Clinical trial NCT05166876
Conditions: COVID-19
Keywords: SARS-CoV-2 Oral antiviral DHODH Inhibitor brequinar
Sponsor: Clear Creek Bio, Inc.
Start date: 2022-02-01; Completion date: 2022-06-04
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2 multi-center, assessor-blind, randomized study to assess the safety, tolerability, and antiviral activity of brequinar in combination with dipyridamole.

Detailed description:
This is a Phase 2 clinical trial in two parts. The first part of the trial will study up to 64 subjects using a dose escalation approach, with 16 subjects per cohort for up to 4 cohorts. The brequinar dose will start at 50 mg per day in Cohort 1, escalating in the next cohort of 16 to 100 mg, then to 150 mg, and finally to 200 mg if safety parameters are met. The dipyridamole dose will be 75 mg three times a day (TID) for subjects assigned to the combination arm for all cohorts. All subjects will also receive standard of care (SOC) for treatment of patients with COVID-19 infection. After identifying the highest brequinar dose that is safe and well tolerated, 48 subjects will be treated in an expansion part comparing the chosen brequinar dose in combination with 75 mg dipyridamole TID to the chosen dose of brequinar alone. The combination of brequinar and dipyridamole shows potent in vitro antiviral activity by blocking DHODH and the pyrimidine salvage pathway, respectively, and the purpose of this study is to establish the safety and antiviral effect of the combination.

During the dose escalation part of the study, subjects with confirmed mild to moderate COVID-19 will receive 5 days of one of the following oral doses: brequinar alone, brequinar in combination with dipyridamole, or placebo. Subjects will have a Screening Visit followed as soon as possible with Study Day 1. Study visits (virtual or in person) will take place at Screening and on specified days. The visits that include bloodwork must be conducted at the study site or arrangements made for sample collection at the subject's home or other appropriate location. Other visits/visit activities for that visit may be conducted remotely using telemedicine or other remote technique. A viral load sample, vital signs (respiratory rate, heart rate, body temperature and SpO2), and a symptom assessment will be completed on specified days.

Arms: arm 1: Brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met. arm 2: Placebo matching brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met. arm 3: Brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met. All subjects assigned to this arm will also receive dipyridamole 75 mg tablets TID.
Interventions: intervention 1: Brequinar Sodium intervention 2: Dipyridamole 75 MG intervention 3: Placebo
Intervention descriptions: intervention 1: 50 mg, 100 mg, 150 mg, 200 mg x 5 days intervention 2: 75 mg TID for 5 days intervention 3: 50 mg, 100 mg, 150 mg, 200 mg x 5 days

Protocol documents:
Prot_SAP_000.pdf: 
The CCB-CRISIS-04 Study: A phase II, randomized, assessor-blind, multicenter, multi-dose, 
placebo-controlled study assessing the safety and anti-coronavirus response of brequinar 
combined with dipyridamole in patients with mild to moderate SARS-CoV-2 infection. 
NCT05166876 
Document Date: 12/29/2021 


Table of Contents
Table of Contents ..........................................................................................................................
16.1.1 Protocol and protocol amendments....................................................................................
CCB-CRISIS-04 Protocol dated 24 September 2021 ...................................................................
1.0 AUTHORIZATION OF PROTOCOL........................................................................
1.1 Protocol Preparation and Authorization..........................................................
1.2 Quality Assurance statement...........................................................................
1.3 Sponsor's Review & Approval........................................................................
TABLE OF CONTENTS..................................................................................................
2.0 LIST OF ABBREVIATIONS.....................................................................................
3.0 PROTOCOL SUMMARY..........................................................................................
3.1 Synopsis ..........................................................................................................
3.2 Schedule of Activities .....................................................................................
4.0 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE..................
4.1 Clinical Facilities ............................................................................................
4.2 Biostatistics Services and Quality Assurance .................................................
4.3 Medical Experts...............................................................................................
5.0 BACKGROUND INFORMATION............................................................................
5.1 Introduction.....................................................................................................
5.2 Safety of brequinar..........................................................................................
5.3 Brequinar COVID-19 Studies.........................................................................
5.4 Rationale..........................................................................................................
5.5 Hypothesis.......................................................................................................
6.0 STUDY OBJECTIVE .................................................................................................
7.0 STUDY ENDPOINTS ................................................................................................
8.0 SELECTION AND WITHDRAWAL OF PATIENTS ..............................................
8.1 Inclusion Criteria.............................................................................................
8.2 Exclusion Criteria............................................................................................
8.3 Withdrawal Criteria.........................................................................................
9.0 STUDY PROCEDURE...............................................................................................
9.1 Study Design ...................................................................................................
9.2 Study Procedure ..............................................................................................
9.3 Hospitalization ................................................................................................
9.4 Unscheduled Visits and Early Discontinuation Visit......................................
9.5 Sample Collection Procedure..........................................................................
9.6 Sample Size.....................................................................................................
7
7
8
9
9
10
11
12
15
18
18
32
35
35
35
35
36
36
37
38
39
40
40
41
42
42
42
43
44
44
46
48
48
48
49


9.7 Patient identification and Randomisation .......................................................
9.8 Blinding...........................................................................................................
9.8.1 Unblinding of treatment assignment ............................................................
9.8.2 Emergency unblinding of treatment assignment..........................................
9.9 Study Duration ................................................................................................
9.10Treatment .......................................................................................................
9.11Clinical Safety Measures................................................................................
9.12Discontinuation/ Termination of Study..........................................................
10.0 STUDY TREATMENT ............................................................................................
10.1 Investigational Medicinal Product and Combination Product Dosage .........
10.1.1 Assessment of Compliance ............................................................
10.2 Procurement, Storage and Accountability Procedures for Investigational
Products.................................................................................................................
10.2.1 Receipt and storage of investigational products.............................
10.2.2 Accountability of investigational products ....................................
10.2.3 Handling of Unused Investigational products................................
10.2.4 Maintenance of Dispensing Record ...............................................
10.2.5 Concomitant medication ................................................................
11.0 EFFICACY ASSESSMENT.....................................................................................
12.0 SAFETY ASSESSMENT .........................................................................................
12.1 Demographic Characteristics ........................................................................
12.2 Medical and Medication History...................................................................
12.3 Physical Examination....................................................................................
12.4 Vital Signs.....................................................................................................
12.5 Abnormal Vital Sign Values .........................................................................
12.6 Clinical Safety Laboratory Assessments.......................................................
12.7 Other safety evaluations as appropriate and as indicated in the schedule
of activities............................................................................................................
12.8  Abnormal Laboratory Values.......................................................................
12.9 Handling and Reporting of Adverse Events..................................................
12.10 Serious Adverse Events (SAEs) ................................................................
12.11 Reporting and Follow-up ............................................................................
12.12 Classification of Severity of Adverse Event ...............................................
12.13 Causality Assessment/Association with the Study Medication ..................
12.14 Outcome Categories....................................................................................
13.0 SAMPLE PROCESSING AND TRANSFER PROCEDURES ...............................
14.0 BIOANALYTICAL PROCEDURES .......................................................................
50
51
52
53
53
53
53
55
55
55
56
56
56
56
56
56
56
57
58
58
58
59
59
59
60
60
60
61
63
64
66
67
68
68
70


14.1 Method Validation.........................................................................................
14.2 Assay of Samples ..........................................................................................
14.3 Incurred Study Sample Re-analysis ..............................................................
15.0 STATISTICAL ANALYSIS.....................................................................................
15.1 Statistical Analysis Plan................................................................................
15.2 Sample Size Estimation.................................................................................
15.3 Study Population for Analysis ......................................................................
15.4 Analysis of Efficacy Data .............................................................................
15.5 Safety Analysis..............................................................................................
16.0 AMENDMENT TO THE PROTOCOL....................................................................
17.0 SOURCE DATA ACCESSIBILITY ........................................................................
18.0 STUDY MONITORING...........................................................................................
19.0 QUALITY CONTROL AND QUALITY ASSURANCE AUDITS ........................
20.0 ETHICS.....................................................................................................................
20.1 Ethics Committee..........................................................................................
20.2 Written Informed Consent.............................................................................
21.0 DATA HANDLING AND RECORD KEEPING.....................................................
22.0 STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS ............................
23.0 ARCHIVING ............................................................................................................
24.0 INSURANCE POLICY.............................................................................................
25.0 CONFIDENTIALITY OF DATA.............................................................................
26.0 PUBLICATION POLICY.........................................................................................
27.0  REFERENCES.........................................................................................................
28.0 CLINICAL LABORATORY TESTS.......................................................................
SIGNATURE(S) OF INVESTIGATOR(S)
..................................................................
CCB-CRISIS-04 Protocol Amend 1 dated 29 December 2021 ....................................................
1.0 AUTHORIZATION OF PROTOCOL........................................................................
1.1 Protocol Preparation and Authorization..........................................................
1.2 Quality Assurance statement...........................................................................
1.3 Sponsor's Review & Approval........................................................................
2.0 LIST OF ABBREVIATIONS.....................................................................................
TABLE OF CONTENTS..................................................................................................
3.0 PROTOCOL SUMMARY..........................................................................................
3.1 Synopsis ..........................................................................................................
3.2 Schedule of Activities .....................................................................................
4.0 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE..................
4.1 Clinical Facilities ............................................................................................
70
70
70
70
70
71
71
71
72
73
73
73
73
74
74
74
75
75
75
75
75
76
77
78
79
80
81
81
82
83
87
84
90
90
104
107
107


4.2 Biostatistics Services and Quality Assurance .................................................
4.3 Medical Experts...............................................................................................
5.0 BACKGROUND INFORMATION............................................................................
5.1 Introduction.....................................................................................................
5.2 Safety of brequinar..........................................................................................
5.3 Safety of Dipyridamole...................................................................................
5.4 Brequinar COVID-19 Studies.........................................................................
5.5 Adverse Reactions...........................................................................................
5.6 Rationale..........................................................................................................
5.7 Hypothesis.......................................................................................................
6.0 STUDY OBJECTIVE .................................................................................................
7.0 STUDY ENDPOINTS ................................................................................................
8.0 SELECTION AND WITHDRAWAL OF PATIENTS ..............................................
8.1 Inclusion Criteria.............................................................................................
8.2 Exclusion Criteria............................................................................................
8.3 Withdrawal Criteria.........................................................................................
9.0 STUDY PROCEDURE...............................................................................................
9.1 Study Design ...................................................................................................
9.2 Study Procedure ..............................................................................................
9.3 Hospitalization ................................................................................................
9.4 Unscheduled Visits and Early Discontinuation Visit......................................
9.5 Sample Collection Procedure..........................................................................
9.6 Sample Size.....................................................................................................
9.7 Patient identification and Randomisation .......................................................
9.8 Blinding...........................................................................................................
9.8.1 Unblinding of treatment assignment ................................................
9.8.2 Emergency unblinding of treatment assignment..............................
9.9 Study Duration ................................................................................................
9.10 Treatment ......................................................................................................
9.11 Clinical Safety Measures...............................................................................
9.12 Discontinuation/ Termination of Study.........................................................
10.0 STUDY TREATMENT ............................................................................................
10.1 Investigational Medicinal Product and Combination Product Dosage .........
10.1.1 Assessment of Compliance ............................................................
10.2.1 Receipt and storage of investigational products.............................
10.2 Procurement, Storage and Accountability Procedures for Investigational
Products
107
107
108
108
109
110
110
112
113
114
114
115
116
116
117
117
119
119
120
122
122
122
123
124
125
126
126
127
127
127
128
129
129
129
129


