 
NEWS2 Assessments 
 
X 
D3, D5, D7 
X 
 
Dispense Study Medication if assigned to brequinar** 
 
X 
D2 – 5 
 
 
Drug Accountability 
 
 
D7 
 
 
Survival Assessment Day 29 
 
 
 
 
X 
Collect information from available electronic health record (EHR), Progress Notes, and medication records; 
a special visit by research staff is not to be performed. Results for Hematology, Chemistry and available 
inflammatory markers analyzed locally are to be obtained from the EHR; do not draw another set of labs. 
Missed samples due to hospital staff too busy or for technical reasons unable to obtain samples will not be 
counted as protocol deviations. Record urinalysis results if urinalysis is clinically indicated and results are 
available in the EHR. Note that if the subject is discharged before Day 15, follow instructions provided in 
Section 8.5. 
Note that any visits other than Screening/Day 1 may be conducted via telephone or digital media. Missed 
samples/assessments when phone visits occur will not be counted as protocol deviations. 
*Inflammatory markers are to be collected from the EHR when available; otherwise process and ship 
samples to the central laboratory per the Laboratory Manual. DHO and brequinar samples will also be sent 
to the central laboratory. 
**If a subject in the brequinar group is discharged prior to Day 5 (has not completed taking brequinar all 5 
days) the subject may be dispensed study medication to take at home on a daily basis. In this instance the 
subject is also to be provided with the study medication diary for drug accountability purposes. 
 
 
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15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-01 
STUDY TITLE:  The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in hospitalized adults with 
coronavirus-19 (COVID-19). 
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: __________________ 
 
Site Address: 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
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15.3 Appendix C: National Early Warning Score (NEWS2)  
Use SpO2 Scale 2 if target range is 88 – 92%, e.g., in hypercapnic respiratory failure. 
National Early Warning System Score (NEWS) 2 Royal College of Physicians 2017 [14]. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
STUDY PROTOCOL 
The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in 
hospitalized adults with coronavirus-19 (COVID-19) 
 
Study No: CCB-CRISIS-01 
Version Date: 10 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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
TABLE OF CONTENTS 
2 SYNOPSIS ............................................................................................................................ 9 
3 INTRODUCTION .............................................................................................................. 18 
3.1 Background ................................................................................................................ 18 
3.2 Coronavirus-19 (COVID-19) ..................................................................................... 18 
3.2.1 Coronavirus Biology .................................................................................................... 18 
3.3 Host Nucleotide Synthesis ......................................................................................... 18 
3.4 Dihydroorotate dehydrogenase (DHODH) ................................................................ 18 
3.5 Brequinar .................................................................................................................... 19 
3.6 Rationale for the Planned Trial .................................................................................. 19 
3.6.1 Brequinar Dose Selection ............................................................................................. 20 
3.6.2 Risk/Benefit of Brequinar ............................................................................................ 20 
3.7 Risks Associated with Participation in the Clinical Study ......................................... 20 
3.8 Possible Interactions with Concomitant Medical Treatments .................................... 21 
3.8.1 CYP Interactions .......................................................................................................... 21 
3.9 Steps to be Taken to Control or Mitigate Risks ......................................................... 21 
4 TRIAL OBJECTIVES ........................................................................................................ 23 
4.1 Primary Objective ...................................................................................................... 23 
4.2 Secondary Objectives ................................................................................................. 23 
4.3 EXPLORATORY OBJECTIVES .............................................................................. 23 
5 TRIAL DESIGN ................................................................................................................. 24 
6 TRIAL ENDPOINTS.......................................................................................................... 25 
6.1 Primary Endpoint ....................................................................................................... 25 
6.2 Secondary Endpoints .................................................................................................. 25 
6.3 EXPLORATORY Endpoints ..................................................................................... 25 
7 TRIAL POPULATION ....................................................................................................... 26 
7.1 Number of Subjects .................................................................................................... 26 
7.2 Inclusion criteria ......................................................................................................... 26 
7.3 Exclusion Criteria ....................................................................................................... 26 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
7.4 Inclusion of Women and Minorities........................................................................... 27 
8 STUDY TREATMENTS .................................................................................................... 28 
8.1 Description of Study Medications .............................................................................. 28 
8.1.1 Brequinar ...................................................................................................................... 28 
8.2 Treatment Administration .......................................................................................... 28 
8.2.1 Safety/Tolerability ........................................................................................................ 28 
8.3 Study Discontinuation ................................................................................................ 29 
8.4 Stopping Criteria ........................................................................................................ 29 
8.4.1 Individual Stopping Criteria ......................................................................................... 29 
8.4.2 Study-Level Stopping Criteria...................................................................................... 29 
8.5 Hospital Discharge Prior to Study Day 15 ................................................................. 29 
8.6 Concomitant Medication/Treatment .......................................................................... 30 
8.7 Treatment Compliance ............................................................................................... 30 
8.8 Storage, Stability, Labeling and Packaging ............................................................... 30 
8.8.1 Storage and Stability .................................................................................................... 30 
8.8.2 Labeling and Packaging ............................................................................................... 30 
8.8.3 Blinding and Randomization ........................................................................................ 31 
8.8.4 Unblinding/Expectedness ............................................................................................. 31 
8.8.5 Study Drug Accountability ........................................................................................... 31 
8.9 Prohibited Medications .............................................................................................. 32 
8.10 Study Adjustments Due to COVID-19....................................................................... 32 
9 CONDUCT OF THE TRIAL.............................................................................................. 33 
9.1 Ethical and Regulatory Considerations ...................................................................... 33 
9.2 Informed Consent ....................................................................................................... 33 
9.3 Institutional Review Board......................................................................................... 34 
9.4 Schedule of Events ..................................................................................................... 34 
9.5 Study Conduct ............................................................................................................ 35 
9.5.1 Unscheduled Visits ....................................................................................................... 37 
9.6 Compliance with Study Procedures ........................................................................... 37 
9.7 Early Withdrawal from the Study .............................................................................. 37 
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9.8 Early Termination of the Study .................................................................................. 38 
10 ADVERSE EVENT REPORTING..................................................................................... 39 
10.1 Follow Up of Grade 3 or 4 Toxicities ........................................................................ 40 
10.2 Infection Follow Up ................................................................................................... 40 
10.3 Classification of Causality ......................................................................................... 40 
10.4 Classification of Severity ........................................................................................... 41 
10.5 Serious Adverse Event (SAE) Reporting ................................................................... 41 
10.6 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 43 
10.7 Pregnancies................................................................................................................. 43 
10.8 Safety Monitoring for Hematologic Toxicities .......................................................... 44 
10.9 Data Safety Monitoring Board ................................................................................... 45 
10.9.1 
DSMB Safety Review Schedule ............................................................................. 45 
11 STATISTICAL CONSIDERATIONS................................................................................ 46 
11.1 Study Populations for Analysis .................................................................................. 46 
11.2 Safety Analyses .......................................................................................................... 46 
11.3 Efficacy Analyses ....................................................................................................... 46 
11.4 DHO and Brequinar Concentration Levels ................................................................ 46 
11.5 Sample Size Considerations ....................................................................................... 46 
11.6 Randomization ........................................................................................................... 46 
11.7 Pooling of Study Centers............................................................................................ 46 
11.8 Interim Analysis ......................................................................................................... 47 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 48 
12.1 Investigator’s Performance ........................................................................................ 48 
12.2 Confidentiality ............................................................................................................ 48 
12.3 Source Documentation ............................................................................................... 48 
12.4 Data Collection ........................................................................................................... 49 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 49 
12.6 Non-Protocol Research .............................................................................................. 50 
12.7 Publication .................................................................................................................. 50 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 51 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 5 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
13.1 General ....................................................................................................................... 51 
13.2 Indemnity ................................................................................................................... 51 
13.3 Data Monitoring ......................................................................................................... 51 
13.4 Audit ........................................................................................................................... 51 
13.5 Confidentiality ............................................................................................................ 52 
13.6 Finance ....................................................................................................................... 52 
14 REFERENCES ................................................................................................................... 53 
15 APPENDICES .................................................................................................................... 55 
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events .................................................. 55 
15.2 Appendix B: Investigator’s Statement and Agreement .............................................. 56 
15.3 Appendix C: National Early Warning Score (NEWS2) ............................................. 57 
15.4 Appendix D: Massachusetts General Hospital COVID-19 Treatment Guidance. ..... 58 
 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 6 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 7 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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 
DSMB 
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 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 8 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
Abbreviation 
Definition 
US 
United States 
XMP 
Xanthosine-5’ phosphate 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 9 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
2 
SYNOPSIS  
CCB-CRISIS-01 SYNOPSIS  
IND 
149291 
Title 
The CRISIS Study: A randomized open-label study assessing the safety and anti-
coronavirus response of suppression of host nucleotide synthesis in hospitalized 
adults with coronavirus-19 (COVID-19) 
Protocol 
CCB-CRISIS-01 
Rationale 
Brequinar is a potent DHODH inhibitor that has been studied in more than 1,000 
cancer, psoriasis, and organ transplant patients. 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. 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 primary dose-limiting adverse effects have included 
thrombocytopenia and mucositis. 
The CRISIS trial will study standard of care (SOC) and SOC with 5 days of 
DHODH inhibition. 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. 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. Brequinar has not been previously tested as an anti-
viral. 
Investigational 
Product and 
Dosage 
Subjects will be randomized in a 1:2 ratio to either standard of care (SOC) alone, 
or SOC + brequinar. 
Brequinar is available as 100 mg oral capsules. Five once daily doses of brequinar 
100 mg are to be administered on Study Days 1 – 5 for those assigned to the SOC 
+ brequinar group.  
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 11 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
Inclusion 
Criteria: 
 
1. Willing and able to provide informed consent for the trial, written, 
electronic, verbal or other method deemed acceptable by the institution and 
IRB.  
2. 18 years of age or older.  
3. If discharged from the hospital prior to Study Day 15 or if follow up is 
needed for study drug-related adverse event, willing to go to an outpatient  
facility if feasible or be in contact with the study team (phone call or other 
digital media) for remaining study assessments. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time 
polymerase chain reaction (RT-PCR) or other FDA-cleared commercial or 
public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating 
physician immediately. Men and women treated or enrolled on this protocol 
must also agree to use adequate contraception for the duration of study 
participation, and for 90 days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study 
drug administration until 90 days after the last dose of brequinar. 
8. ≤ 10 days since first COVID-19 symptom as determined by treating 
clinician. 
9. Able to swallow capsules. 
10. At least one COVID-19 symptom including but not limited to fever, cough, 
sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, 
shortness of breath, dyspnea, dysgeusia, or other symptom commonly 
associated with COVID-19. 
Exclusion 
Criteria: 
1. Any physical examination findings and/or history of any illness that, in the 
opinion of the study investigator, might confound the results of the study 
or pose an additional risk to the patient 
2. Active malignancy other than squamous cell carcinoma; anticancer 
treatment such as chemotherapy or radiation therapy within the past month. 
3. Nursing women or women of childbearing potential (WOCBP) with a 
positive pregnancy test. 
4. Treatment 
with 
another 
DHODH 
inhibitor 
(e.g., 
leflunomide, 
teriflunomide), tacrolimus, sirolimus. 
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Clinical Study Report 
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CONFIDENTIAL
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
study drug-related AE or an SAE; the Day 29 mortality assessment is still to take 
place. 
If the subject is unable or not permitted to return for planned study visits, the visit 
activities will be conducted by contacting the subject (phone or other digital media) 
except for the lab draw. The hematology/chemistry sample will be obtained via 
outpatient laboratory, if feasible and the results entered into the EDC and reviewed 
by the study team.  
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF. A subject is considered completed the study if 
they have assessments through Day 15, whether conducted in the hospital or 
contacted via phone or other digital media. 
Safety/ 
Tolerability 
Safety/Tolerability  
Adverse events will be collected from the time of informed consent through Day 
15. After Day 15, collect/record only Serious Adverse Events (SAEs) or those 
judged by the Investigator or designated person to be related to study drug, 
including but not limited to potential hematologic toxicities. Post-randomization 
adverse events will be those with an onset after the date and time of randomization. 
Subjects who develop Grade 3 or 4 toxicities are to be re-evaluated every 2 days, 
as feasible, until the toxicity returns to Grade ≤ 2 severity. 
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, safety 
laboratory data, and NEWS2 Assessments.  
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of post randomization adverse events, defined as AEs 
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, NEWS2 
Criteria, and other clinical measures will be summarized using appropriate 
descriptive statistics. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
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PROTOCOL VERSION FINAL DATE: 10SEPT2020 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Title: 
Address: 
Telephone No.: 
Fax No.: 
E-mail: 
Barbara Powers, MSN, Ph.D. Clinical 
Operations 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th 
Floor, Cambridge, MA 02139 
484-686-0545 
617-863-2082 
bpowers@clearcreekbio.com  
MEDICAL MONITOR 
Name:  
Sharon Levy, MD 
Title: 
Prosoft Clinical 
Telephone No.: 
M: (610) 316-9764 
O: (484) 320-2062 
E-mail: 
s.levy@prosoftclinical.com
Sharon.levy27@gmail.com 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
3 
INTRODUCTION 
3.1 Background 
3.2 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]).  
3.2.1 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]). 
3.3  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.  
3.4  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.  
 