10.2.1 Receipt and storage of investigational products.............................
10.2.2 Accountability of investigational products ....................................
10.2.3 Handling of Unused Investigational products................................
10.2.4 Maintenance of Dispensing Record ...............................................
10.2.5 Concomitant medication ................................................................
11.0 EFFICACY ASSESSMENT.....................................................................................
12.0 SAFETY ASSESSMENT .........................................................................................
12.1 Demographic Characteristics ........................................................................
12.2 Medical and Medication History...................................................................
12.3 Physical Examination....................................................................................
12.4 Vital Signs.....................................................................................................
12.5 Abnormal Vital Sign Values .........................................................................
12.6 Clinical Safety Laboratory Assessments.......................................................
12.7 Other safety evaluations as appropriate and as indicated in the schedule
of activities............................................................................................................
12.8  Abnormal Laboratory Values.......................................................................
12.9 Handling and Reporting of Adverse Events..................................................
12.10 Serious Adverse Events (SAEs) ................................................................
12.11 Reporting and Follow-up ............................................................................
12.12 Classification of Severity of Adverse Event ...............................................
12.13 Causality Assessment/Association with the Study Medication ..................
12.14 Outcome Categories....................................................................................
13.0 SAMPLE PROCESSING AND TRANSFER PROCEDURES ...............................
14.0 BIOANALYTICAL PROCEDURES .......................................................................
14.1 Method Validation.........................................................................................
14.2 Assay of Samples ..........................................................................................
14.3 Incurred Study Sample Re-analysis ..............................................................
15.0 STATISTICAL ANALYSIS.....................................................................................
15.1 Statistical Analysis Plan................................................................................
15.2 Sample Size Estimation.................................................................................
15.3 Study Population for Analysis ......................................................................
15.4 Analysis of Efficacy Data .............................................................................
15.5 Safety Analysis..............................................................................................
16.0 AMENDMENT TO THE PROTOCOL....................................................................
17.0 SOURCE DATA ACCESSIBILITY ........................................................................
18.0 STUDY MONITORING...........................................................................................
19.0 QUALITY CONTROL AND QUALITY ASSURANCE AUDITS ........................
129
130
130
130
130
131
132
132
132
132
133
133
133
134
134
135
137
138
140
140
141
142
143
143
143
144
144
144
144
144
144
145
146
146
146
146


20.0 ETHICS.....................................................................................................................
20.1 Ethics Committee..........................................................................................
20.2 Written Informed Consent.............................................................................
21.0 DATA HANDLING AND RECORD KEEPING.....................................................
22.0 STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS ............................
23.0 ARCHIVING ............................................................................................................
24.0 INSURANCE POLICY.............................................................................................
25.0 CONFIDENTIALITY OF DATA.............................................................................
26.0 PUBLICATION POLICY.........................................................................................
27.0  REFERENCES.........................................................................................................
28.0 CLINICAL LABORATORY TESTS.......................................................................
29.0 LIST OF CHANGES IN THE PROTOCOL FROM VERSION 02 TO
VERSION 2.1....................................................................................................................
SIGNATURE(S) OF INVESTIGATOR(S)
..................................................................
147
147
147
148
148
148
148
149
149
150
151
152
159


16.1.1 
Protocol and protocol amendments 
 
 


Confidential 
Confidential                                                                                                                                                      Page 1 of 72 
 
PROJECT NO.: 21-VIN-0372 
Protocol Number 
21-VIN-0372 
Protocol Title 
The CCB-CRISIS-04 Study: A phase II, randomized, assessor-blind, multicenter, 
multi-dose, placebo-controlled study assessing the safety and anti-coronavirus 
response of brequinar combined with dipyridamole in patients with mild to 
moderate SARS-CoV-2 infection. 
Study Phase 
II 
US IND Number 
149291 
Sponsor Study Code CCB-CRISIS-04 
Regulatory 
Submission 
DCGI 
Version Number 
01 
Protocol Date 
24 Sep 2021 
Supersedes 
None 
Date of Supersedes 
NA 
Sponsor 
Clear Creek Bio, Inc. 
585 Massachusetts Ave., 4th Floor 
Cambridge, MA 02139 USA 
Contract Research 
Organization 
(CRO) 
Veeda Clinical Research Ltd., 
Shivalik Plaza, Near I.I.M.,  
Ambawadi, Ahmedabad – 380 015, India 
Phone: +91-79-3001 3000 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of Sponsor (or 
under its control), and therefore provided to you in confidence as an Investigator or consultant, for review 
by you, your staff and an applicable Institutional Ethics Committee. By accepting this document you agree 
that this information will not be disclosed to others without written authorization from Sponsor except to the 
extent necessary to obtain informed consent from those persons (including their legally acceptable 
representatives as applicable) to whom the drug may be administered. 
 
		



RAVI ALAMCHANDANI 
2021.09.24 15:57:17 +05'30'
SUMIT ARORA 
2021.09.24 17:24:03 +05'30'
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 3 of 72
1.2 
Quality Assurance statement 
The contents of the protocol were reviewed for compliance with the applicable VIN SOPs, pertinent 
requirements of the Ethical guidelines for biomedical research on human participants (ICMR) 2017 guidelines, 
New Drugs and Clinical Trial Rules (2019) of India, ICH (Step 5) ‘Guidance on Good Clinical Practice’ ICH 
Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013) and with procedures oriented to Good Laboratory 
Practice and applicable regulatory guidelines.
Authorized signatory
Date
Name
:
Ms. Amee Kanuga
Head - Quality Assurance 
Address
:
Veeda Clinical Research Ltd.
Shivalik Plaza-A,
Near I.I.M., Opp. AMA, Ambawadi,
Ahmedabad – 380015,
Gujarat, India
Tel. No.
:
+91-79-30013000
Email ID
:
Amee.Kanuga@veedacr.com
Digitally signed by AMEE 
MILIND KANUGA 
Date: 2021.09.24 17:38:45 
+05'30'
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 4 of 72
1.3 
Sponsor’s Review & Approval
I, on behalf of Clear Creek Bio, Inc. have read, understood and approve this protocol. We agree to comply with 
all requirements of the Ethical guidelines for biomedical research on human participants (ICMR) 2017 
guidelines, New Drugs and Clinical Trial Rules (2019) of India, ICH (Step 5) ‘Guidance on Good Clinical 
Practice’ ICH Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013) and with procedures oriented to Good 
Laboratory Practice guideline and other applicable regulatory guidelines.
Authorized signatory
Date
Name
:
Vikram Sheel Kumar, MD
Address
:
Clear Creek Bio, Inc.
585 Massachusetts Ave., 4th Floor
Cambridge, MA 02139 USA
Tel. No.
:
+1-671-899-8944
E-mail
:
kumar@clearcreekbio.com
		




Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 5 of 72
 
TABLE OF CONTENTS 
1.0
AUTHORIZATION OF PROTOCOL.................................................................................................... 2
1.1
Protocol Preparation and Authorization........................................................................................... 2
1.2
Quality Assurance statement............................................................................................................ 3
1.3
Sponsor’s Review & Approval ........................................................................................................ 4
2.0
LIST OF ABBREVIATIONS................................................................................................................. 8
3.0
PROTOCOL SUMMARY....................................................................................................................11
3.1
Synopsis .........................................................................................................................................11
3.2
Schedule of Activities ....................................................................................................................25
4.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................................28
4.1
Clinical Facilities ...........................................................................................................................28
4.2
Biostatistics Services and Quality Assurance ................................................................................28
4.3
Medical Experts .............................................................................................................................28
5.0
BACKGROUND INFORMATION......................................................................................................29
5.1
Introduction....................................................................................................................................29
5.2
Safety of brequinar.........................................................................................................................30
5.3
Brequinar COVID-19 Studies........................................................................................................31
5.4
Rationale ........................................................................................................................................32
5.5
Hypothesis......................................................................................................................................33
6.0
STUDY OBJECTIVE ...........................................................................................................................33
7.0
STUDY ENDPOINTS ..........................................................................................................................34
8.0
SELECTION AND WITHDRAWAL OF PATIENTS ........................................................................35
8.1
Inclusion Criteria............................................................................................................................35
8.2
Exclusion Criteria ..........................................................................................................................35
8.3
Withdrawal Criteria........................................................................................................................36
9.0
STUDY PROCEDURE.........................................................................................................................37
9.1
Study Design..................................................................................................................................37
9.2
Study Procedure .............................................................................................................................39
9.3
Hospitalization ...............................................................................................................................41
9.4
Unscheduled Visits and Early Discontinuation Visit.....................................................................41
9.5
Sample Collection Procedure.........................................................................................................41
9.6
Sample Size....................................................................................................................................42
9.7
Patient identification and Randomisation ......................................................................................43
9.8
Blinding..........................................................................................................................................44
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 6 of 72
9.8.1Unblinding of treatment assignment...............................................................................................45
9.8.2Emergency unblinding of treatment assignment.............................................................................46
9.9
Study Duration ...............................................................................................................................46
9.10 Treatment .......................................................................................................................................46
9.11 Clinical Safety Measures ...............................................................................................................46
9.12 Discontinuation/ Termination of Study..........................................................................................48
10.0 STUDY TREATMENT ........................................................................................................................48
10.1 Investigational Medicinal Product and Combination Product Dosage ..........................................48
10.1.1 Assessment of Compliance ........................................................................................................... 49
10.2 Procurement, Storage and Accountability Procedures for Investigational Products .....................49
10.2.1 Receipt and storage of investigational products ..........................................................................49
10.2.2 Accountability of investigational products..................................................................................49
10.2.3 Handling of Unused Investigational products .............................................................................49
10.2.4 Maintenance of Dispensing Record.............................................................................................49
10.2.5 Concomitant medication..............................................................................................................49
11.0 EFFICACY ASSESSMENT.................................................................................................................50
12.0 SAFETY ASSESSMENT.....................................................................................................................51
12.1 Demographic Characteristics .........................................................................................................51
12.2 Medical and Medication History....................................................................................................51
12.3 Physical Examination.....................................................................................................................52
12.4 Vital Signs......................................................................................................................................52
12.5 Abnormal Vital Sign Values..........................................................................................................52
12.6 Clinical Safety Laboratory Assessments........................................................................................53
12.7 Other safety evaluations as appropriate and as indicated in the schedule of activities..................53
12.8 Abnormal Laboratory Values.........................................................................................................53
12.9 Handling and Reporting of Adverse Events ..................................................................................54
12.10Serious Adverse Events (SAEs).....................................................................................................56
12.11Reporting and Follow-up ...............................................................................................................57
12.12Classification of Severity of Adverse Event..................................................................................59
12.13Causality Assessment/Association with the Study Medication .....................................................60
12.14Outcome Categories.......................................................................................................................61
13.0 SAMPLE PROCESSING AND TRANSFER PROCEDURES ...........................................................61
14.0 BIOANALYTICAL PROCEDURES...................................................................................................63
14.1 Method Validation .........................................................................................................................63
14.2 Assay of Samples...........................................................................................................................63
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 7 of 72
14.3 Incurred Study Sample Re-analysis ...............................................................................................63
15.0 STATISTICAL ANALYSIS.................................................................................................................63
15.1 Statistical Analysis Plan.................................................................................................................63
15.2 Sample Size Estimation .................................................................................................................64
15.3 Study Population for Analysis .......................................................................................................64
15.4 Analysis of Efficacy Data ..............................................................................................................64
15.5 Safety Analysis ..............................................................................................................................65
16.0 AMENDMENT TO THE PROTOCOL................................................................................................66
17.0 SOURCE DATA ACCESSIBILITY ....................................................................................................66
18.0 STUDY MONITORING.......................................................................................................................66
19.0 QUALITY CONTROL AND QUALITY ASSURANCE AUDITS ....................................................66
20.0 ETHICS.................................................................................................................................................67
20.1 Ethics Committee...........................................................................................................................67
20.2 Written Informed Consent .............................................................................................................67
21.0 DATA HANDLING AND RECORD KEEPING.................................................................................68
22.0 STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS ........................................................68
23.0 ARCHIVING ........................................................................................................................................68
24.0 INSURANCE POLICY ........................................................................................................................68
25.0 CONFIDENTIALITY OF DATA.........................................................................................................68
26.0 PUBLICATION POLICY.....................................................................................................................69
27.0 REFERENCES......................................................................................................................................70
28.0 CLINICAL LABORATORY TESTS...................................................................................................71
SIGNATURE(S) OF INVESTIGATOR(S) ................................................................................................... 72
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 8 of 72
2.0 LIST OF ABBREVIATIONS
AE
:
Adverse Event
ANOVA
:
Analysis of Variance
ATP
:
Adenosine Triphosphate
β-hCG
:
Beta-human Chorionic Gonadotropin
BA
:
Bioavailability
CBC
:
Complete Blood Count
CFR
:
Code of Federal Regulations
COA
:
Certificate of Analysis
COVID 19
:
Corona virus disease 2019
CRF
:
Case Report Form
CRO
:
Contract Research Organization
CRP
:
C-reactive protein
CTCAE
:
Common Terminology Criteria for Adverse Events
CTP
:
Cytidine Triphosphate
CYP
:
Cytochrome P
DCGI
:
Drug Controller General of India
EC
:
Ethics Committee
ECG
:
Electrocardiogram
ECMO
:
Extracorporeal membrane oxygenation
gm
:
Gram 
GCP
:
Good Clinical Practice
GGT
:
Gamma glutamyl transpeptidase
GLP
:
Good Laboratory Practice
GTP
:
Guanosine Triphosphate
HbsAg
:
Hepatitis B surface Antigen
HCV
:
Hepatitis C Virus
HIV
:
Human Immunodeficiency Virus
Hrs.
:
Hours
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 9 of 72
IB
:
Investigator Brochure
ICD
:
Informed Consent Document
ICH
:
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICMR
:
Indian Council of Medical Research
IMP
:
Investigational Medicinal Product
ITT
:
Intent-To-Treat
IU
:
International Unit
IUD
:
Intrauterine Device
Kg
:
Kilograms 
Ltd.
:
Limited
Mg
:
milligram
mg/dL
:
milligram/deciliter 
mL
:
Milliliter
No.
:
Number
OTC
:
Over the Counter
P/A
:
Postero-anterior 
PD
:
Pharmacodynamic
PK
:
Pharmacokinetic
PP
:
Per protocol
PO2
:
Partial pressure of oxygen
PCO2
:
Partial pressure of carbon dioxide
QA
:
Quality Assurance
qPCR
Quantitative polymerase chain reaction to test SARS-CoV-2 viral load
RLD
:
Reference Listed Drug
RT-PCR
Reverse transcription polymerase chain reaction
SAE
:
Serious Adverse Event
SD
:
Standard Deviation
SGOT
:
Serum Glutamate Oxaloacetate Transaminase
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 10 of 72
SGPT
:
Serum Glutamate Pyruvate Transaminase
SOP
:
Standard Operating Procedure
TEAEs
:
Treatment Emergent Adverse Events
t1/2
:
The time required for the drug concentration to decrease by 50 percent from the 
maximum concentration.
U
:
Units
UDS
:
Urine Drug Scan
UPT
:
Urine Pregnancy Test
USV
:
Unscheduled Visit
UTP
:
Uridine Triphosphate
WBC
:
White Blood Cell
WOCBP
:
Women of child bearing potential
0C
:
Degree Celsius
0F
:
Degree Fahrenheit 
%
:
Percent
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential         
        Page 11 of 72
3.0 PROTOCOL SUMMARY 
3.1 
Synopsis 
Title of Study:
The CCB-CRISIS-04 Study: A phase II, randomized, assessor-blind, multicenter, 
multi-dose, placebo-controlled study assessing the safety and anti-coronavirus 
response of brequinar combined with dipyridamole in patients with mild to moderate 
SARS-CoV-2 infection.
Sponsor:
Clear Creek Bio, Inc.
Clinical Study 
Centre(s):
Clinical facilities will be the clinics/ hospitals at different investigator sites across 
India.
Bio-analytical 
Study centre:
For PK analysis:
Veeda Clinical Research Ltd.
Rev. Sur. No. 12/1, Insignia, Corporate House,
Nr. Grand Bhagvati Hotel, 
Sindhu Bhavan Road, 
S. G. Highway, Bodakdev, Ahmedabad - 380054, Gujarat, India.
Phone: +91-79-67773000
For PD analysis:
Bioneeds India Pvt. Ltd. 
P-3, Peenya Industrial Area,
1st Stage, Bengaluru – 560058, Karnataka, India
Phone: +91-80-22658400
Statistical Centre: 
Veeda Clinical Research Ltd. 
Shivalik Plaza, Near I.I.M., Ambawadi,
Ahmedabad–380 015, India
Phone: +91-79-3001 3000
Fax: +91-79-3001 3010
Type of Study:
Phase II study
Rationale:
Brequinar is a potent DHODH inhibitor that blocks de novo pyrimidine synthesis in the 
host and has been previously studied in more than 1,000 cancer, psoriasis, and organ 
transplant patients. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 12 of 72
Brequinar has potent in vitro antiviral activity against many RNA viruses including 
SARS-CoV-2. The in vitro antiviral activity of brequinar against SARS-CoV-2 is likely 
due to DHODH inhibition and shows nanomolar potency and a high selectivity index 
in inhibiting viral replication these studies. Brequinar has also been studied in two 
clinical trials in patients with confirmed SARS-CoV-2 infection. In these two studies, 
25 were hospitalized (15 treated with brequinar) and 115 were non-hospitalized (56 
treated with brequinar). Results in these 71 COVID-19 patients demonstrated that 
brequinar 100 mg x 5 days was safe and well-tolerated in these populations. 
Brequinar’s antiviral activity was demonstrated in the out-patient study as shown by 
decreased viral load compared to placebo at days 12, 15, 22 and 29 and a shorter 
duration of viral shedding. The strong safety data in 71 COVID-19 subjects treated 
with daily brequinar at 100 mg for 5 days provides strong support for the further 
investigation of brequinar in the treatment of COVID-19.
The antiviral effects of brequinar may be blunted in vivo by pyrimidine salvage. One 
approach to enhancing the antiviral effect of brequinar is to block the pyrimidine 
salvage pathway by combining brequinar with a pyrimidine salvage inhibitor. 
Dipyridamole has been shown in vitro to block pyrimidine salvage and may potentiate 
the antiviral activities of DHODH inhibition on RNA viruses (Liu et al., 2020). 
Blocking pyrimidine salvage via dipyridamole shows improved in vitro antiviral 
efficacy of de novo pyrimidine synthesis inhibition via DHODH inhibition and will be 
used in this study in combination with brequinar to enhance brequinar’s antiviral 
activity. 
Dipyridamole is a well-tolerated, FDA-approved medication that is a nucleoside 
transport inhibitor and PDE3 inhibitor that inhibits blood clot formation and causes 
vasodilation. Dipyridamole was first approved by the US FDA in 1961 for prevention 
of thromboembolism in patients who have had cardiac valve replacement. It has also 
been widely prescribed in combination with aspirin to prevent stroke.
The CCB-CRISIS-04 trial will study subjects who have mild to moderate COVID-19
infection confirmed by a positive SARS-CoV-2 RT-PCR qualitative test / rapid antigen 
test and have mild/moderate signs and/or symptoms ongoing at study entry. The 
purpose of this study is to determine if the antiviral activity of brequinar can be 
improved by combining brequinar with dipyridamole in patients infected with SARS-
CoV-2.
Investigational 
Product and 
Combination 
Product Dosage:
1. Brequinar 50 mg capsules (used for the 50 mg and 150 mg doses)
2. Brequinar 100 mg capsules (used for the 100 mg, 150 mg and 200 mg doses)
3. Dipyridamole 75 mg tablets
4. Brequinar Placebo 50 mg and 100 mg capsules
Note:
x
The subjects will take the study medication as directed on study days 1 – 5.
x
Treatment assignment will be randomized, assessor-blind.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 13 of 72
x
IMP dispensing will be performed by unblinded pharmacist.
x
Study assessments will be performed by blinded Investigator or designate blinded 
site personnel.
x
Brequinar and brequinar placebo doses will be administered once daily.
x
Dipyridamole doses will be given thrice daily.
x
The 150 mg brequinar or brequinar placebo dose will be given as 1 capsule of 100 
mg and 1 capsule of 50 mg; the 200 mg brequinar or brequinar placebo dose will 
be given as 2 capsules of  brequinar or brequinar placebo 100 mg.
Study Design:
The first part of the study will be a phase II, randomized, assessor-blind, multicenter,
multi-dose, placebo-controlled study in approximately 64 subjects with mild to 
moderate COVID-19 infection confirmed by a positive SARS-CoV-2 RT-PCR 
qualitative test /rapid antigen test and who have at least mild to moderate signs and/or 
symptoms ongoing at study entry. 
Approximately 32 subjects (50% of subjects per arm per cohort) at selected sites will 
be invited to participate in the “PK/PD” arm of the study until approximately 8 subjects 
in each cohort have been recruited after providing written informed consent for the 
same. PK/PD includes brequinar and dipyridamole plasma concentrations and analysis 
of intracellular pools of UTP/CTP/ATP/GTP. 
If a particular cohort meets study stopping criteria (as defined in section “Safety 
Criteria”) or is found to be unsafe by DSMB members, then the study will not proceed 
with enrollment of subsequent cohorts. 
An expansion cohort of approximately 48 subjects will be added to the cohort with the 
highest brequinar dose that meets safety criteria.
All subjects will receive SOC as per relevant guidelines for treatment of patients with 
mild to moderate COVID-19 infection. 
Subjects will be randomized to one of the following cohorts in Part 1:
Cohort 1:
x
Arm 1: 5 days of standard of care (SOC) + brequinar 50 mg OD + dipyridamole 
75 mg TID (N = 8) 
x
Arm 2: 5 days of SOC + brequinar 50 mg OD (N = 4).
x
Arm 3: 5 days of SOC + brequinar placebo 50 mg OD (N = 4).
Cohort 2:
If the 50 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-
defined in the protocol the brequinar dose will be escalated to 100 mg.  
x
Arm 1: 5 days of standard of care (SOC) + brequinar 100 mg OD +
dipyridamole 75 mg TID (N = 8) 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 14 of 72
x
Arm 2: 5 days of SOC + brequinar 100 mg OD (N = 4).
x
Arm 3: 5 days of SOC + brequinar placebo 100 mg OD (N = 4).
Cohort 3:
If the 100 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-
defined in the protocol the brequinar dose will be escalated to 150 mg:  
x
Arm 1: 5 days of standard of care (SOC) + brequinar 150 mg (100 mg + 50 mg) 
OD + dipyridamole 75 mg TID (N = 8) 
x
Arm 2: 5 days of SOC + brequinar 150 mg (100 mg + 50 mg) OD (N = 4)
x
Arm 3: 5 days of SOC + brequinar placebo 150 mg (100 mg + 50 mg) OD (N 
= 4).
Cohort 4:
If the 150 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-
defined in the protocol the brequinar dose will be escalated to 200 mg:  
x
Arm 1: 5 days of standard of care (SOC) + brequinar 200 mg (100 mg +100
mg) OD + dipyridamole 75 mg TID (N = 8) 
x
Arm 2: 5 days of SOC + brequinar 200 mg (100 mg +100 mg) OD (N = 4)
x
Arm 3: 5 days of SOC + brequinar placebo 200 mg (100 mg +100 mg) OD (N 
= 4).
Expansion Cohort:
Approximately forty-eight (48) subjects will be added to the cohort with the highest 
brequinar dose that meets safety criteria in a 2 : 1 ratio of active treatment 
(approximately 32 SOC + brequinar + dipyridamole treated and 16 SOC + brequinar 
monotherapy group). Additional sites may be added if required to meet enrollment of 
the expansion cohort in an efficient manner.
Study Duration:
Study duration will be approximately 34 days including a maximum screening period 
of 5 days.
Objectives: 
Primary Objective:
x
To characterize the safety and tolerability of the brequinar-dipyridamole 
combination in COVID-19 subjects as measured by frequencies of grade 3 and 4 
toxicities and serious adverse events (SAEs) considered by the investigator to be 
related to the combination.
Secondary Objectives:
For subjects treated with the brequinar-dipyridamole combination compared to subjects 
treated with brequinar and to subjects treated with placebo through Day 29, to 
determine:
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 15 of 72
x
Reduction of SARS-CoV-2 levels using qPCR through Day 29 and at days 4, 8, 12, 
15, 22, and 29;
x
Reduction in time to symptom improvement;
x
Reduction in percentage of subjects requiring hospital admission/re-admission as 
an in-patient for >24 hours;
x
Reduction in percentage of subjects requiring medical attended visits, e.g., 
hospitalization, emergency room visits, Urgent Care/Family Doctor visits;
x
Reduction in percentage of subjects requiring supplemental support such as 
oxygen.  
Exploratory Objectives:
x
To 
determine 
brequinar-dipyridamole 
combination 
and
brequinar’s 
pharmacokinetic profile in a subset of subjects agreeing to participate in the PK/PD 
aspect of the study;
x
To compare the effects of the brequinar-dipyridamole combination to effects with 
brequinar alone and placebo alone on intracellular nucleotide pools of
UTP/CTP/ATP/GTP.
Study Endpoints:
Primary Endpoints: 
x
Frequencies of grade 3 and 4 toxicities and serious adverse events (SAEs) 
considered by the investigator to be related to the combination, brequinar alone or 
placebo alone.
Secondary Endpoints:
x
qPCR SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29;
x
Time to symptom improvement through Day 29;
x
Percentage of subjects requiring hospital admission/re-admission as an in-patient
for >24 hours through Day 29;
x
Percentage of subjects requiring medical attended visits, e.g., hospitalization, 
emergency room visits, Urgent Care/Family Doctor visits through Day 29;
x
Percentage of subjects requiring supplemental support such as oxygen through Day 
29.
Exploratory Endpoints (PK/PD):
x
Analysis of brequinar’s pharmacokinetic profile in a subset of patients that have 
received brequinar as a part of therapy and have consented to provide PK samples;
x
Analysis of effect on intracellular nucleotide pools of UTP/CTP/ATP/GTP in the
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 16 of 72
subset of patients who received brequinar-dipyridamole combination with 
comparison to brequinar alone and placebo alone.
Study Procedure:
To be eligible for screening, subjects must have a documented positive SARS-CoV-2 
test result within 5 days of first dose of study drug and have at least one ongoing 
symptom consistent with SARS-CoV-2 infection rated as at least mild to moderate in 
the opinion of the investigator. The subject’s earliest symptom must have an onset date 
within 5 days of first dose of study drug.
Subjects will undergo screening (day -4 to 0) for confirming eligibility for participation 
in the study. Study Day 1 includes randomization visit. 
Subjects will be randomized to a cohort as described above.
Screening activities as well as randomization can take place on the same day as a 
combined Screening/Day 1 visit, if the site team is able to obtain Screening lab results 
on the same day. Otherwise, Day 1 is to take place as soon as Screening lab results are 
available.
Study Day 1 and first dose of study drug must take place ≤5 days from onset of first 
symptom. 
Subjects may be hospitalized as many as 9 days in the study (day 0 to 8) or more for 
the PK/PD sample as per Investigator discretion.
For subjects participating in the PK/PD subset, 
Blood samples for estimating brequinar concentrations will be drawn (PK): 
x
Day 1: Pre-dose (within 1 hour prior to study drug administration) and post dose at 
1h, 2h, 4h, and 8h; note that the 8h sample is to be obtained prior to the next dose 
of dipyridamole.
x
Days 2 – 5 pre-dose and Day 8.
Blood samples for nucleotide pool analysis will be drawn (PD):
x
Days 1 – 5 pre-dose and Day 8.
Aliquots of the NP/OP swab samples are to be stored at the testing laboratory for 
possible additional virological testing.
Screening visit and study visits on Days 1, 8, 15, 22 and 29 will be either in person or 
a combination of in-person and virtual visit (telemedicine or other remote technique) 
or by visit to patient’s home by site team. 
Study visits on Day 4 and 12 may be virtual visits (telemedicine or other remote 
technique) or in person.
On Days 2, 3, 5, 6 and 7, the site will have a telephone call / or in-person 
communication with the subject for changes in concomitant medications and 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 17 of 72
assessment of adverse events (same will also be captured by the subject using a patient 
diary card or these visits will be conducted in person).
Note:
x
Study procedures are presented in detail in the Schedule of Events. 
x
Days 1, 8, 15 and 29 require sample collection for performing laboratory tests and 
will be conducted at the site or via home visit. 
x
Any in-person visit may also have telemedicine or telephone components if all 
study activities cannot be completed in person.
x
The visits that include bloodwork must be conducted at the study site or 
arrangements made for sample collection at the subject’s home or other appropriate 
location. 
x
Site staff (in case of an in-person visit) or subjects (in case of a remote visit) will 
assess respiratory rate, heart rate, body temperature and SpO2 (a thermometer and 
pulse oximeter are to be provided to subjects who are home quarantined, leave the 
hospital or are unable to return for study visits).
x
Subjects will record details of concomitant medications, adverse events in the 
patient diary card (PDC). 
x
Subjects will complete a symptom assessment form on designated days during the 
study period (days 1 – 8, 12, 15, 22, and 29).
x
In case the subject is hospitalized during the course of study, the activities specified 
in scheduled visits / time points will be carried out within the hospital facility. 
x
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF.
DSMB Meeting:
A Data Safety Monitoring Board (DSMB) will meet to review the safety and scientific 
conduct of the study. At a minimum, the DSMB will review the protocol and study 
design prior to study start, after the end of the first part of the study prior to the 
expansion phase, and at the end of the study.
At each interim meeting the DSMB members will determine whether to stop the study, 
amend the protocol, or continue the study per protocol. The study enrollment will not 
be suspended for routine DSMB meetings.
The DSMB will be convened and enrollment suspended if Cohort-Level Stopping 
Criteria are met. The DSMB may allow the enrollment to resume following their review 
if safety criteria are met.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 18 of 72
Hospitalization:
Subjects may be hospitalized for approximately 9 days (days 0 to 8) in the study as per
Investigator discretion for the PK/PD blood sample draws. Subjects may leave after 
this period (if medically discharged) after the Day 8 blood work has been drawn. 
Extended stays beyond study Day 8 are permitted if the facility is a dedicated COVID-
19 unit or other relevant hospital type or if per the Investigator the extended stay 
facilitates study procedures; this continuation will not be considered as an SAE. 
However, prolongation of hospitalization due to increase in disease severity or any 
other safety concerns related to the subjects will be considered as an SAE.
Hospitalization for the purpose of PK/PD sample collection may be done at 
Investigator’s discretion, in this case hospitalization may be for selected few days and 
may not be for entire 8 days duration. Appropriate documentation of the same will be 
done in source file.