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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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]).    
3.5  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]). 
3.6  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 CRISIS trial will study standard of care (SOC) and SOC with 5 days of DHODH inhibition. 
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, 
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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.  
3.6.1 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 
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 reassuring the safety of 
this regimen (see Brequinar IB [5]).  
3.6.2    Risk/Benefit of Brequinar 
As presented in the Brequinar IB [5], an extensive database exists with more than 800 cancer 
patients 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. Brequinar has 
also been utilized at lower doses than used in the cancer studies in 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. While no DHODHi has been tested to date in the clinic for 
infection with SARS-CoV-2 and no brequinar safety information is available in treatment of this 
disease, DHODHi therapy in the context of trials for patients with cancer has the expected safety 
side-effects of mucositis and bone marrow suppression. 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 mucositis and only 1 (2.6%) episode of mild thrombocytopenia. The 100 mg per day dose 
proposed for administration in this study should be safe and well tolerated.  
The possible 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. As discussed above, inhibition of DHODH is expected to reduce the ability 
of the virus to replicate and it is for this reason that study CCB-CRISIS-01 will administer 
brequinar to patients with COVID-19. 
 
3.7 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration of brequinar in patients with refractory 
solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis have 
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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.  
COVID-19 patients are at higher risk of complications and poor outcomes when their infection is 
combined with comorbidities including hypertension, diabetes, chronic kidney disease, chronic 
obstructive pulmonary disease (COPD) or asthma, cardiovascular disease (coronary artery disease 
or congestive heart failure), liver cirrhosis, age > 65, and BMI > 30 [15]. It is likely that participants 
in this protocol who are sick enough to be hospitalized will have at least one of these comorbidities. 
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).  
3.8 Possible Interactions with Concomitant Medical Treatments 
While not previously tested in patients with viral infections, brequinar has been administered to 
subjects taking a variety of concomitant medications that are typical in severely ill cancer patients. 
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. Brequinar has also been used concomitantly with antibiotics, antifungals and other 
critical care medications. 
 
There is no experience with brequinar for treatment of SARS-CoV-2 and other severe viral 
infections and no formal interaction studies have been conducted.  
3.8.1 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).  
3.9 Steps to be Taken to Control or Mitigate Risks 
All subjects will be treated in the hospital setting by highly experienced infectious disease or other 
critical care specialists and other qualified staff familiar with the treatment of severe viral 
infections and their complications. Subjects will be followed for study purposes through at least 
Day 15 even if improved enough to be discharged from the hospital. 
Subjects in the Brequinar Treatment Group 
If the subject is in the brequinar treatment group and is being discharged prior to completing the 
study, ensure a hematology/chemistry sample is obtained prior to discharge on the day of 
discharge. The subject is to return to the research or out-patient facility for the Days 7 and 15 visits 
if able and permitted. If unable or not permitted to return to the research facility due to COVID-
19 restrictions, the remaining visit activities except for the lab draw will be conducted by phone 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
or other digital media. The lab draw will be performed by an outpatient laboratory at a designated 
facility. Lab draws for any outpatient visits for the Day 7 and 15 visits are limited to safety labs 
(hematology and chemistry). Additional outpatient laboratory or study visits are to be conducted 
as needed for follow up of adverse events including hematologic toxicities. 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 24 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
5 
TRIAL DESIGN 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care per institutional guidelines for treatment of patients with 
SARS-CoV-2 infection. In addition to standard of care, the brequinar group will receive brequinar 
100 mg once daily for 5 days.    
The Massachusetts General Hospital (MGH) COVID-19 Treatment Guidance is provided in 
Appendix D Section 15.4. This guidance provides an example of standard of care instructions for 
treatment of COVID-19. The guidance is provided as informational only, it is not required that this 
guidance be used for treatment as standards of care may differ between institutions. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Study procedures are presented in 
detail in Section 8. Subjects will be followed through Day 15, with mortality assessed via a phone 
call/other digital media acceptable to institution on Day 29. 
If the subject is being discharged prior to Day 7, see Section 8.5. 
It is understood that some assessments may not be conducted if the subject is unable to return to 
the clinic after discharge due to restricted travel. If an assessment is missed due to after hospital 
discharge, e.g., samples or blood draws, this will not be counted as a protocol deviation. Any of 
the study visits may be conducted via telephone if the subject has been discharged from the hospital 
and is not permitted to or is unable to return to the hospital/clinic for these visits. 
Information is to be collected using the electronic health record (EHR) whenever possible. It is not 
required to perform study-specific laboratory assessments, NEWS 2 assessments, etc. separately 
for study purposes. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
7 
TRIAL POPULATION 
7.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 24 subjects have completed the study. Subjects will be randomized to either 
standard of care or standard of care plus brequinar or in a 1:2: ratio (approximately 8 subjects 
assigned to standard of care alone and approximately 16 subjects on standard of care plus 
brequinar).  
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. If discharged from the hospital prior to Study Day 15 or if follow up is needed for study 
drug-related adverse event, willing to go to an outpatient  facility if feasible or be in contact 
with the study team (phone call or other digital media) for remaining study assessments. 
4. Laboratory-confirmed SARS-CoV-2 infection as determined by real time polymerase 
chain reaction (RT-PCR) or other Food and Drug Administration (FDA)-cleared 
commercial or public health assay. 
5. Hospitalized (in patient with expected duration ≥ 24 hours) 
6. The effects of brequinar on the developing human fetus are unknown. For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men and women treated or enrolled on this protocol must 
also agree to use adequate contraception for the duration of study participation and for 90 
days after completion of brequinar administration. 
7. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of brequinar.  
8. ≤ 10 days since first COVID-19 symptom as determined by treating clinician. 
9. Able to swallow capsules. 
10. At least one COVID-19 symptom including but not limited to fever, cough, sore throat, 
malaise, headache, muscle pain, gastrointestinal symptoms, shortness of breath, dyspnea, 
dysgeusia, or other symptom commonly associated with COVID-19. [22]. 
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. Active malignancy other than squamous cell carcinoma; anticancer treatment such as 
chemotherapy or radiation therapy within the past month. 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy 
test. 
4. Treatment with another DHODH inhibitor (e.g., leflunomide or teriflunomide), tacrolimus, 
sirolimus. 
5. Platelets ≤150,000 cell/mm3. 
6. Hemoglobin < 10 gm/dL 
7. Absolute neutrophil count < 1500 cells/mm3 
8. Renal dysfunction, i.e., creatinine clearance < 30 mL/min 
9. AST and/or ALT > 1.5 ULN, or total bilirubin > ULN 
10. History of bleeding disorders or recent surgery in the six weeks preceding enrollment 
11. Concomitant use of agents known to cause bone marrow suppression leading to 
thrombocytopenia 
12. History of gastrointestinal ulcer, or history of gastrointestinal bleeding. 
13. History of hepatitis B and/or C infection, active liver disease and/or cirrhosis. 
14. Heart failure, current uncontrolled cardiovascular disease, including unstable angina, 
uncontrolled arrhythmias, major adverse cardiac event within 6 months (e.g. stroke, 
myocardial infarction, hospitalization due to heart failure, or revascularization procedure). 
15.  Life expectancy of < 5 days in the judgment of the treating clinician. 
16. Evidence of critical illness defined by at least one of the following: 
a. Respiratory failure requiring at least one of the following: 
i. Endotracheal intubation and mechanical ventilation, noninvasive positive 
pressure ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., 
clinical need for one of the preceding therapies, but preceding therapies may 
not be able to be administered in setting of resource limitation) 
ii. Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood 
pressure < 60 mm Hg or requiring vasopressors) 
b. Multi-organ dysfunction/failure. See [22].  
7.4 Inclusion of Women and Minorities 
Adult men and women of all races and ethnic groups are eligible for this trial. 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
8 
STUDY TREATMENTS 
8.1 Description of Study Medications 
8.1.1 Brequinar 
Brequinar will be supplied as 100 mg capsules. Dosing will be a single 5-day course of brequinar 
100 mg once daily for 5 doses. The initial brequinar dose (Day 1) should be administered as soon 
as possible based on study drug availability from the investigational pharmacy. At least the first 
dose of study medication is to be taken in the hospital. Subjects in the brequinar group discharged 
before Day 5 will be dispensed brequinar to take at home daily until all 5 doses have been taken. 
8.2 Treatment Administration 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 subjects. 
All subjects will receive standard of care (SOC) per institutional guidelines for SARS-CoV-2 
infection. Subjects will be randomly assigned in a 1:2 ratio to standard of care alone or standard 
of care plus brequinar. The brequinar dosing interval should be 24h ± 6h. If discharged prior to 
Day 5, the subject may take any remaining doses once a day at home. In this case, the subject is to 
record dosing using a medication diary provided by the study team. The diary information will be 
provided to the study team either verbally or electronically or during an in-person visit. 
8.2.1 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE).  
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 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 (Study 785-001 [16], 785-003 [17], and 785-005 [18]) with five 
consecutive days of intravenous (IV) brequinar dosing and 168 subjects, there were no toxic 
deaths. For subjects from these three studies who were treated with a dose of 100 mg or below  
(as will be dosed in CCB-CRISIS-01), 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 [19], 785-031 [20] , and 785-034 [21]), the study drug related 
AEs through 21 days (each observed in one subject only) included diarrhea, headache, nausea, 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
For subjects in the brequinar treatment group discharged from the hospital prior to Day 5, the 
subject is to take home the remaining doses of brequinar for daily self-administration. All subjects 
(brequinar and SOC) should have the scheduled assessments, e.g. lab samples and the 
nasopharyngeal swab, on the day of discharge and enter these results on the appropriate EDC page. 
Following discharge, subjects are to return to the research or out-patient lab collection facility for 
the remaining study visits, if feasible. Out-patient lab results are to be entered into the EDC and 
reviewed by a member of the study team. It is important that every effort be made to have subjects 
return at least on Days 7 and 15, if feasible. Subjects in the brequinar group are to record brequinar 
dosing on the medication diary provided by the study team. The study team will arrange for the 
subject to return any unused study medication to the research facility. 
For all subjects, if discharge occurs on Days 10, 11, or 12, ensure a hematology/chemistry sample 
has been obtained on the day of discharge and record these results on the appropriate EDC page. 
Following discharge, the subject is to return to the research or out-patient lab collection facility for 
the Day 15 visit, if feasible. Out-patient lab results are to be entered into the EDC and reviewed 
by a member of the study team. 
If discharge occurs on Days 13, 14 or 15, complete the Day 15 Final Visit activities prior to 
discharge. No further visits are required unless follow up is needed for a study drug-related AE or 
an SAE; the Day 29 mortality assessment is still to take place. 
If the subject is unable or not permitted to return for planned study visits, the visit activities will 
be conducted by contacting the subject (phone or other digital media) except for the lab draw. The 
lab draw will be completed at a research facility or an outpatient laboratory, if feasible, and the 
results entered into the EDC and reviewed by the study team.  
Study completion or the reason for study discontinuation will be recorded in the source document 
and the eCRF. A subject is considered completed the study if they have assessments through Day 
15, whether conducted in the hospital or contacted via phone or other digital media. 
8.6 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 8.9.  
8.7 Treatment Compliance 
Compliance will be assessed by reviewing the subject’s EHR, the study medication diary when 
applicable, and other study records as appropriate. 
8.8 Storage, Stability, Labeling and Packaging 
8.8.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.8.2 Labeling and Packaging  
Each brequinar bottle/dispensing container for subject use will be labeled with at least the 
following information: 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
For Clinical Trial Use Only 
Study Number: 
CCB-CRISIS-01 
Contents: Brequinar 100 mg capsules 
For oral use only. Take with approximately 8 ounces water. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
Clinical Batch Number: XXXXXXX 
 
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.8.3 Blinding and Randomization 
The trial will be conducted in an open-label manner with random assignment to standard of care 
or standard of care plus brequinar. The brequinar capsules will be provided to each participating 
institution in bulk to be dispensed by the institution’s pharmacist for each subject. Randomization 
assignments will be provided by the sponsor. 
8.8.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment will be known for 
each subject. 
Expectedness will be determined by establishing whether the 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.   
8.8.5 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, used and discarded.  It must 
be clear from the records whether the subject received study medication or was assigned to 
standard of care. 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.  
Subjects in the brequinar group who are discharged prior to Day 5 will be given a study medication 
diary for recording at home treatment administration.  The diary information will be collected by 
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the study team either verbally or electronically or in person during a visit to the research facility. 
Unused study drug at the patient’s home is to be returned to the research facility.  
At the end of the study, any unused study drug in the pharmacy will be returned to the Sponsor for 
destruction or may be destroyed locally; disposition of study drug will be documented. The study 
team will make arrangements for the subject to return any unused study medication to the research 
facility. 
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. 
8.9 Prohibited Medications 
Treatment is prohibited with another DHODH inhibitor (e.g., leflunomide and teriflunomide), 
tacrolimus, sirolimus. Treatment is prohibited with agents known to cause bone marrow 
suppression leading to thrombocytopenia.  
8.10 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 telephone or other digital media. Study information is to be 
collected from the EHR as much as possible such as NEWS2 Assessments, height, weight, 
hematology/chemistry, from Progress Notes for AEs, and from medication records for new or 
changed concomitant medications. Visits to an outpatient laboratory post hospital discharge may 
be required if subjects are not able or permitted to return to the research facility for follow up study 
visits.  
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). Remdesivir may be used in this clinical trial as a component of standard of care 
of patients hospitalized with severe disease in settings where remdesivir is available via the 
Emergency Use Authorization (EUA) or other FDA approval. 
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. 
 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 556 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 33 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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), 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.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures. Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be subject to review by the Sponsor; a copy will be 
given to the subject and a copy will be filed with the subject’s medical notes. 
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 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 557 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 558 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 559 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 561 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 562 of 582


PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
Page 39 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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 15. After Day 
15, collect/record only Serious Adverse Events (SAEs) or those judged 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.   
Any serious adverse events (SAEs) experienced after 30 days post the last dose of study drug 
should only be reported to the sponsor if the investigator suspects a causal relationship to the 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, or require therapy. 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the appropriate electronic data capture form.  
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 
Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 563 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 564 of 582


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Clinical Study Report 
Protocol Reference: CCB-CRISIS-01
CONFIDENTIAL
03 May 2021
Appendix 16.1.1
Page 565 of 582


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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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 Medical Monitor 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 is to 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 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to 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 knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must 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 the Sponsor Contact 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 pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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-
up with 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 selecting a relatively brief 5-day exposure and a low brequinar dose, all 
subjects in the clinical trial will initially be hospitalized as in-patients and will be under the care 
of highly qualified infectious disease, critical care, and associated medical personnel. As is 
standard of care for moderately to severely ill in-patients, daily samples will be obtained for 
hematology assessments including complete blood count with full differential (WBC, RBC, 
hemoglobin, hematocrit, platelet count, absolute neutrophils, absolute lymphocytes, absolute 
monocytes, absolute eosinophils, and absolute basophils). Any clinically significant out-of-range 
laboratory values will be assessed by hospital staff in a timely manner and treatment needs 
addressed as appropriate. 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 Clear Creek Medical Monitor 
will assess the available hematology data on a weekly 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, the Sponsor, and the Medical Monitor. In 
addition, the Data Safety Monitoring Board 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. 
Subjects who are discharged from the hospital before Day 7 will have follow up contacts with 
study staff (phone calls or other digital media) on Days 7, 15 and 29. Early discharge subjects in 
the brequinar treatment group will also have samples for safety labs (hematology and chemistry) 
obtained either at the research facility or at an outpatient laboratory on Study Days 7 ± 2 and 15 ± 
2. The safety laboratory results are to be initially assessed in real time by the Principal Investigator 
or designated person and the Medical Monitor. 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-hospital assessments and phone call visits will specifically ask about possible hematologic 
toxicity including any evidence of the list below. Early discharge 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. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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 analyses will be based on the ITT population, which is defined as all randomized subjects.   
11.2 Safety Analyses 
Safety and tolerability will be assessed in terms of AEs, SAEs, NEWS2 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 
NEWS2 Assessments will be summarized using appropriate descriptive statistics. 
11.3 Efficacy Analyses 
Efficacy will be assessed in terms of mortality, hospitalization status and duration, NEWS2 score, 
viral load (plasma and nasopharyngeal), and inflammatory markers. 
11.4 DHO and Brequinar Concentration Levels 
DHO and brequinar concentrations levels will be summarized using descriptive statistics. 
11.5 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 24 
subjects are planned to be entered in this trial.  Additional subjects may be enrolled following data 
review. 
11.6 Randomization 
A randomization scheme will be provided by the Sponsor to ensure subjects are randomly assigned 
to SOC or SOC + brequinar in a 1:2 ratio.  
11.7 Pooling of Study Centers 
Not applicable to this small, early phase study. 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
11.8 Interim Analysis 
No interim analysis is planned for this trial. 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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 NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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) 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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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
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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PROTOCOL NUMBER:  CCB-CRISIS-01  
Page 53 of 58 
PROTOCOL VERSION FINAL DATE: 10SEPT2020 
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. Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the
assessment of acute-illness severity in the NHS. Updated report of a working party.
London: RCP, 2017.
15. Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K, and the 
Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. 
JAMA. April 22, 2020. https://jama.doi:10:1001/jama.2020.6775.
16. Study DUP 785-001 Clinical Study Report (on file with Clear Creek)
17. Study DUP 785-003 Clinical Study Report (on file with Clear Creek)
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18. Study DUP 785-005 Clinical Study Report (on file with Clear Creek)
19. Study DUP 785-022 Clinical Study Report (on file with Clear Creek)
20. Study DUP 785-031 Clinical Study Report (on file with Clear Creek)
21. Study DUP 785-034 Clinical Study Report (on file with Clear Creek)
22. 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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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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15 APPENDICES 
15.1 Appendix A:  CCB-CRISIS-01 Schedule of Events 
CCB-CRISIS-01  
Schedule of Events 
 
Procedures 
Screen 
D1 
D2 - D7 
(± 8 hours) 
Final Visit  
D15 
(± 2 days) 
F/U  
Phone 
Call 
2 weeks/ 
Survival 
(± 3 days) 
Informed Consent 
X 
 
 
 
 
AE/Concomitant Medications (daily until discharge) 
X 
X 
D1-7 
X 
 
Medical history / History of current illness 
X 
 
 
 
 
Demographics, collect Height and weight 
X 
 
 
 
 
Check for Physical Exam abnormalities 
X 
 
 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
 
 
Hematology/Chemistry 
X 
X (pre-dose) 
 D1-7 
X 
 
Inflammatory Markers* 
 
X (pre-dose) 
D3, D5, D7 
X 
 
DHO/brequinar PK Sample Collection & Processing 
 
X (pre-dose) 
D3, D5, D7 
X (DHO only) 
 
Swab collection for nasopharyngeal viral load 
 
X (pre-dose) 
D3, D5, D7 
X 
 
Clinical SARS-CoV-2 testing RT-PCR 
X 
 
 
 
 
Hospital Status 
 
 
D3, D5, D7 
X 
 
NEWS2 Assessments 
 
X 
D3, D5, D7 
X 
 
Dispense Study Medication if assigned to brequinar** 
 
X 
D2 – 5 
 
 
Drug Accountability 
 
 
D7 
 
 
Survival Assessment Day 29 
 
 
 
 
X 
Collect information from available electronic health record (EHR), Progress Notes, and medication records; 
a special visit by research staff is not to be performed. Results for Hematology, Chemistry and available 
inflammatory markers analyzed locally are to be obtained from the EHR; do not draw another set of labs. 
Missed samples due to hospital staff too busy or for technical reasons unable to obtain samples will not be 
counted as protocol deviations. Record urinalysis results if urinalysis is clinically indicated and results are 
available in the EHR. Note that if the subject is discharged before Day 15, follow instructions provided in 
Section 8.5. 
Note that any visits other than Screening/Day 1 may be conducted via telephone or digital media. Missed 
samples/assessments when phone visits occur will not be counted as protocol deviations. 
*Inflammatory markers are to be collected from the EHR when available; otherwise process and ship 
samples to the central laboratory per the Laboratory Manual. DHO and brequinar samples will also be sent 
to the central laboratory. 
**If a subject in the brequinar group is discharged prior to Day 5 (has not completed taking brequinar all 5 
days) the subject may be dispensed study medication to take at home on a daily basis. In this instance the 
subject is also to be provided with the study medication diary for drug accountability purposes. 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
 
 
 
 
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
15.2 Appendix B: Investigator’s Statement and Agreement 
STUDY NUMBER:   CCB-CRISIS-01 
STUDY TITLE:  The CRISIS Study: A randomized open-label study assessing the safety and 
anti-coronavirus response of suppression of host nucleotide synthesis in hospitalized adults with 
coronavirus-19 (COVID-19). 
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: __________________ 
 
Site Address: 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
 
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PROTOCOL NUMBER:  CCB-CRISIS-01  
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PROTOCOL VERSION FINAL DATE: 10SEPT2020  
15.3 Appendix C: National Early Warning Score (NEWS2)  
Use SpO2 Scale 2 if target range is 88 – 92%, e.g., in hypercapnic respiratory failure. 
National Early Warning System Score (NEWS) 2 Royal College of Physicians 2017 [14]. 
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SAP_001.pdf: 
CCB-CRISIS-01 
THE CRISIS STUDY: A RANDOMIZED OPEN-LABEL STUDY 
ASSESSING THE SAFETY AND ANTI-CORONAVIRUS RESPONSE OF 
SUPPRESSION OF HOST NUCLEOTIDE SYNTHESIS IN 
HOSPITALIZED ADULTS WITH CORONAVIRUS-19 (COVID-19) 
 
NCT04425252 
 
STATISTICAL ANALYSIS PLAN DATE: 17-DEC-2020 
 


Doc. No.: TMP-BS-01 
Rev No.: 4.0 
Eff. Date: 08-Mar-2018 
 
 
 
Statistical Analysis Plan 
 
Sponsor: 
Clear Creek Bio, Inc 
Protocol No: 
CCB-CRISIS-01 
Protocol Title: 
A randomized open-label study assessing the 
safety and anti-coronavirus response of 
suppression of host nucleotide synthesis in 
hospitalized adults with coronavirus-19 
(COVID-19) 
Document Date: 
17-Dec-2020 
Document Revision 
1.0 
 
 


 
 
CCB-CRISIS-01 Statistical Analysis Plan  
Revision No. 
1.0 
Document Date:   17-Dec-2020 
Page 2 of 17  
 
Confidential Document 
Doc No.: TMP-BS-01 
Rev No.: 4.0 
Eff. Date: 08-Mar-2018 
 
APPROVAL SIGNATURES 
 
Prosoft Personnel 
Title 
Printed Name 
Signature 
Date 
Manager,  
Statistics 
Daisy Chen 
 
 
Associate Vice 
President, Statistics 
Diane Tipping 
 
 
 
CCB Personnel 
Title 
Printed Name 
Signature 
Date 
Vice President, 
Clinical Operations 
Barbara Powers, PhD 
 
 
 
 
DOCUMENT HISTORY 
 
Rev No 
Date 
Description 
1.0 
17-Dec-2020 
Original document 
 
 
17-Dec-2020
17-Dec-2020
17-Dec-2020


 
 
CCB-CRISIS-01 Statistical Analysis Plan  
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Page 3 of 17  
 
Confidential Document 
Doc No.: TMP-BS-01 
Rev No.: 4.0 
Eff. Date: 08-Mar-2018 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................................. 6 
1.1 
Background ...................................................................................................................... 6 
1.2 
Trial Design ...................................................................................................................... 6 
1.2.1 
Number of Subjects and Randomization .................................................................. 7 
1.3 
Trial Objectives ................................................................................................................ 7 
1.3.1 
Primary Objectives.................................................................................................... 7 
1.3.2 
Secondary Objectives................................................................................................ 7 
1.3.3 
Exploratory Objectives ............................................................................................. 7 
2. 
STATISTICAL METHODOLOGY .................................................................................... 7 
2.1 
General Principles ............................................................................................................ 7 
2.2 
Sample Size Determination .............................................................................................. 8 
2.3 
Trial Populations .............................................................................................................. 8 
2.4 
Subject Accounting and Baseline Characteristics ............................................................ 8 
2.5 
Efficacy Analyses ............................................................................................................. 8 
2.5.1 
Primary Efficacy Analyses ....................................................................................... 8 
2.5.2 
Secondary Efficacy Analyses ................................................................................... 8 
2.5.3 
Exploratory Efficacy Analyses ................................................................................. 9 
2.6 
Safety Analyses .............................................................................................................. 10 
2.7 
Interim Analyses ............................................................................................................ 11 
3. 
DATA HANDLING ............................................................................................................. 11 
3.1 
Baseline and Study Visits ............................................................................................... 11 


 
 
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Rev No.: 4.0 
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3.2 
Derived Data .................................................................................................................. 11 
3.3 
Missing Data and Data Conventions .............................................................................. 13 
4. 
CHANGES FROM THE PROTOCOL ............................................................................. 14 
APPENDIX 1 CTCAE V4.03 GRADING FOR LABORATORY VALUES ........................ 15 
 
 
 
 


 
 
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Confidential Document 
Doc No.: TMP-BS-01 
Rev No.: 4.0 
Eff. Date: 08-Mar-2018 
List of Abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019 
CTCAE  
Common Terminology Criteria for Adverse Events 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate Dehydrogenase 
DSMB 
Data Safety Monitoring Board 
EHR 
Electronic Health Record 
ICU 
Intensive Care Unit 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
mITT 
Modified Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEWS2 
National Early Warning System 2 
Q1 
First Quartile 
Q3 
Third Quartile 
RNA 
Ribonucleic Acid 
SARS-CoV-2  
Severe Acute Respiratory Syndrome Coronavirus 2 
SE 
Standard Error 
SOC 
Standard of Care 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHODrug 
World Health Organization Drug Dictionary 
 
 
 


 
 
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Confidential Document 
Doc No.: TMP-BS-01 
Rev No.: 4.0 
Eff. Date: 08-Mar-2018 
1. 
INTRODUCTION 
1.1 Background 
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 
Organization (WHO). 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 (ICU). Coronaviruses, like other Ribonucleic acid (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. 
Dihydroorotate dehydrogenase (DHODH) is a clear therapeutic target for the inhibition of host 
pyrimidine synthesis. 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.  
The CRISIS trial will study standard of care (SOC) and SOC with 5 days of DHODH inhibition. 
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. 
1.2 Trial Design 
This will be a phase 1a randomized, open label, multi-center study with approximately 24 
subjects. All subjects will receive SOC per institutional guidelines for treatment of patients with 
COVID-19 infection. In addition to SOC, the brequinar group will receive brequinar 100 mg 
once daily for 5 days. 
Subjects will have a Screening Visit followed as soon as possible with Study Day 1 (Day 1 may 
take place on the same day if entry criteria data are available). Subjects will be followed through 
Day 15, with mortality assessed via a phone call/other digital media acceptable to institution on 
Day 29. 