Treatment:
All subjects will receive standard of care (SOC) including treatment for COVID-19 
signs and/or symptoms as required. Study encounters may be conducted remotely or at 
the study site depending on visit requirements, site facilities and subject and study team 
preferences.
Clinical Safety 
Measures:
It is the responsibility of the investigator to ensure that adequate medical supervision 
and care is available for the study subjects during the study to ensure their utmost safety 
and well being.
x
Demography (subject reported / measured height and weight, age, sex and 
race/ethnicity): At screening
x
Medical history (relevant within 30 days or ongoing) / History of current illness 
(date of symptom onset or change in baseline co-morbidity thought to be due to 
COVID-19 infection): At screening
x
Physical Examination (subject self-reported / examiner evaluated): At screening
x
Vital signs (body temperature, respiratory rate, heart rate, SpO2) assessment: At 
screening, Day 4 (±8 hrs), Day 8 (±8 hrs), Day 12 (± 1 day), Day 15 (±1 day), Day 
22 (±1 day), End of study [EoS; Day 29 (±2 day)].
Note: If subject is hospitalized, vital signs assessment will be done on daily basis 
by site team during hospitalization through Day 8 then following the Vital signs 
visits as listed above.
x
Hematology, biochemistry and urine analysis: At screening, Day 1 unless same day 
as Screening visit, Day 8 (±8 hrs), Day 15 (±1 day), End of study [EoS; Day 29 (±2 
day)].
x
HCV, HbSAg, HIV Test: At screening
x
Serum pregnancy test (Women of child bearing potential (WOCBP)): At screening.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 19 of 72
x
Urine pregnancy test (WOCBP): End of study [EoS; Day 29 (±2 day)].
Note: WOCBP: A premenopausal female capable of becoming pregnant
x
Rapid antigen test / SARS-CoV-2 RT-PCR Qualitative (in a clinically relevant 
specimen (Naso-Oro-Pharyngeal as appropriate)): Screening
Note: Test need not be repeated in those with possession of confirmed positive 
report. Date of positive report must be ≤5 days prior to randomization.
x
RT-PCR Quantitative Viral (in a clinically relevant specimen (Naso-Oro-
Pharyngeal as appropriate)): Day 1 (Prior to dosing), Day 4 (±8 hrs), Day 8 (±8 
hrs), Day 12 (±1 day), Day 15 (±1 day), Day 22 (±1 day) and End of study [EoS; 
Day 29 (±2 day)]
x
Ordinal Scale Assessment: Screening, Day 8 (±8 hrs), Day 15 (±1 day), Day 22 (±1 
day) and End of study [EoS; Day 29 (±2 day)]
x
Adverse events/ Serious Adverse Events: Adverse events/ Serious Adverse Events 
will be recorded from the time of first study drug administration till end of study 
safety assessments. Other medical events not related to disease condition under 
study and occurring before IMP administration, but after signing the informed 
consent form will be recorded on the medical history/current medical conditions of 
case report form.
x
In addition to protocol-specific laboratory tests and/or clinical examinations at 
scheduled time points, additional tests/clinical examination may be conducted to 
evaluate subject safety at any time during the study, at the discretion of the 
Investigator (can be done in local laboratory or nearby clinic/hospital/institution).
x
Medication taken prior to first dosing: All prescription medications and over-the-
counter drugs (including vitamins) taken within 30 days prior to screening must be 
recorded in the eCRF as Medication history.
x
Concomitant medications: Medications taken from time of signing of Informed 
Consent form until study completion (i.e. End of study) will be captured as 
concomitant medications.
x
Prohibited medications: Any other antiviral medications or medication with 
antiviral potential.
Note: 
x
It is recommended that general precautions need to be taken by the staff caring for
COVID patients during the trial.
x
In case the subject is hospitalized during the course of study, the activities specified 
in scheduled visits / time points will be carried out within the hospital facility. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 20 of 72
Sample Size:
In Part 1, approximately 64 subjects will be randomized to up to 4 cohorts of 5 
consecutive days of one of the following regimens in addition to SOC in 2:1:1 ratio as 
shown below:
Treatment 
Arm
Day 1
Day 2
Day 3
Day 4
Day 5
Brequinar + 
Dipyridamole
(N=8)
BRQ XX mg OD
DPY 75 mg TID
BRQ XX mg OD
DPY 75 mg TID
BRQ XX mg OD
DPY 75 mg TID
BRQ XX mg OD
DPY 75 mg TID
BRQ XX mg OD
DPY 75 mg TID
Brequinar
(N=4)
BRQ XX mg OD
BRQ XX mg OD
BRQ XX mg OD
BRQ XX mg OD
BRQ XX mg OD
Placebo
(N=4)
PBO XX 
mgPlacebo OD
PBO XX 
mgPlacebo OD
PBO XX 
mgPlacebo OD
PBO XX 
mgPlacebo OD
PBO XX 
mgPlacebo OD
The brequinar dose will start at 50 mg and may be escalated to 100 mg, 150 mg, and 
200 mg if safety criteria are met for each cohort (see Safety Criteria below).
The hospital pharmacist is to be unblinded. Bulk supplies of investigational medicinal 
product (IMP) of brequinar 50 mg, brequinar 100 mg, dipyridamole 75 mg, brequinar 
placebo 50 mg and brequinar placebo 100 mg will be supplied to the unblinded hospital 
pharmacist. 
The unblinded hospital pharmacist is to prepare the assigned IMP for each individual 
subject at that institution and create an appropriately labeled bottle/zip lock bag of study 
medication sufficient for a 5-day treatment course. Randomization code will be 
supplied using an IWRS.
Alternatively, the hospital pharmacist and study team may decide to distribute IMP on
a daily basis for each of the 5 days for brequinar and dipyridamole while the subject is 
hospitalized, depending on the most convenient method.
Inclusion 
Criteria:
Subjects will be eligible if they meet all of the following 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. Subjects between ≥18 and ≤65 years of age. 
3. Subjects found positive for SARS-CoV-2 either by rapid antigen test or by reverse 
transcription polymerase chain reaction (RT-PCR) using ICMR-validated kit.
Note: Test need not be repeated in those with possession of confirmed positive 
report but positive result test date must be ≤5 days of first dose of study drug.
4. Mild or Moderate COVID-19 as per latest updated version of CLINICAL 
MANAGEMENT PROTOCOL for COVID-19 (in Adults) released by 
Government of India Ministry of Health and Family Welfare Directorate General 
of Health Services (EMR Division).
5. The effects of brequinar on the developing human fetus are unknown. For this 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 21 of 72
reason, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately. Men and women 
treated or enrolled on this protocol must also agree to use adequate contraception 
for the duration of study participation, and for 90 days after completion of brequinar 
administration.
6. Male subjects must agree to refrain from sperm donation and female subjects must 
agree to refrain from ovum donation from initial study drug administration until 90 
days after the last dose of brequinar.
7. At least one non-respiratory COVID-19 symptom characterized as moderate to 
severe by the Investigator including but not limited to fatigue, chills, fever, body 
aches, nasal congestion, nausea, vomiting, or other sign or symptom commonly 
associated with COVID-19 in the opinion of the investigator. Symptom onset must 
be ≤5 days prior to first dose. Subject must have one or more signs/symptoms 
present at first dose.
8. Willing to participate in the PK/PD subset if at one of the identified sites.
9. Able to swallow capsules.
Exclusion 
Criteria:
Subjects will not be eligible for this study if any of the following in present at the time 
of study inclusion: 
1. Have an oxygen saturation of <90% while breathing ambient air.
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 subject.
3. Nursing women or women of childbearing potential (WOCBP) with a positive 
pregnancy test.
4. Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide) or 
other agents known to cause bone marrow suppression leading to 
thrombocytopenia.
5. Ongoing treatment with aspirin and or dipyridamole, famotidine or cimetidine. 
Remdesivir and ivermectin are prohibited through Study Day 8. Steroids are 
permitted per the guidelines.
6. Platelets ≤125,000 cell/mm3.
7. Hemoglobin <10 gm/dL.
8. Absolute neutrophil count <1000 cells/mm3.
9. Renal dysfunction, i.e., creatinine clearance <30 mL/min.
10. AST or ALT >3 x ULN, or total bilirubin >ULN. Gilbert’s Syndrome is allowed.
11. Bleeding disorders or blood loss requiring transfusion in the six weeks preceding 
enrollment.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 22 of 72
12. Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks of first 
dose.
13. Chronic hepatitis B infection, active hepatitis C infection, active liver disease 
and/or cirrhosis per subject report.
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).
PK/PD Sample 
Collection and 
Processing:
Blood collection and processing for PK analysis:
Brequinar/Dipyridamole PK/PD blood samples are to be collected either through an 
indwelling intravenous cannula (Venflon or similar) or may also be collected through 
a fresh vein puncture at each time point.
For PK samples, collect a 10 mL sample using syringe/adaptor and transfer to a pre-
labelled vacutainer containing K2EDTA as anticoagulant. Immediately following blood 
collection, gently invert the vacutainer 5 - 7 times to mix the anticoagulant. Place the 
filled vacutainer on wet ice bath (below 10 0C) during sample collection activity until 
storage of plasma.
Centrifuge the PK blood sample at 4000 RPM for 10 minutes at 5 ± 3°C to separate 
plasma. Keep the samples on wet ice bath (below 10 0C) both before centrifugation and 
after separation. 
Transfer the separated plasma to pre-labeled polypropylene tubes in 2 aliquots: 
Aliquot 1: Approximately 1.7 mL of plasma
Aliquot 2: Approximately 1.2 mL of plasma
Aliquots are to be stored upright in a box containing dry ice or in a freezer at a 
temperature –15 °C or colder for interim storage at the sites until shipment to Veeda 
Clinical Research Ltd., Ahmedabad.
Note: Entire activity from blood sample collection to storage in a freezer should be 
completed within 60 minutes time.
Ship each aliquot separately. During shipment the samples are to be packed in 
thermocol boxes containing an adequate amount of dry ice. The temperature will be 
monitored using calibrated data logger during shipment. Samples will be stored 
at -78±8°C until completion of analysis at Veeda Clinical Research Ltd., Ahmedabad.
Shipment for the backup Aliquot 2 will be carried out after confirmation of receipt of 
Aliquot 1.
A designated person or designate from bioanalytical department will take receipt of the
samples at Veeda Clinical Research Ltd., Ahmedabad. The condition of the samples is 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 23 of 72
to be examined on arrival at Veeda Clinical Research Ltd., Ahmedabad. If any of the 
samples are not in a frozen condition, clinical facility and\or Sponsor is to be informed. 
After receiving the samples at Veeda Clinical Research Ltd., Ahmedabad, the samples 
will be stored at -78 ± 8 °C until completion of analysis.
Blood collection and Processing for PD analysis:
For PD (nucleotide pools) samples, collect a 10 mL blood sample in a  K2EDTA 
vaccutainer per subject per time point is required to process for isolating the PBMCs 
in order to analyse the intracellular nucleotide content. The filled vacutainer tube is 
slowly inverted 2-3 times to ensure the collected blood mixes with the anticoagulant. 
No centrifugation will be performed on the PD samples at the site. 
Freshly collected blood samples are to be shipped once daily in 2-8 °C shipment 
condtions to Bioneeds  laboratory for further  processing. The blood should  reach the 
laboratory within 24-36 hours.
Note: Samples of patients enrolled in Arm 3 (SOC + Placebo) of each cohort will not 
be analysed.
Quantitative PCR 
(qPCR)
x
Obtain a NP/OP swab sample to be processed as outlined in the laboratory manual 
and sent to a central lab for analysis of quantitative PCR.
Drug and 
Nucleotide Pool
Analysis:
x
Plasma concentration of brequinar and dipyridamole will be quantified at the 
Bioanalytical facility of Veeda Clinical Research Ltd.
x
Intracellular nucleotide pool concentration (ATP/GTP/UTP/CTP) from isolated 
PBMCs will be estimated at the Bioanalytical facility of Bioneeds India Private 
Limited, Bengaluru.
Safety Criteria:
An independent, unblinded study physician (from CRO) will assess each cohort for 
safety. A cohort will be declared safe are as soon as all results are available for the Day 
15 visit if the following conditions are met:
x
No toxic deaths (deaths judged by the investigator to be related to either study 
drug);
x
Not more than 1 toxic SAE (SAEs judged by the investigator to be related to 
either study drug);
x
No Grade 3 or higher toxicities (including laboratory AEs as per CTCAE 
version 5.0 or higher) (AEs judged by the investigator to be related to either 
study drug);
x
<4 subjects with any grade toxicity (AEs judged by the investigator to be related 
to either study drug).
In addition to the cohort-level safety, the independent study physician (from CRO) will
determine if any subjects meet Individual Stopping Criteria: 
x
Subjects who develop a Grade 3 toxicity that is assessed by the investigator to 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 24 of 72
be related to the study drug are to be permanently discontinued from study 
treatment but will continue in the study for safety assessments.
x
Subjects who develop a Grade 4 toxicity, regardless of relatedness to study 
drug, are to be permanently discontinued from study treatment but will continue 
in the study for safety assessments.
In addition to the individual subject-level safety, the independent study physician (from 
CRO) will determine if a cohort meets Cohort-level Stopping Criteria prior to 
completing the 16 subjects, in which case no additional subjects will be enrolled into 
that cohort and no higher brequinar doses will be assessed:
x
≥3 brequinar-treated or combination-treated subjects meet the individual 
stopping criteria;
x
≥5 brequinar-treated or combination-treated subjects develop a Grade 3 or 
higher AE regardless of relationship to study drug.
Statistical 
methods:
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, standard error, 
minimum, and maximum. For qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome, and the 95% CI, when 
appropriate.  Any statistical testing will be considered exploratory and descriptive. All 
computations will be performed using SAS® (Version 9.4 or higher). Safety and 
tolerability will be assessed in terms of AEs, SAEs, and safety laboratory data. 
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of treatment-emergent adverse events, defined as TEAEs 
occurring after first dose will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and 
relationship to study treatment. All laboratory results and other clinical measures will 
be summarized using appropriate descriptive statistics.
Ethical Issues:
The study will commence only after a written approval is obtained from the 
Institutional Ethics Committee and applicable regulatory authorities. The trial will be 
conducted as per the biomedical research on human participants (ICMR) 2017 
guidelines, New Drugs and Clinical Trial Rules (2019) of India, ICH (Step 5) 
‘Guidance on Good Clinical Practice’ ICH Guidance E6 (R2), Declaration of Helsinki 
(Brazil, 2013) and with procedures oriented to Good Laboratory Practice and 
applicable regulatory guidelines.
		