 
 
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Rev No.: 4.0 
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1.2.1 Number of Subjects and Randomization 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the 
study until approximately 24 subjects have completed the study. Subjects will be randomized to 
either SOC or SOC plus brequinar or in a 1:2: ratio (approximately 8 subjects assigned to SOC 
alone and approximately 16 subjects on SOC plus brequinar). 
1.3 Trial Objectives 
1.3.1 Primary Objectives 
The primary objective of this study is to determine the safety and tolerability of SOC and SOC 
plus brequinar in hospitalized COVID-19 subjects. 
1.3.2 Secondary Objectives 
The secondary objectives of this study are  
 To determine the changes in clinical status measures through Day 15 
o hospitalization status 
o duration of hospitalization 
o NEWS2 Score 
 To determine survival status through Day 29 
1.3.3 Exploratory Objectives 
 To determine the change in SARS-CoV-2 nasopharyngeal viral load through Day 15 
 To determine the change in inflammatory markers through Day 15 
 To determine the change in DHO levels through Day 15 
 To determine the change in brequinar concentration levels through Day 7 
2. 
STATISTICAL METHODOLOGY 
2.1 General Principles 
In general, continuous parameters will be summarized by number of non-missing observations 
(N), mean, standard error (SE), median, quartiles, minimum, and maximum. Categorical 
parameters will be summarized by count and percentage of the non-missing observations, and 


 
 
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95% confidence interval (CI), when appropriate. All statistical analyses will be performed using 
SAS® Version 9.4. Adverse events (AEs), procedures and medical history will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0. Prior and concomitant 
medications will be coded using World Health Organization Drug Dictionary (WHODrug) 
Enhanced March 2020. Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.03 will be utilized for adverse event and laboratory reporting. 
All study data collected will be presented in listings. 
2.2 Sample Size Determination 
Formal sample size calculations are not applicable for this phase 1a, open label study. Up to 24 
subjects are planned to be entered in this trial. Additional subjects may be enrolled following 
data review. 
2.3 Trial Populations 
The modified Intent to Treat (mITT) population will include all randomized subjects who had at 
least one post-randomization assessment, and who received at least one dose of study medication 
if randomized to SOC + Brequinar group. All analyses will be based on the mITT population. 
2.4 Subject Accounting and Baseline Characteristics 
Demographics and baseline characteristics (including NEWS2 score and ICU level of care at 
randomization) will be summarized by treatment. Prior and concomitant medications/procedures 
will be summarized by treatment. A medication/procedure may be classified as both prior and 
concomitant. Medical history will be summarized by treatment. 
2.5 Efficacy Analyses 
2.5.1 Primary Efficacy Analyses 
None 
2.5.2 Secondary Efficacy Analyses 
Hospitalization Status and Duration 
Hospitalization status (died, hospitalized in ICU, hospitalized not in ICU, discharged for initial 
hospitalization and re-hospitalization) will be summarized on Study Day 3, 5, 7 and 15. Kaplan 


 
 
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Meier estimates and plots will be provided to assess the duration of hospitalization (Study Day at 
time of initial discharge). Subjects who were not discharged by the Day 15 visit will be censored 
at the Day 15 visit. Subjects who did not complete the trial while still hospitalized will be 
censored at the date of last contact. 
NEWS2 Score  
Changes from baseline to Day 3, 5, 7, and 15 in NEWS2 scores will be summarized by 
treatment. In addition, the NEWS2 scores will be summarized by category (0-4, 5-6, 7 or above). 
The NEWS2 parameters will be summarized at each visit, including changes from baseline for 
continuous parameters. (See Section 3.2 for derivation of NEWS2 score). 
Mortality 
Mortality will be summarized through Day 29 by treatment group. Kaplan Meier estimates and 
plots will be provided to assess the time to death (date of death minus date of randomization).  
Subjects who are alive at the Day 29 contact will be censored at the Day 29 contact. Subjects 
whose Day 29 survival is unknown will be censored at the date of last contact. 
2.5.3 Exploratory Efficacy Analyses 
Changes from baseline will be summarized by treatment: 
 
Viral load (nasopharyngeal) (Days 3, 5, 7, and 15) 
 
Inflammatory markers (Days 3, 5, 7, and 15) 
 
DHO levels (Days 3, 5, 7, and 15) 
 
Brequinar concentration levels (Days 3, 5 and 7) 
For inflammatory markers (including pro-inflammatory cytokines), results from both local and 
central laboratories will be combined, where the local test result will be normalized where 
necessary. (See Section 3.2 for normalization method).  
Viral culture results will be provided in data listings only. 
 
 


 
 
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2.6 Safety Analyses 
Adverse Events 
An overall summary of treatment-emergent adverse events (TEAEs) will be presented by 
treatment and total, including the total number of events, frequency counts and percentages for: 
o Any TEAE 
o Treatment-related TEAEs 
o CTCAE Grade 3 or above TEAEs 
o TEAEs leading to drug withdrawn 
o TEAEs leading to study discontinuation 
o Serious TEAEs 
o Fatal TEAEs  
o TEAEs of interest 
The incidence of TEAEs by treatment and total will be tabulated by MedDRA system organ 
class and preferred term for: 
o All TEAEs 
o Treatment-related TEAEs 
o TEAEs by severity 
o TEAEs leading to study discontinuation 
o Serious TEAEs 
o TEAEs of interest 
AEs will be considered treatment-emergent if the onset date is on or after the day of 
randomization. “Drug related” will include ‘Definite’, ‘Probable’ and ‘Possible’ relationship to 
drug as determined by the Investigator. 
Safety Laboratory Assessments 
Safety laboratory tests (Chemistry and Hematology) will be performed throughout the study. 
Laboratory parameters of interest (AST, ALT, ALP, Total Bilirubin, Creatinine, Hemoglobin, 
WBC, Absolute Neutrophils, Absolute Lymphocytes and Platelets) will be summarized for 
changes from baseline. 


 
 
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NCI CTCAE grades will be derived for the lab parameters included in Appendix 1 and presented 
in data listings. Separate listings of Grade 3 or 4 values will also be provided. 
2.7 Interim Analyses 
No interim analysis is planned for this trial. A Data Safety Monitoring Board (DSMB) will meet 
periodically to review the safety and scientific conduct of the study. At a minimum, the DSMB is 
to review adverse events and safety laboratory assessments after the first six subjects complete 
Day 5 of treatment, and again after the first 12 subjects complete Day 5 of treatment. 
3. 
DATA HANDLING 
3.1 Baseline and Study Visits 
Study Day 1 will be the day of randomization.  
The summary of hospitalization status will be based on the Study Day (derived relative to the 
day of randomization). 
For the summary of inflammatory markers, Baseline will be the last assessment prior to dosing 
(SOC plus brequinar group) or last assessment on or prior to Study Day 1 (SOC group). .Post-
baseline timepoints will be based on the Study Day (derived relative to the day of 
randomization), where Day 15 includes a 4-day window (Study Day 11-19).  If there are multiple 
results on the same day, the earliest result will be used. 
For all other summaries, post-baseline timepoints will use the visit as recorded on the case report 
form, and Baseline will be the last non-missing value prior to randomization, including 
unscheduled assessments. Otherwise, unscheduled data will not be used in the analyses, but will 
be presented in the listings.  
3.2 Derived Data 
Prior and Concomitant Medication/Procedure 
A prior medication/procedure is any medication/procedure that started prior to date of 
randomization. A concomitant medication/procedure is any medication/procedure that either has 
a start date on or after date of randomization, or is ongoing on the date of randomization. 
 
 


 
 
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Hospitalization Status 
If a subject experiences multiple hospitalization status types on the given day, the worst status 
will be summarized on the day of interest.  
NEWS2 Score 
 
Use Chart 1 NEW2 scoring system to derive NEW2 score of each physiological parameter 
collected from case report forms. If hypercapnic respiratory failure, use SpO2 Scale 2; otherwise 
use SpO2 Scale 1. The total possible score ranges from 0 to 20. If any one of the NEWS2 
parameters is not available on the study visit, the NEWS2 score will not be derived.  
 
 


 
 
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Normalization 
In order to summarize inflammatory marker results across the laboratories which have different 
normal ranges, normalization will be performed. The scale model will be applied for data 
transformation using the scale normalization formula: 
𝑆= 𝑋× 𝑈𝐿𝑁𝑠
𝑈𝐿𝑁𝑥 
where X represents an assay value from the local laboratory, ULNx is the ULN from the 
laboratory, and ULNs is the upper limit of normal (ULN) from Site 02. Markers that are 
performed only at the central laboratory will not be normalized. 
3.3 Missing Data and Data Conventions 
No imputation is planned for missing data. 
The follow conventions will be used for data handling: 
 If SARS-Cov-2 is “not detected” in specimen, the test result will be set to 0 for analysis.  
 For DHO and brequinar concentration levels, samples below the lower limit of 
quantitation (LLOQ) will be set to half of the LLOQ value for the summary tables 
(LLOQ of DHO is 5 ng/mL, LLOQ of concentration level is 5 mcg/mL). 
 If a laboratory test result is reported as “< xxx” or “> xxx”, the value of “xxx” will be 
used for analysis.  
 If a medication or procedure has an incomplete start date, it is assumed to have started 
prior to randomization, unless the month and year are after randomization. 
 If a medication or procedure is not checked as ongoing and has an incomplete stop date, 
it is assumed to have stopped after randomization, unless the month and year are prior to 
randomization. 
 
 


 
 
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4. 
CHANGES FROM THE PROTOCOL 
Plasma viral load was listed in the protocol (Section 11.3) but will not be collected.  
Nasopharyngeal viral culture was not listed in the protocol but was added to the central 
laboratory assessments. 
The mITT population was not included in the protocol, but will be used for all analyses instead 
of the ITT population. 
 
 


 
 
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APPENDIX 1 CTCAE V4.03 GRADING FOR LABORATORY VALUES 
Lab Test 
Lab Unit Grade 1  
Grade 2  
Grade 3  
Grade 4  
Albumin 
G/DL 
3 to <LLN 
2 to <3 
<2 
Clinical Review 
Needed: Life-
threatening 
consequences; urgent 
intervention indicated 
Alkaline 
Phosphatase 
U/L 
>ULN to 
2.5xULN 
>2.5xULN 
to 5xULN 
>5xULN to 
20xULN 
>20xULN 
Alanine 
Amino 
Transferase 
U/L 
>ULN to 
3xULN 
>3xULN to 
5xULN 
>5xULN to 
20xULN 
>20xULN 
Aspartate 
Amino 
Transferase 
U/L 
>ULN to 
2.5xULN 
>2.5xULN 
to 5xULN 
>5xULN to 
20xULN 
>20xULN 
Bilirubin 
Total 
MG/DL 
>ULN to 
1.5xULN 
>1.5xULN 
to 3xULN 
>3xULN to 
10xULN 
>10xULN 
Calcium 
MG/DL 
>ULN to 11.5 
>11.5 to 
12.5 
>12.5 to 
13.5 
>13.5 
Calcium 
MG/DL 
8 to <LLN 
7 to <8 
6 to <7 
<6  
Creatinine 
MG/DL 
>ULN to 
1.5xULN 
>1.5xULN 
to 3xULN 
>3xULN to 
6xULN 
>6xULN 
Glucose 
MG/DL 
>ULN to 160 
 >160 to 250  >250 to 500 
>500 
Glucose 
MG/DL 
55 to <LLN  
40 to <55 
30 to <40 
<30 
Potassium 
MMOL/
L 
>ULN to 5.5 
>5.5 to 6 
>6 to 7 
>7 


 
 
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Lab Test 
Lab Unit Grade 1  
Grade 2  
Grade 3  
Grade 4  
Potassium 
MMOL/
L 
Clinical Review 
Needed: Check 
Grade 2 and 
reassign if not 
symptomatic 
and no 
intervention 
indicated 
3 to <LLN 
2.5 to <3 
<2.5  
Sodium 
MMOL/
L 
>ULN to 150  
>150 to 155  >155 to 160  >160  
Sodium 
MMOL/
L 
130 to <LLN  
 - 
120 to <130 
<120  
Lymphocytes, 
Absolute 
10^3/UL 
 - 
>4 to 20 
>20 
 - 
Lymphocytes, 
Absolute 
10^3/UL 
0.8 to <LLN  
0.5 to <0.8  
0.2 to <0.5  
<0.2  
Neutrophils, 
Absolute 
10^3/UL 
 - 
 - 
 <1  
Clinical Review 
Needed: Life-
threatening 
consequences; urgent 
intervention indicated 
Neutrophils, 
Absolute 
10^3/UL 
1.5 to <LLN  
1 to <1.5  
 0.5 to <1  
 <0.5  
Hemoglobin 
G/DL 
 >0 to 2   
 >2 to 4   
>4  
 
Hemoglobin 
G/DL 
 >ULN to 
ULN+2   
>ULN+2 to 
ULN+4  
>ULN+4  
 
Hemoglobin 
G/DL 
10 to <LLN  
8 to <10  
<8 
Clinical Review 
Needed: Life-
threatening 
consequences; urgent 
intervention indicated 
Platelet Count 10^3/UL 
75 to <LLN  
50 to <75 
25 to <50  
<25 


 
 
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Lab Test 
Lab Unit Grade 1  
Grade 2  
Grade 3  
Grade 4  
White Blood 
Cell 
10^3/UL 
 - 
 - 
>100 
Clinical Review 
Needed: Clinical 
manifestations of 
leucostasis; urgent 
intervention indicated 
White Blood 
Cell 
10^3/UL 
3 to <LLN  
2 to <3  
1 to <2  
 <1 
Note: For these laboratory tests, Grade 0 is assigned if result does not meet above ranges. 