Protocol for clinical study of Brequinar
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential         
        Page 25 of 72
3.2 
Schedule of Activities 
Windows are relative to time of first dose
Procedures
Screeninga/
Day 1
(Day -4 to 0)
Day 2, 3
(± 8 hrs)
Day 4
(± 8 hrs)
Day     
5, 6, 7
(±8 hrs)
Day 8
(±8 hrs)
Day 12
(±1 day)
Day 15
(±1 day)
Day 22
(±1 day)
Final Visitk
Day 29
(±2 days)
Type of visitg
IPVf
TCf
TM
TC
IPV+TM
TM
IPV+TM IPV+TM
IPV+TM
Informed Consent (note Date and Time)
X
AE/Concomitant Medications (dose, route, duration or 
ongoing)
X
X
X
X
X
X
X
X
X
Medical history (relevant within 30 days or ongoing)/ 
History of current illness (date of symptom onset or 
change in baseline co-morbidity thought to be due to 
COVID-19 infection)
X
Demographics (subject reported/ measured height and 
weight, age, sex, race/ethnicity)
X
Check for Physical Exam abnormalities (subject self-
reported/examiner evaluated)
X
Pregnancy Test (WOCBP) (serum at Screen and urine at 
D29)
X
X
Hematology / Biochemistry / Urine Analysisj
X
Xm
X
X
X
HCV, HbSAg, HIV Test
X
Vital Signsb
X
X
X
X
X
X
X
Symptom Assessmentc
X
X
X
X
X
X
X
X
X
Rapid antigen test/SARS-CoV-2 RT-PCR Qualitatived
X
RT-PCR Quantitative Viral Loadl
X
X
X
X
X
X
X
PK/PD Sampling (subset of subjects)h
X
X
X
X
X
Hospitalized Days 0 to 8i
Day 0
X
X
X
X
Hospital/Healthcare utilization Status
X
X
X
Ordinal Scale Assessment
X
X
X
X
X
Confirm Eligibility
3
Randomize subject and dispense Study Medication
X
Study drug administration (Days 1 – 5 only)f
X
X
X
X
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 26 of 72
Windows are relative to time of first dose
Procedures
Screeninga/
Day 1
(Day -4 to 0)
Day 2, 3
(± 8 hrs)
Day 4
(± 8 hrs)
Day     
5, 6, 7
(±8 hrs)
Day 8
(±8 hrs)
Day 12
(±1 day)
Day 15
(±1 day)
Day 22
(±1 day)
Final Visitk
Day 29
(±2 days)
Type of visitg
IPVf
TCf
TM
TC
IPV+TM
TM
IPV+TM IPV+TM
IPV+TM
Drug Accountability (Unblinded pharmacist)
X
PDC distribution
X
X
X
X
PDC collection and review
X
X
X
X
Symptom assessment form distribution
X
X
X
X
Symptom assessment form collection and review
X
X
X
X
a.
Day -4 to 0 includes screening activities.
b.
Vital signs (include heart rate, respiratory rate, body temperature, SpO2) assessment will be done at screening, Day 4 (±8 hrs), Day 8 (±8 hrs), Day 12 (± 1 
day), Day 15 (±1 day), Day 22 (±1 day), End of study [EoS; Day 29 (±2 day)]. Subjects who leave the hospital will be provided with a thermometer and 
pulse oximeter with heart rate monitoring capability. Training will be provided during the first home visit. Vital signs parameters will be observed and 
recorded by study staff via telemedicine or in-person visit (IPV) (at the study site or home visit).
Note: If subject is hospitalized, vital signs assessment will be done on daily basis by site team during hospitalization through day 8 then following the Vital 
signs visits as listed above.
c.
Symptom Assessment will capture respiratory symptoms as well as sore throat, cough, GI symptoms (vomiting, diarrhea), fatigue, anosmia, dysgeusia, 
other (specify), etc. Severity None, Mild, Moderate, or Severe will be collected. Longest symptom(s) onset date must be within 5 days of first dose.
d.
Documentation of a positive SARS-CoV-2 result from Rapid antigen test/RT-PCR or other regulatory agency-approved test is required to qualify for 
Screening. Test need not be repeated in those with possession of confirmed positive report. Date of positive report must be ≤5 days prior to randomization.
e.
Day 1 PK/PD baseline sample must be obtained prior to dosing. 
f.
Subject will take study drug once daily Days 1 – 5 and record doses in a medication diary. Note that some visits/visit activities post hospital discharge may 
be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology/PK/PD sample collections. These 
labs may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home visit.
g.
IPV= in-person visit (subject’s home or at clinical site, may also include TM or TC if all study visit activities cannot be completed by the in-person 
personnel); TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 
h.
PK/PD Sampling: For PK, day 1 samples will be drawn pre-dose, and after dosing at 1h, 2h, 4h, and 8h (Note: 8h sample is to be obtained prior to the next 
dose of dipyridamole), and pre-dose days 2, 3, 4, 5 and on day 8. For PD, samples will be drawn pre-dose days 1-5 and on day 8. One 10 mL sample is 
required for PK at each timepoint; one 10 mL sample is required for PD at each time point.
i.
Subjects hospitalization will be based on the discretion of the Investigator. Hospitalization for the purpose of PK/PD sample collection can be done at 
Investigator’s discretion, in this case hospitalization may be for selected few days and may not be for entire 8 days duration. Subjects may leave the hospital 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 27 of 72
after the Day 8 samples have been obtained if medically able to be discharged. In case the subject is hospitalized during the course of study, the activities 
specified in scheduled visits / time points will be carried out within the hospital facility.
j.
Sample collection for performing laboratory tests on days 1, 8, 15 and 29 will be conducted at the site or via home visit.
k.
If a study subject is discontinued from the study during an unscheduled visit, the unscheduled visit will be referred to as an Early Discontinuation Visit and 
all procedures scheduled for End of Study Visit will be performed.
l.
RT-PCR Quantitative Viral will be done at Day 1 (Prior to dosing), Day 4 (±8 hrs), Day 8 (±8 hrs), Day 12 (±1 day), Day 15 (±1 day), Day 22 (±1 day) 
and End of study [EoS; Day 29 (±2 day)]
m. Day 1 unless same day as Screening visit.
Note:
x
If the unscheduled visit is not an Early Discontinuation Visit (i.e., the study subject will continue to take part in the study), then the reason for unscheduled 
visit is to be documented and required procedures at the discretion of investigator considering the reason for visit, will be performed.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential         
        Page 28 of 72
4.0 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
4.1 
Clinical Facilities 
Clinical facilities will be the clinics/ hospitals of investigators’ site.
4.2 
Biostatistics Services and Quality Assurance 
Biostatistics
:
Dr. Ghanshyam Patel
Quality Assurance
:
Mrs. Amee Kanuga
Authorised Signatory
:
Dr. Sumit Arora  
Veeda clinical research Ltd.,
Shivalik Plaza, Near I.I.M., Ambawadi, Ahmedabad – 380 015, India.
Phone No.: +91-79-3001 3000
4.3 
Medical Experts 
Veeda’s Medical Expert:
Sponsor’s Medical Expert:
Dr. Ravi Alamchandani
Veeda Clinical Research Ltd.,
Shivalik Plaza, 
Near I.I.M., Ambawadi, 
Ahmedabad – 380 015, India.
Phone No.: +91-79-3001 3000
E-mail: Ravi.A1950@veedacr.com
John Pottage, MD
E-mail: John.pottagemd@gmail.com
Phone No: +1-610-761-0840
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 29 of 72
5.0 BACKGROUND INFORMATION 
5.1 
Introduction 
Coronaviruses are large group of viruses that cause illness in humans and animals. Rarely, animal coronaviruses
can evolve and infect people and then spread between people such as has been seen with MERS and SARS. 
The current outbreak of novel coronavirus disease (COVID-19) was initially noticed in Wuhan city in Hubei 
Province of China in mid December, 2019 has now spread to 215 countries/territories/areas worldwide. WHO 
(under International Health Regulations) has declared this outbreak as a “Public Health Emergency of 
International Concern” (PHEIC) on 30th January 2020. WHO subsequently declared COVID- 19 a pandemic 
on 11th March, 2020. 
Pathophysiology of COVID 19: 
Most adult patients with COVID-19 predominantly have a respiratory tract infection associated with SARS-
CoV-2 infection. However, in a small proportion of cases, the disease can progress to a more severe stage 
characterized by a dysregulated immune response with hyperinflammation with subsequent development of 
ARDS.  
Clinical Features: 
COVID-19 patients reporting to various COVID-19 treatment facilities have reported the following signs and 
symptoms: 
x
Fever, 
x
cough, 
x
general weakness/ fatigue, 
x
headache, 
x
myalgia, 
x
sore throat, coryza, 
x
dyspnoea, 
x
anorexia/nausea/vomiting, 
x
diarrhoea, 
x
altered mental status. 
x
loss of smell (anosmia) or loss of taste (ageusia) preceding the onset of respiratory symptoms has also been 
reported. 
Older people and immune-suppressed patients in particular may present with atypical symptoms such as fatigue, 
reduced alertness, reduced mobility, diarrhoea, loss of appetite, delirium, and absence of fever.  
Diagnosis of COVID 19: 
COVID-19 diagnosis is currently based on using a reverse transcriptase polymerase chain reaction (RT-PCR) 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 30 of 72
assay to detect viral RNA in respiratory samples. The high specificity of RT-PCR removes the need for lower 
respiratory tract samples to diagnose COVID-19 when a nasopharyngeal swab is positive for a patient with 
recent onset of the disease.  
5.2 
Safety of brequinar 
Introduction: 
Brequinar is an orally available and potent inhibitor of dihydroorotate dehydrogenase (DHODH). DHODH 
catalyzes the fourth step in pyrimidine synthesis, the conversion of dihydroorotate (DHO) to orotate. DHODH 
inhibitors, including brequinar, inhibit de novo pyrimidine synthesis thereby leading to a depletion of the 
cellular pool of uridine, cytidine, and thymidine ribonucleotides and deoxyribonucleotides. Brequinar has 
previously been evaluated for the treatment of hematologic malignancies, autoimmune disorders and COVID 
19. There are other DHODH inhibitors that have been approved for use in the treatment of rheumatoid arthritis 
and multiple sclerosis. 
Brequinar has been shown to have significant in vitro antiviral activity against several RNA viruses, including 
SARS-CoV-2, the cause of COVID-19 disease. As RNA viruses cannot synthesize their own ribonucleotides, 
they depend upon the host intracellular pool of ribonucleotides as the source for viral gene expression and 
replication. By transiently depleting the pool of host of pyrimidines, DHODH inhibition denies a virus of its 
source of ribonucleotide building blocks and thereby suppresses viral replication. This antiviral strategy 
targeting a host rather than viral protein also is less likely to select for resistant viruses. 
Preclinical study data: 
Initial nonclinical pharmacology studies of brequinar confirmed that its mechanism of action is the inhibition 
of de novo pyrimidine synthesis. Further studies with partially purified enzymes isolated from L1210 cells 
showed that brequinar inhibited DHODH activity, the fourth biochemical step in pyrimidine synthesis
Clinical study data: 
Brequinar has been studied under FDA IND 149,291 in 138 patients in two studies as an antiviral for coronavirus 
disease 2019 (COVID-19); 71 of these patients were treated with brequinar. Brequinar was administered as a 
single daily dose for five consecutive days with standard of care (SOC) in these COVID-19 studies.
Brequinar has also been previously studied in more than 1,000 patients in 30 clinical trials for treatment of solid 
tumors, psoriasis, and organ transplant. More recently Clear Creek Bio has studied brequinar use for acute 
myeloid leukemia (AML). In the oncology, psoriasis and organ transplant studies brequinar was administered 
as a single dose and as multiple courses with once weekly, twice weekly, single dose every 3 weeks, daily times 