CLEAR CREEK BIO. INC. 
PROPOSED TABLES and LISTINGS 
PROTOCOL CCB-CRISIS-01 
 
Version 1.0 
17-Dec-2020 
 
 


CLEAR CREEK BIO. INC. 
PROPOSED TABLES and LISTINGS 
PROTOCOL CCB-CRISIS-01 
 
Version 1.0 
17-Dec-2020 
 
 
Signature Page 
 
The proposed tables and listings have been reviewed and approved by the following 
personnel: 
 
 
Prosoft Personnel 
Title 
Printed Name 
Signature 
Date 
Manager,  
Statistics 
Daisy Chen 
 
 
Associate Vice 
President, Statistics 
Diane Tipping 
 
 
 
CCB Personnel 
Title 
Printed Name 
Signature 
Date 
Vice President, 
Clinical Operations 
Barbara Powers, PhD 
 
 
 
 
 
17-Dec-2020
17-Dec-2020
17-Dec-2020


 
 
CLEAR CREEK BIO. INC. 
PROPOSED TABLES and LISTINGS 
PROTOCOL CCB-CRISIS-01 
 
TABLES 
 
BOLD = SAMPLE IS PROVIDED. 
Table 14.1.1 
Summary of Population by Site and Treatment  
Table 14.1.2 
Summary of Subject Disposition by Site and Treatment (Modified Intent-
to-Treat Population) 
Table 14.1.3 
Summary of Demographics and Baseline Characteristics by Treatment 
(Modified Intent-to-Treat Population) 
Table 14.1.4 
Summary of Medical History by Treatment (Modified Intent-to-Treat 
Population) 
Table 14.1.5.1 
Summary of Prior Medications by Treatment (Modified Intent-to-Treat 
Population) 
Table 14.1.5.2 
Summary of Concomitant Medications by Treatment (Modified Intent-to-
Treat Population) 
Table 14.1.6.1 
Summary of Prior Procedures by Treatment (Modified Intent-to-Treat 
Population) 
Table 14.1.6.2 
Summary of Concomitant Procedures by Treatment (Modified Intent-to-Treat 
Population) 
Table 14.2.1 
Summary of Hospitalization Status and Mortality Rate by Treatment and 
Visit (Modified Intent-to-Treat Population) 
Table 14.2.2.1 
Summary of Kaplan Meier Estimates for Duration of Hospitalization by 
Treatment (Modified Intent-to-Treat Population) 
Figure 14.2.2.2 
Duration of Hospitalization by Treatment (Modified Intent-to-Treat 
Population) 
Table 14.2.3.1 
Summary of Kaplan Meier Estimates for Time to Death by Treatment 
(Modified Intent-to-Treat Population)  
Figure 14.2.3.2 
Time to Death by Treatment (Modified Intent-to-Treat Population) 
Table 14.2.4.1 
Summary of NEWS2 Scores by Treatment and Visit (Modified Intent-to-
Treat Population)  
Table 14.2.4.2 
Summary of NEWS2 Parameters by Treatment and Visit (Modified 
Intent-to-Treat Population)  
Table 14.2.5 
Summary of Change from Baseline in SARS-CoV-2 Viral Load 
(copies/mL) by Treatment and Visit (Modified Intent-to-Treat 
Population) 
Table 14.2.6 
Summary of Change from Baseline in Inflammatory Markers by 
Treatment and Visit (Modified Intent-to-Treat Population)  
Table 14.2.7 
Summary of Change from Baseline in DHO Level (ng/mL) by Treatment 
and Visit (Modified Intent-to-Treat Population)  


Table 14.2.8 
Summary of Change from Baseline in Brequinar Concentration Level 
(mcg/mL) by Treatment and Visit (Modified Intent-to-Treat Population)  
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events by Treatment 
(Modified Intent-to-Treat Population) 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by Treatment 
(Modified Intent-to-Treat Population) 
Table 14.3.1.3  
Summary of Related Treatment-Emergent Adverse Events by Treatment 
(Modified Intent-to-Treat Population) 
Table 14.3.1.4 
Summary of Serious Treatment-Emergent Adverse Events by Treatment 
(Modified Intent-to-Treat Population) 
Table 14.3.1.5  
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by Treatment (Modified Intent-to-Treat Population) 
Table 14.3.1.6  
Summary of Treatment-Emergent Adverse Events of Interest by Treatment 
(Modified Intent-to-Treat Population) 
Table 14.3.1.7 
Summary of Treatment-Emergent Adverse Events by Severity and 
Treatment (Modified Intent-to-Treat Population) 
Table 14.3.2 
Summary of Change from Baseline in Laboratory Parameters of Special 
Interest by Treatment and Visit (Modified Intent-to-Treat Population) 
 
 


LISTINGS 
 
Listing 16.2.1 
Listing of End of Study Status by Treatment 
Listing 16.2.2 
Listing of Inclusion/Exclusion Criteria and Randomization 
Listing 16.2.3 
Listing of Informed Consent and Study Populations by Treatment 
Listing 16.2.4.1 
Listing of Subject Demographics by Treatment 
Listing 16.2.4.2 
Listing of Medical History by Treatment 
Listing 16.2.4.3 
Listing of Prior and Concomitant Medications by Treatment 
Listing 16.2.4.4 
Listing of Prior and Concomitant Procedures by Treatment 
Listing 16.2.5.1 
Listing of Dosing Information (SOC + Brequinar Only)  
Listing 16.2.5.2 
Listing of PK/DHO Results by Treatment 
Listing 16.2.6.1 
Listing of NEWS2 Assessments by Treatment 
Listing 16.2.6.2 
Listing of Inflammatory Markers by Treatment 
Listing 16.2.6.3 
Listing of SARS-CoV-2 Viral Load and Viral Culture by Treatment 
Listing 16.2.6.4 
Listing of Hospitalization Log by Treatment 
Listing 16.2.6.5 
Listing of Survival Status by Treatment 
Listing 16.2.7.1 
Listing of Adverse Events by Treatment 
Listing 16.2.7.2 
Listing of Related Adverse Events by Treatment 
Listing 16.2.7.3 
Listing of Serious Adverse Events by Treatment 
Listing 16.2.7.4 
Listing of Grade 3 or 4 Adverse Events by Treatment 
Listing 16.2.8.1.1 
Listing of Chemistry Laboratory Tests by Treatment 
Listing 16.2.8.1.2 
Listing of Grade 3 or 4 Chemistry Laboratory Tests by Parameter and 
Treatment 
Listing 16.2.8.2.1 
Listing of Hematology Laboratory Tests by Treatment 
Listing 16.2.8.2.2 
Listing of Grade 3 or 4 Hematology Laboratory Tests by Parameter and 
Treatment 
Listing 16.2.8.3 
Listing of Urinalysis Laboratory Tests by Treatment 
 
 


Conventions: 
 
For categorical data: 
 
Percents are displayed with one decimal 
 
When displaying counts and percents, the percent is contained within parentheses and does not 
include the “%” symbol 
 
If the count is zero, no percent is displayed 
 
If missing data occurs, a “Missing” row will be added to the summary table. The count of missing 
will be presented (no percent). The percentages for remaining rows will be based on the number 
of non-missing responses (i.e., the denominator does not include the missing counts) 
 
For continuous data, rounding will be based on the following conventions unless otherwise specified 
 
Min and Max displayed to the same number of decimals as the original data 
 
Mean, Median, and other percentiles displayed to 1 more decimal than the original data 
 
SE and CIs displayed to 2 more decimals than the original data 
 


 
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Table 14.1.1 
Summary of Populations by Site and Treatment 
 
 
 
SOC + Brequinar 
n (%) 
SOC 
n (%) 
Overall 
 
Randomized 
 
Modified Intent-to-Treata 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
Site xx 
 
Randomized 
xx  
xx  
 
Modified Intent-to-Treata 
xx (xx.x) 
xx (xx.x) 
a:  Modified Intent-to-Treat (mITT) population includes all randomized subjects who had at least one post-randomization 
assessment, and who received at least one dose of study medication if randomized to SOC + Brequinar group.  
Source:  Listing 16.X.X.X 


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Table 14.1.2 
Summary of Subject Disposition by Site and Treatment 
Modified Intent-to-Treat Population 
Programming note:  Sort in descending frequency based on the number of subjects in the SOC + Brequinar group, 
except for “Other” that shall stay at the last row.  Sort alphabetically to break ties. 
 
 
 
SOC + Brequinar 
(N=xx)  
n (%) 
SOC 
(N=xx) 
n (%) 
Overall 
 
Completed the study (through Day 15) 
xx (xx.x) 
xx (xx.x) 
 
Discontinued 
xx (xx.x) 
xx (xx.x) 
 
 
Physician Decision  
xx (xx.x) 
xx (xx.x) 
 
 
Adverse Event 
xx (xx.x) 
xx (xx.x) 
 
 
Withdrawal by Subject 
xx (xx.x) 
xx (xx.x) 
 
 
Study Terminated by Sponsor 
xx (xx.x) 
xx (xx.x) 
 
 
Protocol Violation 
xx (xx.x) 
xx (xx.x) 
 
 
Lost to Follow-Up 
xx (xx.x) 
xx (xx.x) 
 
 
Other 
xx (xx.x) 
xx (xx.x) 
Site xx 
 
Completed the study (through Day 15) 
xx (xx.x) 
xx (xx.x) 
 
Discontinued 
xx (xx.x) 
xx (xx.x) 
 
 
Physician Decision  
xx (xx.x) 
xx (xx.x) 
 
 
Adverse Event 
xx (xx.x) 
xx (xx.x) 
 
 
Withdrawal by Subject 
xx (xx.x) 
xx (xx.x) 
 
 
Study Terminated by Sponsor 
xx (xx.x) 
xx (xx.x) 
 
 
Protocol Violation 
xx (xx.x) 
xx (xx.x) 
 
 
Lost to Follow-Up 
xx (xx.x) 
xx (xx.x) 
 
 
Other 
xx (xx.x) 
xx (xx.x) 
Source:  Listing 16.X.X.X 


 
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Table 14.1.3 
Summary of Demographics and Baseline Characteristics by Treatment 
Modified Intent-to-Treat Population 
Parameter 
SOC + Brequinar 
(N=xx)  
SOC 
(N=xx) 
Age (years) 
 
n 
xx 
xx 
 
Mean (SE) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max 
xx, xx 
xx, xx 
Sex, [n (%)] 
 
Male 
xx (xx.x) 
xx (xx.x) 
 
Female 
xx (xx.x) 
xx (xx.x) 
Ethnicity, [n (%)] 
 
Hispanic or Latino 
xx (xx.x) 
xx (xx.x) 
 
Not Hispanic or Latino 
xx (xx.x) 
xx (xx.x) 
Race, [n (%)] 
 
White 
xx (xx.x) 
xx (xx.x) 
 
Black or African American 
xx (xx.x) 
xx (xx.x) 
 
Asian 
xx (xx.x) 
xx (xx.x) 
 
American Indian or Alaska Native 
xx (xx.x) 
xx (xx.x) 
 
Native Hawaiian or Other Pacific Islander 
xx (xx.x) 
xx (xx.x) 
 
Other 
xx (xx.x) 
xx (xx.x) 
Height (cm) 
 
n 
xx 
xx 
 
Mean (SE) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max 
xx, xx 
xx, xx 
Weight (kg) 
 
n 
xx 
xx 
 
Mean (SE) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max 
xx, xx 
xx, xx 
BSA (m2) 
 
n 
xx 
xx 
 
Mean (SE) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max 
xx, xx 
xx, xx 
Source:  Listing 16.X.X.X 


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Table 14.1.3 
Summary of Demographics and Baseline Characteristics by Treatment 
Intent-to-Treat Population 
Parameter 
SOC + Brequinar 
(N=xx)  
SOC 
(N=xx) 
NEWS2 Score 
 
n 
xx 
xx 
 
Mean (SE) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max 
xx, xx 
xx, xx 
ICU Level of Care at Randomization, [n (%)] 
 
Yes 
xx (xx.x) 
xx (xx.x) 
 
No 
xx (xx.x) 
xx (xx.x) 
Source:  Listing 16.X.X.X 
 
 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.1.4 
Summary of Medical History by Treatment 
Modified Intent-to-Treat Population 
System Organ Class 
 
Preferred Term 
SOC+ Brequinar 
(N=xx) 
n (%) 
SOC 
(N=xx) 
n (%) 
Any Medical History Event 
 
Overall 
xx (xx.x) 
xx (xx.x) 
SOC 1 
 
Overall 
xx (xx.x) 
xx (xx.x) 
 
Preferred Term 1 
xx (xx.x) 
xx (xx.x) 
 
Preferred Term 2 
xx (xx.x) 
xx (xx.x) 
SOC 2 
 
Overall 
xx (xx.x) 
xx (xx.x) 
 
Preferred Term 1 
xx (xx.x) 
xx (xx.x) 
 
Preferred Term 2 
xx (xx.x) 
xx (xx.x) 
etc. 
Note: Subjects reporting multiple occurrences of the same preferred term are only counted once within a given cell. 
Source:  Listing 16.X.X.X 
Programming note:  Sort in descending frequency based on the number of subjects in the SOC+ Brequinar group.  
Sort alphabetically to break ties. 
 
 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.1.5.1 
Summary of Prior Medications by Treatment 
Modified Intent-to-Treat Population 
 
Pharmacological Subgroup 
 
Prior Medication 
SOC+ Brequinar 
(N=xx) 
n (%) 
SOC 
(N=xx) 
n (%) 
Any Prior Medication 
 
Overall 
xx (xx.x) 
xx (xx.x) 
Subgroup 1 
 
Overall 
xx (xx.x) 
xx (xx.x) 
 
Medication 1 
xx (xx.x) 
xx (xx.x) 
 
Medication 2 
xx (xx.x) 
xx (xx.x) 
Subgroup 2 
 
Overall 
xx (xx.x) 
xx (xx.x) 
 
Medication 1 
xx (xx.x) 
xx (xx.x) 
 
Medication 2 
xx (xx.x) 
xx (xx.x) 
etc. 
Note: Subjects reporting multiple medications of the same coded term are only counted once within a given cell. 
Source:  Listing 16.X.X.X 
Programming note:  Sort medications in descending frequency based on the number of subjects in the SOC + 
Brequinar group.  Sort alphabetically to break ties. Pharmacological Subgroup comes from ATC3.  If ATC3 is not 
available, use ATC2 
 
Change column header to “System Organ Class  Preferred Term” for Procedure tables. 
 