5 every 4 weeks, and daily times 21 days regimens. The maximum single intravenous dose of 3250 mg/m2 was 
administered in an oncology study; the maximum oral dose of 950 mg/m2 twice weekly was also dosed during 
an oncology study. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 31 of 72
5.3 
Brequinar COVID-19 Studies 
CCB-CRISIS-01 in Hospitalized Patients 
The CRISIS-01 trial studied standard of care (SOC) and SOC with 5 days of brequinar administration in patients 
hospitalized for treatment of COVID-19. This was a phase 1 randomized, open label, multi-center study 
designed to enroll approximately 24 subjects. All subjects received SOC per institutional guidelines for 
treatment of patients with SARS-CoV-2 infection. In addition to SOC, the brequinar group received brequinar 
100 mg as an oral capsule once daily for 5 days. 
A total of 25 subjects were randomized in study CRISIS-01 at 5 sites. Two subjects assigned to the SOC plus 
brequinar group were randomized but withdrew consent and were never treated with brequinar. The modified
Intent-to-Treat (mITT) population which was used for all study analyses included all 23 randomized subjects 
who had at least one post-randomization assessment, and who received at least one dose of study medication if 
randomized to the SOC plus brequinar group. A total of 15 subjects were exposed to SOC plus brequinar and 8 
subjects had SOC treatment only. 
Brequinar was generally safe and well-tolerated in this population. No subjects discontinued study drug 
treatment due to an AE. No subjects died. 4 subjects (17.4%) experienced a total of 6 SAEs (1 in the SOC + 
brequinar group and three in the SOC only group). 12 subjects (52.2%) experienced a total of 28 treatment 
emergent AEs (TEAEs); 10/15 subjects (66.7%) reported 22 TEAEs in the SOC plus brequinar group; 2/8 
(25.0%) reported 6 TEAEs in the SOC only group. The most common TEAE was hyperglycaemia reported in 
3 subjects (20.0%) in the SOC plus brequinar group. Increased ALT was experienced by 2 subjects (13.3%) in 
the SOC plus brequinar group in subjects who had also received remdesivir. No other AEs were reported for 
more than one subject in either treatment group.
CCB-CRISIS-02 in Non-Hospitalized Patients 
The CRISIS-02 trial: A phase 2, randomized, double blind, placebo-controlled, multi-center study assessing the 
safety and anti-coronavirus response of suppression of host nucleotide synthesis in out-patient adults with 
SARS-CoV-2.
The CRISIS-02 trial studied outpatients (non-hospitalized patients) who had a positive SARS-CoV-2 RT-PCR 
test using a saliva sample and were symptomatic. Subjects were randomized to receive SOC + 5 days of 
brequinar or SOC + 5 days of placebo. The purpose of this study was to determine if the in vitro antiviral activity 
of brequinar translated to patients infected with SARS-CoV-2 by measuring the effect of treatment with 
brequinar on SARS-CoV-2 RNA levels (henceforth called “viral load”). 
The study enrolled 115 subjects (56 in the SOC plus brequinar group and 59 in the SOC plus placebo group). 
All subjects received SOC for treatment of patients with COVID-19 infection. In addition to SOC, the subjects 
self-administered one capsule of brequinar or placebo once daily for 5 days. Subjects were randomly assigned 
in a 1:1 ratio to SOC plus brequinar or SOC plus placebo. 
The median decrease in viral load was higher in the SOC plus brequinar group beginning at Day 12 (Days 12, 
15, 22, and 29). None of the comparisons to placebo reached statistical significance. None of the other efficacy 
endpoints showed a difference between the SOC plus brequinar compared to the SOC plus placebo treatments. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 32 of 72
There was no effect in reducing the time to clinical symptom resolution, however the majority of patients had 
very mild disease making improvements difficult to assess. 
Brequinar was safe and well-tolerated in this population. No subjects discontinued study drug treatment or 
discontinued from the study due to an AE. No subjects died. One subject in the brequinar plus SOC group 
(1.8%) experienced one non-study-drug-related SAE (admitted to hospital for COVID-19 penumonia). A total 
of 23 subjects (52.2%) experienced a total of 28 TEAEs; 10/56 subjects (17.9%) reported 22 TEAEs in the SOC 
plus brequinar group; 13/59 (22.0%) reported 6 TEAEs in the SOC plus placebo group. AEs were experienced 
by one subject only with the exceptions of nausea and rash each of which were experienced by two subjects. 
The majority of AEs were mild or moderate; there was one subject (1.8%) with a non-related Grade 3 AE in the 
SOC plus brequinar group (COVID-19 pneumonia) and 3 subjects with Grade 3 AEs in the SOC plus placebo 
group (chills, pain, injury and breast pain); all of the related AEs were considered Mild (Grade 1) by the 
investigators. There were no Grade 4 or higher AEs in either treatment group.
A total of 6 subjects had AEs considered possibly related to treatment, 3 in each group. 
5.4 
Rationale 
Rationale for the use of brequinar and dipyridamole in COVID-19 disease:
Brequinar is a potent DHODH inhibitor that blocks de novo pyrimidine synthesis in the host and has been 
previously studied in more than 1,000 cancer, psoriasis, and organ transplant patients.  
Brequinar has potent in vitro antiviral activity against many RNA viruses including SARS-CoV-2. The in vitro
antiviral activity of brequinar against SARS-CoV-2 is likely due to DHODH inhibition and shows nanomolar 
potency and a high selectivity index in inhibiting viral replication these studies. Brequinar has also been studied 
in two clinical trials in patients with confirmed SARS-CoV-2 infection. In these two studies, 25 were 
hospitalized (15 treated with brequinar) and 115 were non-hospitalized (56 treated with brequinar). Results in 
these 71 COVID-19 patients demonstrated that brequinar 100 mg x 5 days was safe and well-tolerated in these 
populations. Brequinar’s antiviral activity was demonstrated in the out-patient study as shown by decreased 
viral load compared to placebo at days 12, 15, 22 and 29 and a shorter duration of viral shedding. The strong 
safety data in 71 COVID-19 subjects treated with daily brequinar at 100 mg for 5 days provides strong support 
for the further investigation of brequinar in the treatment of COVID-19.  
The antiviral effects of brequinar may be blunted in vivo by pyrimidine salvage. One approach to enhancing the 
antiviral effect of brequinar is to block the pyrimidine salvage pathway by combining brequinar with a 
pyrimidine salvage inhibitor. Dipyridamole has been shown in vitro to block pyrimidine salvage and may 
potentiate the antiviral activities of DHODH inhibition on RNA viruses (Liu et al., 2020). Blocking pyrimidine 
salvage via dipyridamole shows improved in vitro antiviral efficacy of de novo pyrimidine synthesis inhibition 
via DHODH inhibition and will be used in this study in combination with brequinar to enhance brequinar’s 
antiviral activity.  
Dipyridamole is a well-tolerated, FDA-approved medication that is a nucleoside transport inhibitor and PDE3 
inhibitor that inhibits blood clot formation and causes vasodilation. Dipyridamole was first approved by the US 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 33 of 72
FDA in 1961 for prevention of thromboembolism in patients who have had cardiac valve replacement. It has 
also been widely prescribed in combination with aspirin to prevent stroke. 
The CCB-CRISIS-04 trial will study subjects who have mild to moderate COVID-19 infection confirmed by a
positive SARS-CoV-2 RT-PCR qualitative test / rapid antigen test and have mild/moderate signs and/or 
symptoms ongoing at study entry. The purpose of this study is to determine if the antiviral activity of brequinar 
can be improved by combining brequinar with dipyridamole in patients infected with SARS-CoV-2.
5.5 
Hypothesis 
Treatment with brequinar combined with dipyridamole in patients with SARS-CoV-2 viral infection will reduce 
viral load, decrease time to resolution of COVID-19-related clinical signs and/or symptoms and improve clinical 
outcomes compared with current standard care.
6.0 STUDY OBJECTIVE 
Primary Objective: 
x
To characterize the safety and tolerability of the brequinar-dipyridamole combination in COVID-19 subjects 
as measured by frequencies of grade 3 and 4 toxicities and serious adverse events (SAEs) considered by the 
investigator to be related to the combination.
Secondary Objectives:
For subjects treated with the brequinar-dipyridamole combination compared to subjects treated with brequinar 
and to subjects treated with placebo through Day 29, to determine: 
x
Reduction of qPCR SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29; 
x
Reduction in time to symptom improvement; 
x
Reduction in percentage of subjects requiring hospital admission/re-admission as an in-patient for >24 
hours;
x
Reduction in percentage of subjects requiring medical attended visits, e.g., hospitalization, emergency room 
visits, Urgent Care/Family Doctor visits; 
x
Reduction in percentage of subjects requiring supplemental support such as oxygen.   
Exploratory Objectives: 
x
To determine brequinar-dipyridamole combination and brequinar’s pharmacokinetic profile in a subset of
subjects agreeing to participate in the PK/PD aspect of the study; 
x
To compare the effects of the brequinar-dipyridamole combination to effects with brequinar alone and 
placebo alone on intracellular nucleotide pools of UTP/CTP/ATP/GTP. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential         
        Page 34 of 72
7.0 STUDY ENDPOINTS 
Primary Endpoints:  
x
Frequencies of grade 3 and 4 toxicities and serious adverse events (SAEs) considered by the investigator to
be related to the combination, brequinar alone or placebo alone.
Secondary Endpoints: 
x
qPCR SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29;
x
Time to symptom improvement through Day 29;
x
Percentage of subjects requiring hospital admission/re-admission as an in-patient for >24 hours through Day
29;
x
Percentage of subjects requiring medical attended visits, e.g., hospitalization, emergency room visits, Urgent
Care/Family Doctor visits through Day 29;
x
Percentage of subjects requiring supplemental support such as oxygen through Day 29.
Exploratory Endpoints (PK/PD): 
x
Analysis of brequinar’s pharmacokinetic profile in a subset of patients that have received brequinar as a part
of therapy and have consented to provide PK samples.
x
Analysis of effect on intracellular nucleotide pools of UTP/CTP/ATP/GTP in the subset of patients who
received brequinar-dipyridamole combination with comparison to brequinar alone and placebo alone.
Clinical improvement will be defined as a 2-point or greater improvement on an 8-point WHO ordinal scale in 
every subject measured on each designated day, from the date of randomization through day 29. This scale has 
been used in the current COVID-19 outbreak.    
Ordinal Scale for Clinical Improvement 
Patient State
Descriptor
Score
Uninfected
No clinical or virological evidence of infection
0
Ambulatory
No limitaion of activities
1
Limitation of activities
2
Hospitalized
Mild disease
Hospitalized, no oxygen therapy
Oxygen by mask or nasal prongs
3
4
Hospitalized 
Severe Disease
Non-invasive ventilation or high-flow oxygen
5
Intubation and mechanical ventilation
6
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential         
        Page 35 of 72
Ventilation + additional organ support – pressors, RRT, ECMO
7
Dead
Death
8