 


Study Day 
 
Hospitalization Status 
SOC + Brequinar 
(N=xx) 
n (%) 
SOC 
(N=xx) 
n (%) 
Study Day 3 
 
Died 
xx (xx.x) 
xx (xx.x) 
 
Hospitalized in ICU 
xx (xx.x) 
xx (xx.x) 
 
 
Initial Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
 
Re-Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
Hospitalized (not ICU)  
xx (xx.x) 
xx (xx.x) 
 
 
Initial Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
 
Re-Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
Discharged 
xx (xx.x) 
xx (xx.x) 
 
 
Initial Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
 
Re-Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
Missing 
xx 
xx 
etc. 
Study Day 15 
 
Died 
xx (xx.x) 
xx (xx.x) 
 
Hospitalized in ICU 
xx (xx.x) 
xx (xx.x) 
 
 
Initial Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
 
Re-Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
Hospitalized (not ICU) 
xx (xx.x) 
xx (xx.x) 
 
 
Initial Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
 
Re-Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
Discharged 
xx (xx.x) 
xx (xx.x) 
 
 
Initial Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
 
Re-Hospitalization 
xx (xx.x) 
xx (xx.x) 
 
Missing 
xx 
xx 
Day 29 Contact 
 
Died 
xx (xx.x) 
xx (xx.x) 
 
Alive 
xx (xx.x) 
xx (xx.x) 
 
Missing 
xx 
xx 
Source:  Listing 16.x.x.x 
   Programming notes: summarize hospitalization status and death on Study Day 3, 5, 7, 15; summarize only death on Day 29.   
    Include missing rows to capture unknown status. 
 
Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.1 
Summary of Hospitalization Status and Mortality Rate by Treatment and Visit 
Modified Intent-to-Treat Population 


 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Total Patients Discharged 
xx 
xx  
Number of Censoreda 
 
Not Discharged by Day 15 Visit 
 
Did Not Complete Study 
xx 
xx 
xx 
xx 
xx 
xx 
Q1 
xx 
xx  
Median 
xx 
xx  
Q3 
xx 
xx  
Note: Duration of hospitalization is defined as Study Day at time of initial discharge. 
a: Subjects who were not discharged by the Day 15 visit will be censored at the Day 15 visit. Subjects who did not 
complete the trial while still hospitalized will be censored at the date of last contact. 
Source:  Listing 16.x.x.x 
 
 
Page 1 of 1 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.2.1 
Summary of Kaplan Meier Estimates for Duration of Hospitalization by Treatment 
Modified Intent-to-Treat Population 


Page 1 of 1 
DRAFT 
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Figure 14.2.2.2 
Duration of Hospitalization by Treatment  
Modified Intent-to-Treat Population  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Duration of hospitalization is defined as the Study Day at time of initial discharge. Subjects who were not discharged by the Day 15 visit will be censored at the Day 15 visit. 
Subjects who did not complete the trial while still hospitalized will be censored at the date of last contact. 
Source: 16.x.x.x 
 


 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Number of Deaths 
xx 
xx  
Number of Censoreda 
 
Alive at Day 29 Contact 
 
Unknown 
xx 
xx 
xx 
xx 
xx 
xx 
Q1 
xx 
xx  
Median 
xx 
xx  
Q3 
xx 
xx  
a: Subjects who are alive at the Day 29 contact will be censored at the Day 29 contact. Subjects whose Day 29 survival is 
unknown will be censored at the date of last contact. 
Source:  Listing 16.x.x.x 
 
Page 1 of 1 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.3.1 
Summary of Kaplan Meier Estimates for Time to Death by Treatment 
Modified Intent-to-Treat Population 


Page 1 of 1 
DRAFT 
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio., Inc.:  Protocol CCB-CRISIS-01 
Figure 14.2.3.2 
Time to Death by Treatment  
Intent-to-Treat Population  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Subjects who are alive at the Day 29 contact will be censored at the Day 29 contact. Subjects whose Day 29 survival is unknown will be censored at the date of last contact. 
Source: 16.x.x.x 
 


Page 1 of 1 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio., Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.4.1 
Summary of NEWS2 Scores by Treatment and Visit 
Modified Intent-to-Treat Population 
 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Visit 
Visit 
Change from 
Baseline  
Visit 
Change from 
Baseline  
Baseline 
 
n  
xx 
   
xx 
   
 
Mean (SE)  
xx.x (xx.xx) 
   
xx.x (xx.xx) 
   
 
Median  
xx.x 
   
xx.x 
   
 
Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
 
Min, Max  
xx, xx 
   
xx, xx 
   
 
 
 
 
 
 
0-4 
xx (xx.x) 
   
xx (xx.x) 
   
 
5-6 
xx (xx.x) 
   
xx (xx.x) 
   
 
7 or Higher 
xx (xx.x) 
   
xx (xx.x) 
   
Day 3 
 
n  
xx 
xx 
xx 
xx 
 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
0-4 
xx (xx.x) 
   
xx (xx.x) 
   
 
5-6 
xx (xx.x) 
   
xx (xx.x) 
   
 
7 or Higher 
xx (xx.x) 
   
xx (xx.x) 
   
etc. 
Source:  Listing 16.x.x.x 
Programming note:  Include Day 3, 5, 7, 15. 
 
 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.4.2 
Summary of NEWS2 Parameters by Treatment and Visit 
Modified Intent-to-Treat Population 
 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Parameter 
 
Visit 
Visit 
Change from 
Baseline  
Visit 
Change from 
Baseline  
Systolic Blood Pressure (mmHg) 
 
Baseline 
 
n  
xx 
   
xx 
   
 
Mean (SE)  
xx.x (xx.xx) 
   
xx.x (xx.xx) 
   
 
Median  
xx.x 
   
xx.x 
   
 
Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
 
Min, Max  
xx, xx 
   
xx, xx 
   
 
Day 3 
 
n 
xx 
xx 
xx 
xx 
 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
… 
Supplemental Oxygen 
 
Baseline 
 
Subject with value 
xx  
 
xx  
 
 
Yes, [n (%)] 
xx (xx.x) 
 
xx (xx.x) 
 
 
No, [n (%)] 
xx (xx.x) 
 
xx (xx.x) 
 
… 
Hypercapnic Respiratory Failure 
 
Baseline 
 
Subject with value 
xx  
 
xx  
 
 
Yes, [n (%)] 
xx (xx.x) 
 
xx (xx.x) 
 
 
No, [n (%)] 
xx (xx.x) 
 
xx (xx.x) 
 
 
Unknown, [n (%)] 
xx (xx.x) 
 
xx (xx.x) 
 
etc. 
Note: Percentages of Supplemental Oxygen, Hypercapnic Respiratory Failure and Level of Consciousness Alert are based on 
the Subject with value. 
Source:  Listing 16.x.x.x 
Programming notes: summarize all NEWS2 parameters on Day 3, 5, 7, 15. CFB for Oxygen, Hypercapnic and Alert won’t be 
provided. 
 
 


Page 1 of 1 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.5 
Summary of Change from Baseline in SARS-CoV-2 Viral Load (copies/mL) by Treatment and Visit 
Modified Intent-to-Treat Population 
 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Visit 
Visit 
Change from 
Baseline  
Visit 
Change from 
Baseline  
Baseline 
 
n  
xx 
   
xx 
   
 
Mean (SE)  
xx.x (xx.xx) 
   
xx.x (xx.xx) 
   
 
Median  
xx.x 
   
xx.x 
   
 
Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
 
Min, Max  
xx, xx 
   
xx, xx 
   
Day 3 
 
n  
xx 
xx 
xx 
xx 
 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Day 5 
 
n  
xx 
xx 
xx 
xx 
 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
etc. 
Source:  Listing 16.2.x 
Programming note:  Include Day 3,5,7,15. 
 
 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.6 
Summary of Change from Baseline in Inflammatory Markers by Treatment and Visit 
Modified Intent-to-Treat Population 
 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Parameter 
 
Visit 
Visit 
Change from 
Baseline  
Visit 
Change from 
Baseline  
Parameter 1 (unit), Normal Range=xx-xx 
 
Baseline 
 
n  
xx 
   
xx 
   
 
Mean (SE)  
xx.x (xx.xx) 
   
xx.x (xx.xx) 
   
 
Median  
xx.x 
   
xx.x 
   
 
Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
 
Min, Max  
xx, xx 
   
xx, xx 
   
 
Day 3 
 
n 
xx 
xx 
xx 
xx 
 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
Day 5 
 
n 
xx 
xx 
xx 
xx 
 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
etc. 
Parameter 2 (unit), Normal Range=xx-xx 
 
Baseline 
Source:  Listing 16.x.x.x 
Programming note: Include all parameters from local and central labs on Day 3, 5, 7, 15. 
 
 


Page 1 of 1 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio., Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.7 
Summary of Change from Baseline in DHO Level (ng/mL) by Treatment and Visit 
Intent-to-Treat Population 
 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Visit 
Visit 
Change from 
Baseline  
Visit 
Change from 
Baseline  
Baseline 
n  
xx 
   
xx 
   
Mean (SE)  
xx.x (xx.xx) 
   
xx.x (xx.xx) 
   
Median  
xx.x 
   
xx.x 
   
Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
Min, Max  
xx, xx 
   
xx, xx 
   
Day 3 
n  
xx 
xx 
xx 
xx 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Day 5 
n  
xx 
xx 
xx 
xx 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
etc. 
Source:  Listing 16.x.x.x 
Programming note:  Include Day 3, 5, 7, 15. 
 
 


Page 1 of 1 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio., Inc.:  Protocol CCB-CRISIS-01 
Table 14.2.8 
Summary of Change from Baseline in Brequinar Concentration Level (mcg/mL)  
by Treatment and Visit 
Intent-to-Treat Population 
 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Visit 
Visit 
Change from 
Baseline  
Visit 
Change from 
Baseline  
Baseline 
n  
xx 
   
xx 
   
Mean (SE)  
xx.x (xx.xx) 
   
xx.x (xx.xx) 
   
Median  
xx.x 
   
xx.x 
   
Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
Min, Max  
xx, xx 
   
xx, xx 
   
Day 3 
n  
xx 
xx 
xx 
xx 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Day 5 
n  
xx 
xx 
xx 
xx 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Day 7 
n  
xx 
xx 
xx 
xx 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Source:  Listing 16.x.x.x 
 
 


Page 1 of 1 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events by Treatment 
Modified Intent-to-Treat Population 
 
SOC + Brequinar 
(N=xx) 
n (%) 
SOC 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
Subjects with 1 or more TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subjects with 1 or more treatment-relateda TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subjects with 1 or more Grade 3 or above TEAE  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subjects with 1 or more TEAE leading to drug withdrawn 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subjects with 1 or more TEAE leading to study discontinuation  
Subjects with 1 or more serious TEAE 
Subjects with fatal TEAE 
Subjects with TEAE of interest 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Total number of TEAEs  
xx 
xx 
xx 
Total number of study drug-relateda TEAEs  
xx 
xx 
xx 
Total number of Grade 3 or above TEAEs  
xx 
xx 
xx 
Total number of TEAEs leading to drug withdrawn  
Total number of TEAEs leading to study discontinuation 
Total number of serious TEAEs 
Total number of TEAEs of interest 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
a: Includes possible, probable and definite. 
Source:  Listing 16.X.X.X 
 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by Treatment 
Modified Intent-to-Treat Population 
 
SOC + Brequinar (N=xx) 
SOC (N=xx) 
Total (N=xx) 
System Organ Class 
 
Preferred Term  
Subjectsa 
n (%)  
Events 
n  
Subjectsa 
n (%) 
Events 
n  
Subjectsa 
n (%) 
Events 
n  
Any Adverse Event  
 
Overall  
xx (xx.x) 
xx 
xx (xx.x) 
xx  
xx (xx.x) 
xx  
SOC 1 
 
Overall  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
 
Preferred Term 1 
xx (xx.x) 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
 
Preferred Term 2 
xx (xx.x) 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
 
Preferred Term 3 
xx (xx.x) 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
SOC 1 
 
Overall  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
 
Preferred Term 1 
xx (xx.x) 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
 
Preferred Term 2 
xx (xx.x) 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
 
Preferred Term 3 
xx (xx.x) 
xx  
xx (xx.x) 
xx  
xx (xx.x) 
xx  
etc. 
a: Subjects experiencing one or more TEAEs are counted only once for each adverse event term. 
Source: Listing 16.X.X.X 
Programming note:  Sort SOCs in descending frequency using total number of subjects in the SOC + Brequinar group, then sort preferred terms in descending 
frequency.  Sort alphabetically to break ties. 
 
 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Table 14.3.1.7 
Summary of Treatment-Emergent Adverse Events by Severity and Treatment 
Modified Intent-to-Treat Population 
Programming note:  Sort SOCs in descending frequency using total number of subjects in the SOC + Brequinar group, then sort preferred terms in descending 
frequency.  Sort alphabetically to break ties. 
 
SOC + Brequinar (N=xx) 
SOC (N=xx) 
System Organ Class 
 
Preferred Term  
Subjectsa 
n (%)  
Grade 1b 
n  
Grade 2b 
n 
Grade 3b 
n  
Grade 4b 
n 
Grade 5b 
n 
Subjectsa 
n (%)  
Grade 1b 
n  
Grade 2b 
n 
Grade 3b 
n  
Grade 4b 
n 
Grade 5b 
n 
Overall   
Overall  
xx (xx.x) 
xx 
xx 
xx 
xx 
xx 
xx (xx.x) 
xx 
xx 
xx 
xx 
xx 
SOC1 
Preferred Term 1 
xx (xx.x) 
xx 
xx 
xx 
xx 
xx 
xx (xx.x) 
xx 
xx 
xx 
xx 
xx 
Preferred Term 2 
xx (xx.x) 
xx 
xx 
xx 
xx 
xx 
xx (xx.x) 
xx 
xx 
xx 
xx 
xx 
Preferred Term 3 
xx (xx.x) 
xx 
xx 
xx 
xx 
xx 
xx (xx.x) 
xx 
xx 
xx 
xx 
xx 
a: Subjects experiencing one or more TEAEs are counted only once for each adverse event term.  
b: Subjects experiencing one or more TEAEs are counted only once for each adverse event term and counted only by the maximum severity. 
Source: Listing 16.X.X.X 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio., Inc.:  Protocol CCB-CRISIS-01 
Table 14.3.2 
Summary of Change from Baseline in Laboratory Parameters of Special Interest by Treatment and Visit 
Modified Intent-to-Treat Population 
 
 
SOC + Brequinar 
(N=xx) 
SOC 
(N=xx) 
Parameter 
 
Visit 
Visit 
Change from 
Baseline  
Visit 
Change from 
Baseline  
Parameter 1 (unit) 
 
Baseline 
 
 
n  
xx 
   
xx 
   
 
 
Mean (SE)  
xx.x (xx.xx) 
   
xx.x (xx.xx) 
   
 
 
Median  
xx.x 
   
xx.x 
   
 
 
Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
 
 
Min, Max  
xx, xx 
   
xx, xx 
   
 
Day 2 
 
 
n  
xx 
xx 
xx 
xx 
 
 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
Day 3 
 
 
n  
xx 
xx 
xx 
xx 
 
 
Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
Min, Max  
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
etc. 
Parameter 2 (unit) 
 
Baseline 
Source:  Listing 16.x.x.x 
Programming note: Include selected lab parameters: AST, ALT, ALP, Total Bilirubin, Creatinine, Hemoglobin, 
WBC, Absolute Neutrophils, Absolute 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.1 
Listing of End of Study Status by Treatment 
Site-Subject 
Date of Last 
Contact 
Did the patient 
complete the study? 
Primary Reason Did Not Complete 
Comments  
SOC + Brequinar 
xx-xxxx 
9999-99-99 
Yes  
   
   
xx-xxxx 
9999-99-99 
Yes 
   
  xxxxxxxxxxxxxx 
SOC 
xx-xxxx 
9999-99-99 
No 
xxxxxxxxxxxxxx 
  xxxxxxxxxxxxxx 
xx-xxxx 
9999-99-99 
Yes 
 
   
 
 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
pgmid.sas 
 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
 
Listing 16.2.2 
 
Listing of Inclusion/Exclusion Criteria and Randomization 
 
Site-
Subject 
Does the subject meet all 
the Inclusion/Exclusion 
criteria? 
Criterion 
Not Met 
Comment / Explain Reason 
for Ineligibility 
Date of 
Randomization 
Time of 
Randomization 
Treatment 
Assignment 
ICU Level of 
Care at 
Randomization 
xx-xxxx 
Yes 
 
 
9999-99-99 
99:99 
SOC 
No 
xx-xxxx 
No 
Exclusion 2 
Inclusion 1 
xxxxxxxxxxx 
xxxxxxxxxxx 
 
 
 
Yes 
xx-xxxx 
Yes 
 
 
9999-99-99 
99:99 
SOC + Brequinar 
No 
xx-xxxx 
No 
Inclusion 3 
xxxxxxxxxxx 
 
 
 
No 
xx-xxxx 
Yes 
 
 
9999-99-99 
99:99 
SOC + Brequinar 
Yes 
xx-xxxx 
Yes 
 
 
9999-99-99 
99:99 
SOC 
No 
 


 
Page 1 of x 
DRAFT ` 
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.3 
Listing of Informed Consent and Study Populations by Treatment 
Site-Subject 
Date of Informed Consent 
Time of Informed Consent 
Modified Intent-to-Treat Populationa 
SOC + Brequinar 
 
 
xx-xxxx 
9999-99-99 
99:99 
Yes 
xx-xxxx 
9999-99-99 
99:99 
Yes 
xx-xxxx 
9999-99-99 
99:99 
Yes 
SOC  
 
 
xx-xxxx 
9999-99-99 
99:99 
xxx 
xx-xxxx 
9999-99-99 
99:99 
xxx 
xx-xxxx 
9999-99-99 
99:99 
xxx 
a: 
Modified Intent-to-Treat (mITT) population includes all randomized subjects who had at least one post-randomization assessment, and who received at least one dose 
of study medication if randomized to SOC + Brequinar group. 


Site-Subject 
Date of Birth 
Age 
(years)  
Sex 
Ethnicity  
Race  
Height 
(unit) 
Weight 
(unit) 
BSA 
(m2) 
SOC + Brequinar 
xx-xxxx 
9999-99-99 
9999-99-99 
9999-99-99 
xx 
Male 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxx (in) 
xxx (lb) 
x.x 
xx-xxxx 
xx 
Female 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxx (cm) 
Not Done 
 
xx-xxxx 
xx 
Male 
xxxxxxxxxxxxx 
Other: xxxxxxxxxxxxx 
Not Done 
xxx (kg) 
 
SOC 
xx-xxxx 
9999-99-99 
9999-99-99 
9999-99-99 
xx 
xxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxx 
xxxx 
x.x 
xx-xxxx 
xx 
xxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxx 
xxxx 
x.x 
xx-xxxx 
xx 
xxxxx 
xxxxxxxxxxxxx 
Other: xxxxxxxxxxxxx 
xxxx 
xxxx 
x.x 
Page 1 of x 
DRAFT 
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.4.1 
Listing of Subject Demographics by Treatment 


Page 1 of x 
DRAFT 
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.4.2 
Listing of Medical History by Treatment 
Site-Subject 
Diagnosis and/or Procedure  
System Organ Class / Preferred Term 
Onset Date 
Resolution Date 
(Ongoing) 
SOC + Brequinar 
xx-xxxx 
COVD-19 
xxxxxxxxxxx / xxxxxxxxxxx 
9999-99-99 
 Ongoing 
xxxxxxxxxxx  
xxxxxxxxxxx / xxxxxxxxxxx 
9999-99-99 
9999-99-99 
xx-xxxx 
COVD-19 
SOC  
xx-xxxx 
COVD-19 
xxxxxxxxxxx / xxxxxxxxxxx 
9999-99-99 
 Ongoing 
xxxxxxxxxxx  
xxxxxxxxxxx  
xxxxxxxxxxx / xxxxxxxxxxx 
xxxxxxxxxxx / xxxxxxxxxxx 
9999-99-99 
9999-99-99 
9999-99-99 
9999-99-99 
xx-xxxx 
COVD-19 
xxxxxxxxxxx / xxxxxxxxxxx 
9999-99-99 
Ongoing 


Page 1 of x 
DRAFT 
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.4.3 
Listing of Prior and Concomitant Medications by Treatment 
Site-
Subject 
M: Medication or Treatmenta 
P: Pharmacological Subgroup 
C: Coded Term 
Indication  
Start Date 
Stop Date 
(Ongoing) 
  
Dose 
Unit 
Route  
Prior/ 
Cona 
SOC + Brequinar 
xx-xxxx 
M: xxxxxxxxxxx 
P: xxxxxxxxxxx 
C: xxxxxxxxxxx 
xxxxxxx 
9999-99-99 
9999-99-99 
xxx 
xxx 
xxxxx 
P 
xx-xxxx 
M: xxxxxxxxxxx* 
P: xxxxxxxxxxx 
C: xxxxxxxxxxx 
xxxxxxx 
9999-99-99 
Ongoing 
xxx 
xxx 
Other: xxxxx 
P, C 
 
M: xxxxxxxxxxx 
P: xxxxxxxxxxx 
C: xxxxxxxxxxx 
xxxxxxx 
9999-99-99 
9999-99-99 
xxx 
xxx 
xxxxx 
C 
SOC 
xx-xxxx 
None 
 
 
 
 
 
 
 
xx-xxxx 
M: xxxxxxxxxxx* 
P: xxxxxxxxxxx 
C: xxxxxxxxxxx 
xxxxxxx 
9999-99-99 
Ongoing 
xxx 
Other: xxx 
xxxxx 
C 
a:  P=Prior medication, C=Concomitant medication. A prior medication is any medication that started prior to date of randomization. A concomitant medication is any 
medication that either has a start date on or after date of randomization, or is ongoing on the date of randomization. 
Programming Note: Pharmacological Subgroup comes from ATC3.  If ATC3 is not available, use ATC2. 
 


Page 1 of x 
DRAFT 
 
YYYY-MM-DD 
pgmid.sas 
 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.4.4 
Listing of Prior and Concomitant Procedures by Treatment 
Site-
Subject 
P: Procedure 
S: System Organ Class 
T: Preferred Term 
Indication  
Start Date 
Stop Date 
(Ongoing)  
Dose 
Unit 
Route  
Prior/ 
Cona 
SOC + Brequinar 
xx-
xxxx 
P: xxxxxxxxxxx 
S: xxxxxxxxxxx 
T: xxxxxxxxxxx 
xxxxxxx 
9999-99-99 
9999-99-99 
xxx 
xxx 
xxxxx 
P 
xx-
xxxx 
P: xxxxxxxxxxx 
S: xxxxxxxxxxx 
T: xxxxxxxxxxx 
xxxxxxx 
9999-99-99 
Ongoing 
xxx 
xxx 
Other: 
xxxxx 
P, C 
 
P: xxxxxxxxxxx 
S: xxxxxxxxxxx 
T: xxxxxxxxxxx 
xxxxxxx 
9999-99-99 
9999-99-99 
xxx 
xxx 
xxxxx 
C 
SOC 
xx-
xxxx 
None 
 
 
 
 
xx-
xxxx 
P: xxxxxxxxxxx 
S: xxxxxxxxxxx 
T: xxxxxxxxxxx 
xxxxxxx 
9999-99-99 
Ongoing 
xxx 
Other: xxx 
xxxxx 
C 
a:  P=Prior procedure, C=Concomitant procedure. A prior procedure is any procedure that started prior to date of randomization. A concomitant procedure is any procedure 
that either has a start date on or after date of randomization, or is ongoing on the date of randomization. 


Page 1 of x 
DRAFT 
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.5.1 
Listing of Dosing Information (SOC + Brequinar Only) 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Site-Subject 
Date of Dosing  
Time of 
Dosing 
Date of Dosing 
Time of 
Dosing 
Date of Dosing 
Time of 
Dosing 
Date of Dosing 
Time of 
Dosing 
Date of Dosing 
Time of 
Dosing 
xx-xxxx 
9999-99-99 
99:99 
Not Done 
9999-99-99 
99:99 
9999-99-99 
99:99 
9999-99-99 
99:99 
xx-xxxx 
9999-99-99 
99:99 
9999-99-99 
99:99 
9999-99-99 
99:99 
9999-99-99 
99:99 
9999-99-99 
99:99 
xx-xxxx 
9999-99-99 
99:99 
9999-99-99 
99:99 
9999-99-99 
99:99 
9999-99-99 
99:99 
Not Done 
 
xx-xxxx 
Not Done 
 
9999-99-99 
99:99 
9999-99-99 
99:99 
9999-99-99 
99:99 
9999-99-99 
99:99 
 
 


Page 1 of x 
DRAFT 
YYYY-MM-DD 
Pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.5.2 
Listing of PK/DHO Results by Treatment 
Site-Subject 
Visit 
Not Done 
Date Collected 
Time Collected 
PK Result (mcg/mL)a 
DHO Result (ng/mL)a 
SOC + Brequinar 
xx-xxxx 
Day 1 
 
9999-99-99 
99:99 
xxx 
xxxx 
Day 3 
 
9999-99-99 
99:99 
xxx 
xxxx 
 
Day 5 
Not Done 
 
 
 
Day 7 
 
9999-99-99 
99:99 
xxx 
xxxx 
 
Day 15 
 
9999-99-99 
99:99 
xxx 
xxxx 
SOC 
xx-xxxx 
Day 1 
 
9999-99-99 
99:99 
BLOQ (<5) 
xxxx 
 
Day 3 
 
9999-99-99 
99:99 
xxx 
xxxx 
 
Day 5 
 
9999-99-99 
99:99 
xxx 
xxxx 
 
Day 7 
 
9999-99-99 
99:99 
xxx 
BLOQ (<5) 
 
Day 15 
 
9999-99-99 
99:99 
xxx 
xxxx 
a:   BLOQ = Below Limit of Quantification (limit of quantification in parentheses) 
 
 


Page 1 of x 
DRAFT  
YYYY-MM-DD 
Pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.6.1 
Listing of NEWS2 Assessments by Treatment 
Site-
Subject 
Visit 
Date and Time 
Collected 
SBPa 
(mmHg) 
DBPa 
(mmHg) 
Pulse 
(Beats/Min.) 
Respiration 
(Breath/ 
Min.) 
SpO2 / 
SaO2 
(%) 
Temp. 
(Celsius) 
Supplemental 
Oxygen? 
Hypercapnic 
respiratory 
failure? 
Alert? 
NEWS
2 Score 
SOC + Brequinar 
xx-xxxx 
Day 1 
9999-99-99T99:99 
xxx 
xxx 
ND 
xxx 
xxx 
xx.x 
Yes 
Yes 
Yes 
xx 
 
Day 3 
9999-99-99T99:99 
xxx 
xxx 
xxx 
xxx 
xxx 
xx.x 
Yes 
No 
No 
xx 
 
Day 5 
9999-99-99T99:99 
xxx 
xxx 
xxx 
xxx 
ND 
xx.x 
No 
Yes 
No 
xx 
 
Day 7 
Not Done 
 
 
 
 
 
Day 15 
9999-99-99T99:99 
xxx 
xxx 
xxx 
xxx 
xxx 
xx.x 
No 
Unknown 
Yes 
xx 
SOC 
xx-xxxx 
Day 1 
9999-99-99T99:99 
xxx 
xxx 
xxx 
ND 
xxx 
xx.x 
xxx 
xxx 
xxx 
xx 
 
Day 3 
9999-99-99T99:99 
xxx 
xxx 
xxx 
xxx 
xxx 
ND 
xxx 
xxx 
xxx 
xx 
 
Unsche
duled 
 
 
 
 
 
 
 
 
 
 
 
 
Day 5 
9999-99-99T99:99 
xxx 
xxx 
xxx 
xxx 
xxx 
xx.x 
xxx 
xxx 
xxx 
xx 
 
Day 7 
9999-99-99T99:99 
ND 
ND 
xxx 
xxx 
xxx 
xx.x 
xxx 
xxx 
xxx 
xx 
 
Day 15 
9999-99-99T99:99 
xxx 
xxx 
xxx 
 
 
xx.x 
xxx 
xxx 
xxx 
xx 
Note: ND=Not Done 
a: SBP=Systolic Blood Pressure, DBP=Diastolic Blood Pressure. 
 
 


Page 1 of 3 
DRAFT 
 
 
 
YYYY-MM-DD 
Program.sas 
 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
 
Listing 16.2.6.2 
 
Listing of Inflammatory Markers by Treatment 
Parameter 
Visit 
Not Done 
Laboratory 
Date and Time 
Collected 
Result 
Abnormal? 
Reference Range 
SOC + Brequinar 
       Site-Subject= xx-xxxx 
Parameter 1 (unit) 
Day 1 
Local 
9999-99-99T99:99 
xx.x 
High 
 
 
Day 3 
 
Local 
9999-99-99T99:99 
xx.x 
High 
 
 
Day 5 
 
Central 
9999-99-99T99:99 
xx.x 
 
 
 
Day 7 
Not Done 
 
 
 
 
 
 
Day 15 
Local 
9999-99-99T99:99 
xx.x 
 
 
Parameter 2 (unit) 
Day 1 
Local 
9999-99-99T99:99 
xx.x 
Abnormal 
 
 
Day 3 
 
Local 
9999-99-99T99:99 
xx.x 
 
 
 
Unscheduled 
 
Local 
9999-99-99T99:99 
xx.x 
 
 
 
Day 5 
 
Local 
9999-99-99T99:99 
xx.x 
 
 
 
Day 7 
Not Done 
 
 
 
 
 
 
Day 15 
 
Local 
9999-99-99T99:99 
xx.x 
 
 
SOC 
       Site-Subject= xx-xxxx 
Parameter 1 (unit) 
Day 1 
Central 
9999-99-99T99:99 
xx.x 
 
 
 
Day 3 
Central 
9999-99-99T99:99 
xx.x 
 
 
 
Day 5 
Central 
9999-99-99T99:99 
xx.x 
 
 
 
Day 7 
 
Central 
9999-99-99T99:99 
xx.x 
 
 
 
Day 15 
 
Central 
9999-99-99T99:99 
xx.x 
 
 
Programming note: Include all data collected in local and central labs, including the tests done in both labs or done multiple times.  


Page 1 of x 
DRAFT 
 
 
YYYY-
MM-DD 
Pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.6.3 
Listing of SARS-CoV-2 Viral Load and Viral Cultureunit by Treatment 
Site-Subject 
Visit 
Not Done 
Date Collected 
Time Collected 
Viral Load (copies/mL) 
Viral Culture (unit) 
SOC + Brequinar 
xx-xxxx  
Day 1 
 
9999-99-99 
99:99 
 
 
Day 3 
 
9999-99-99 
99:99 
 
 
 
Day 5 
Not Done 
 
 
 
Day 7 
 
9999-99-99 
99:99 
 
 
 
Day 15 
 
9999-99-99 
99:99 
 
 
SOC 
xx-xxxx  
Day 1 
 
9999-99-99 
99:99 
 
 
 
Day 3 
 
9999-99-99 
99:99 
 
 
 
Day 5 
 
9999-99-99 
99:99 
 
 
 
Day 7 
 
9999-99-99 
99:99 
 
 
 
Day 15 
 
9999-99-99 
99:99 
 
 
 


Page 1 of x 
DRAFT 
YYYY-MM-DD 
Pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.6.4 
Listing of Hospitalization Log by Treatment 
Site-Subject 
Event Type 
 
Event Date 
 
SOC + Brequinar 
xx-xxxx 
xxxxxxxxxxxxx 
9999-99-99 
xx-xxxx 
xxxxxxxxxxxxx 
9999-99-99 
 
Other: xxxxxxxxxxxxx 
9999-99-99 
 
xxxxxxxxxxxxx 
 
SOC 
xx-xxxx 
None 
 
xx-xxxx 
Other: xxxxxxxxxxxxx 
9999-99-99 
 
xxxxxxxxxxxxx 
 
 


Page 1 of x 
DRAFT 
YYYY-MM-DD 
Pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.6.5 
Listing of Survival Status by Treatment 
Site-Subject 
Visit 
 
Date of Contact 
Survival Status 
Date of Death  
Not Done, Comment 
SOC + Brequinar 
xx-xxxx 
Day 1 – Day 15 
Alive 
 
 
Day 29 Contact 
9999-99-99 
Alive 
 
 
xx-xxxx 
Day 1 – Day 15 
Patient Died 
9999-99-99 
 
xx-xxxx 
Day 1 – Day 15 
 
Alive 
 
 
 
Day 29 Contact 
 
 
 
Not Done: xxxxxxxxxxxxxxx 
SOC  
xx-xxxx 
Day 1 – Day 15 
 
Alive 
 
 
 
Day 29 Contact 
9999-99-99 
Patient Died 
9999-99-99 
 
xx-xxxx 
Day 1 – Day 15 
Alive 
 
 
Day 29 Contact 
9999-99-99 
Alive 
 
 


Page 1 of x 
DRAFT 
YYYY-MM-DD 
pgmid.sas 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
Listing 16.2.7.1 
Listing of Adverse Events by Treatment 
Site-
Subject 
Adverse Event Term/ System 
Organ Class/ Preferred Term 
Onset Date and 
Time/ Resolution 
Date and Time 
Continuing? 
Outcomea 
Severity 
Causality 
Action Taken 
with Study 
Treatment 
Action 
Taken 
 
Serious? 
SOC + Brequinar 
xx-xxxx 
xxxxxxx/ xxxxxxx / xxxxxxx* 
9999-99-99T99:99/ 
9999-99-99T99:99 
Continuous 
RG 
Grade 2 
Definite 
Drug 
Interrupted 
None 
No 
xx-xxxx 
xxxxxxx/ xxxxxxx / xxxxxxx 
9999-99-99T99:99/ 
9999-99-99T99:99 
Intermittent 
RD 
Grade 4 
Probable 
Drug 
Withdrawn 
Treatment 
Prescribed 
No 
xxxxxxx/ xxxxxxx / xxxxxxx 
9999-99-99T99:99/ 
9999-99-99T99:99 
Continuous 
RS 
Grade 1 
Possible 
Unknown 
Discontinued 
Study 
No 
SOC  
xx-xxxx 
xxxxxxx/ xxxxxxx / xxxxxxx 
9999-99-99T99:99/ 
9999-99-99T99:99 
Intermittent 
NR 
Grade 5 
Unlikely 
Not Applicable 
Treatment 
Prescribed, 
Discontinued 
Study 
Yes 
xxxxxxx/ xxxxxxx / xxxxxxx 
9999-99-99T99:99/ 
9999-99-99T99:99 
Continuous 
UN 
Grade 3 
Unrelated 
Dose Not 
Changed 
None 
No 
xx-xxxx 
None 
 
* Not Treatment-Emergent (onset date is prior to the day of randomization 
a:  FA=Fatal, NR=Not Recovered/Not Resolved, RD=Recovered/Resolved, RS=Recovered/Resolved with Sequelae, RG=Recovering/Resolving, UN=Unknown. 
 
 


Page 1 of x 
DRAFT 
 
 
YYYY-MM-DD 
Pgmid.sas 
 
Clear Creek Bio, Inc.:  Protocol CCB-CRISIS-01 
 
Listing 16.2.8.1.1 
 
Listing of Chemistry Laboratory Tests by Treatment 
Parameter 
Visit 
Not Done 
Date and Time 
Collected 
Lab Name 
Result 
Abnormal? 
CTCAE 
Gradea 
Reference Range 
SOC + Brequinar 
 
Site-Subject= xx-xxxx 
Parameter 1 (unit) 
Day 1 
9999-99-99T99:99 
xxx 
xx.x 
High  
2 
xx.x-xx.x 
 
Day 2 
9999-99-99T99:99 
xxx 
xx.x 
High  
2 
xx.x-xx.x 
 
Day 3 
9999-99-99T99:99 
xxx 
xx.x 
High  
2 
xx.x-xx.x 
 
Day 4 
 
9999-99-99T99:99 
xxx 
xx.x 
 
0 
xx.x-xx.x 
 
Day 5 
 
9999-99-99T99:99 
xxx 
xx.x 
 
0 
xx.x-xx.x 
 
Day 6 
 
9999-99-99T99:99 
xxx 
xx.x 
 
0 
xx.x-xx.x 
 
Day 7 
 
9999-99-99T99:99 
Other: xxx 
xx.x 
 
0 
xx.x-xx.x 
 
Day 15 
 
9999-99-99T99:99 
Other: xxx 
xx.x 
 
0 
xx.x-xx.x 
Parameter 2 (unit) 
Day 1 
 
9999-99-99T99:99 
xxx 
xx.x 
Abnormal 
 
xx.x-xx.x 
 
Day … 
 
9999-99-99T99:99 
xxx 
xx.x 
 
 
xx.x-xx.x 
SOC  
 
Site-Subject= xx-xxxx 
Parameter 1 (unit) 
Day 1 
9999-99-99T99:99 
xxx 
xx.x 
0 
xx.x-xx.x 
 
Day 2 
9999-99-99T99:99 
xxx 
xx.x 
0 
xx.x-xx.x 
 
Day 3 
9999-99-99T99:99 
xxx 
xx.x 
0 
xx.x-xx.x 
 
Day 4 
 
9999-99-99T99:99 
xxx 
xx.x 
 
0 
xx.x-xx.x 
 
Day 5 
Not Done 
 
 
 
 
0 
 
 
Day 6 
 
9999-99-99T99:99 
xxx 
xx.x 
 
0 
xx.x-xx.x 
 
Day 7 
 
9999-99-99T99:99 
xxx 
xx.x 
Low 
1 
xx.x-xx.x 
 
Day 15 
 
9999-99-99T99:99 
Other: xxx 
xx.x 
Low 
1 
xx.x-xx.x 
a: 
Grades were derived using CTCAE criteria where applicable. Grade 0 was assigned for values that did not meet a CTCAE criteria. 
 


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Signature ID: 
57DEAAD1-7C22-40FE-A72C-57ABA124E827
Using IP Address: 173.44.85.49
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
   I approve this document
Sent: 12/17/2020 4:34:13 PM
Viewed: 12/17/2020 4:39:43 PM 
Signed: 12/17/2020 4:40:11 PM
Electronic Record and Signature Disclosure: 
      Accepted: 12/17/2020 4:39:43 PM
      ID: 602703f1-c8af-4241-a59c-3ddd3fb840e0
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp
Agent Delivery Events
Status
Timestamp
Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
Status
Timestamp
Carbon Copy Events
Status
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Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
12/17/2020 4:28:47 PM
Certified Delivered
Security Checked
12/17/2020 4:39:43 PM
Signing Complete
Security Checked
12/17/2020 4:40:11 PM
Completed
Security Checked
12/17/2020 4:40:11 PM
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time, Prosoft Clinical (we, us or Company) may be required by law to provide to 
you certain written notices or disclosures. Described below are the terms and conditions for 
providing to you such notices and disclosures electronically through the DocuSign system. 
Please read the information below carefully and thoroughly, and if you can access this 
information electronically to your satisfaction and agree to this Electronic Record and Signature 
Disclosure (ERSD), please confirm your agreement by selecting the check-box next to ‘I agree to 
use electronic records and signatures’ before clicking ‘CONTINUE’ within the DocuSign 
system. 
 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
Electronic Record and Signature Disclosure created on: 2/5/2019 7:28:20 AM
Parties agreed to: Daisy Chen, Barbara Powers


Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact Prosoft Clinical:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: t.sammartino@prosoftclinical.com 
 
To advise Prosoft Clinical of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us 
at t.sammartino@prosoftclinical.com and in the body of such request you must state: your 
previous email address, your new email address.  We do not require any other information from 
you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from Prosoft Clinical  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to t.sammartino@prosoftclinical.com and 
in the body of such request you must state your email address, full name, mailing address, and 
telephone number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with Prosoft Clinical  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to t.sammartino@prosoftclinical.com and in the body of such request you 
must state your email, full name, mailing address, and telephone number. We do not need any 
other information from you to withdraw consent..  The consequences of your withdrawing 
consent for online documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify Prosoft Clinical as described above, you consent to receive 
exclusively through electronic means all notices, disclosures, authorizations, 
acknowledgements, and other documents that are required to be provided or made 
available to you by Prosoft Clinical during the course of your relationship with Prosoft 
Clinical.