8.0 SELECTION AND WITHDRAWAL OF PATIENTS 
Subjects will be selected on the basis of the following inclusion and exclusion criteria. 
8.1 
Inclusion Criteria 
Subjects will be eligible if they meet all of the following 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. Subjects between ≥18 and ≤65 years of age.
3. Subjects found positive for SARS-CoV-2 either by rapid antigen test or by reverse transcription polymerase
chain reaction (RT-PCR) using ICMR-validated kit.
Note: Test need not be repeated in those with possession of confirmed positive report but positive result test
date must be ≤5 days of first dose of study drug.
4. Mild or Moderate COVID-19 as per latest updated version of CLINICAL MANAGEMENT PROTOCOL
for COVID-19 (in Adults) released by Government of India Ministry of Health and Family Welfare
Directorate General of Health Services (EMR Division).
5. The effects of brequinar on the developing human fetus are unknown. For this reason, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to
use adequate contraception for the duration of study participation, and for 90 days after completion of
brequinar administration.
6. Male subjects must agree to refrain from sperm donation and female subjects must agree to refrain from
ovum donation from initial study drug administration until 90 days after the last dose of brequinar.
7. At least one non-respiratory COVID-19 symptom characterized as moderate to severe by the Investigator
including but not limited to fatigue, chills, fever, body aches, nasal congestion, nausea, vomiting, or other
sign or symptom commonly associated with COVID-19 in the opinion of the investigator. Symptom onset
must be ≤5 days prior to first dose. Subject must have one or more signs/symptoms present at first dose.
8. Willing to participate in the PK/PD subset if at one of the identified sites.
9. Able to swallow capsules.
8.2 
Exclusion Criteria
Subjects will not be eligible for this study if any of the following in present at the time of study inclusion: 
1. Have an oxygen saturation of <90% while breathing ambient air.
2. Any physical examination findings and/or history of any illness that, in the opinion of the study investigator,
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential         
        Page 36 of 72
might confound the results of the study or pose an additional risk to the subject. 
3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test.
4. Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide) or other agents known to cause
bone marrow suppression leading to thrombocytopenia.
5. Ongoing treatment with aspirin and or dipyridamole, famotidine or cimetidine. Remdesivir and ivermectin
are prohibited through Study Day 8. Steroids are permitted per the guidelines.
6. Platelets ≤125,000 cell/mm3.
7. Hemoglobin <10 gm/dL.
8. Absolute neutrophil count <1000 cells/mm3.
9. Renal dysfunction, i.e., creatinine clearance <30 mL/min.
10. AST or ALT >3 x ULN, or total bilirubin >ULN. Gilbert’s Syndrome is allowed.
11. Bleeding disorders or blood loss requiring transfusion in the six weeks preceding enrollment.
12. Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks of first dose.
13. Chronic hepatitis B infection, active hepatitis C infection, active liver disease and/or cirrhosis per subject
report.
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).
8.3 
Withdrawal Criteria 
Subjects may voluntarily withdraw from the study at any time without assigning any reason thereof by 
withdrawing their consent. They may be considered withdrawn if they state an intention to withdraw, or fail to 
return for visits, or become lost to follow up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must determine the primary reason for a patient’s 
premature withdrawal from the study and record this information in the CRF. For patients who are lost to follow-
up (i.e., those patients whose status is unclear because they fail to appear for study visits without stating an 
intention to withdraw), the investigator should show "due diligence" by documenting in the source documents 
steps taken to contact the patient, e.g., dates of telephone calls, other means of communication even though 
patient is unwilling to attend further visits etc.  
If study participation is discontinued, the final evaluation will be performed as completely as possible. Any 
comments (spontaneous or elicited) or complaints made by the patient and the reason for termination, date of 
stopping the study medication and the total amount of study medication must be recorded in the source 
documents or CRFs. 
Criteria for a withdrawal of patients from clinical study: 
The subject may be withdrawn from the trial at the discretion of the investigator or the sponsor, if judged non-
compliant with trial procedures or due to safety concern.  
A subject must in addition be withdrawn from treatment with IMP if the following applies: 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential         
        Page 37 of 72
x
AE requiring permanent discontinuation of study drug.
x
The subject suffers from significant intercurrent illness or undergoes surgery requiring study discontinuation
during the course of the study.
x
Any subject who requires the use of an unacceptable concomitant medicine.
x
If the Investigator believes it is not in the subject’s best interest to continue.
x
The subject wishes to withdraw his/her consent.
x
Any other justifiable reason, which should be adequately documented.
x
Any subject whose condition worsens, requiring treatment with immunomodulators including but not
limited to tocilizumab and / or antiviral drugs including but not limited to remdesivir as per the best
judgement of the Investigator.
x
Non-compliance: The participant may be withdrawn from the trial at the discretion of the Investigator if it
is judged that participant is non-compliant to study assessment and schedule leading to safety concerns.
x
Positive pregnancy test: A female participant with a positive pregnancy test will be withdrawn from the
trial.
The sponsor or its representative may be contacted for clarification as required on a case-by case basis. 
Handling of Withdrawals: 
In the case of premature discontinuation of study subject, the investigator should schedule a study 
discontinuation visit to complete all assessment according to End of Study / Early Termination visit 
requirements. All reasons for ending participation must be recorded in the source documents or in the CRF.  
If the subject discontinues because of an adverse event (serious or non-serious), the investigator must follow up 
patient’s recovery until resolution or stabilization of AEs or up to 30 days after administration of last dose of 
IMP, whichever is earlier. 
This visit should be documented in the appropriate section of the Case Report Form (CRF). The investigator 
will record the reason for study discontinuation, provide or arrange for appropriate follow-up for such subjects, 
and document the course of the subject’s condition. In addition, the investigator will report the subject’s 
withdrawal to the responsible study monitor immediately.   
Subjects withdrawn from investigational product treatment will be treated as routine subjects. The investigator 
will discuss the appropriate therapy with each subject who withdraws early from this study. Determination of 
the appropriate follow-on therapy will be left to the discretion of the investigator and investigator could treat 
such subjects as per his/her routine practice. 
9.0 STUDY PROCEDURE 
9.1 
Study Design 
The first part of the study will be a phase II, randomized, assessor-blind, multicenter, multi-dose, placebo-
controlled study in approximately 64 subjects with mild to moderate COVID-19 infection confirmed by a 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential         
        Page 38 of 72
positive SARS-CoV-2 RT-PCR qualitative test /rapid antigen test and who have at least mild to moderate signs 
and/or symptoms ongoing at study entry.  
Approximately 32 subjects (50% of subjects per arm per cohort) at selected sites will be invited to participate 
in the “PK/PD” arm of the study until approximately 8 subjects in each cohort have been recruited after 
providing written informed consent for the same. PK/PD includes brequinar and dipyridamole plasma 
concentrations and analysis of intracellular pools of UTP/CTP/ATP/GTP.  
If a particular cohort meets study stopping criteria (as defined in section “Stopping Criteria”) or is found to be 
unsafe by DSMB members, then the study will not proceed with enrollment of subsequent cohorts.  
An expansion cohort of approximately 48 subjects will be added to the cohort with the highest brequinar dose 
that meets safety criteria. 
All subjects will receive SOC as per relevant guidelines for treatment of patients with mild to moderate COVID-
19 infection.  
Subjects will be randomized to one of the following cohorts in Part 1: 
Cohort 1: 
x
Arm 1: 5 days of standard of care (SOC) + brequinar 50 mg OD + dipyridamole 75 mg TID (N = 8)
x
Arm 2: 5 days of SOC + brequinar 50 mg OD (N = 4).
x
Arm 3: 5 days of SOC + brequinar placebo 50 mg OD (N = 4).
Cohort 2: 
If the 50 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-defined in the protocol the 
brequinar dose will be escalated to 100 mg.   
x
Arm 1: 5 days of standard of care (SOC) + brequinar 100 mg OD + dipyridamole 75 mg TID (N = 8)
x
Arm 2: 5 days of SOC + brequinar 100 mg OD (N = 4).
x
Arm 3: 5 days of SOC + brequinar placebo 100 mg OD (N = 4).
Cohort 3: 
If the 100 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-defined in the protocol the 
brequinar dose will be escalated to 150 mg:   
x
Arm 1: 5 days of standard of care (SOC) + brequinar 150 mg (100 mg + 50 mg) OD + dipyridamole 75
mg TID (N = 8)
x
Arm 2: 5 days of SOC + brequinar 150 mg (100 mg + 50 mg) OD (N = 4)
x
Arm 3: 5 days of SOC + brequinar placebo 150 mg (100 mg + 50 mg) OD (N = 4).
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 39 of 72
Cohort 4: 
If the 150 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-defined in the protocol the 
brequinar dose will be escalated to 200 mg:   
x
Arm 1: 5 days of standard of care (SOC) + brequinar 200 mg (100 mg +100 mg) OD + dipyridamole 75 
mg TID (N = 8)  
x
Arm 2: 5 days of SOC + brequinar 200 mg (100 mg +100 mg) OD (N = 4) 
x
Arm 3: 5 days of SOC + brequinar placebo (100 mg + 100 mg) OD (N = 4). 
Expansion Cohort: 
Approximately forty-eight (48) subjects will be added to the cohort with the highest brequinar dose that meets 
safety criteria in a 2 : 1 ratio of active treatment (approximately 32 in SOC + brequinar + dipyridamole treated 
and 16 in SOC + brequinar monotherapy group). Additional sites may be added if required to meet enrollment 
of the expansion cohort in an efficient manner. 
9.2 
Study Procedure 
To be eligible for screening, subjects must have a documented positive SARS-CoV-2 test result within 5 days 
of first dose of study drug and have at least one ongoing symptom consistent with SARS-CoV-2 infection rated 
as at least mild to moderate in the opinion of the investigator. The subject’s earliest symptom must have an 
onset date within 5 days of first dose of study drug.
Subjects will undergo screening (day -4 to 0) for confirming eligibility for participation in the study. Study Day 
1 includes randomization visit. 
Subjects will be randomized to a cohort as described above.
Screening activities as well as randomization can take place on the same day as a combined Screening/Day 1 
visit, if the site team is able to obtain Screening lab results on the same day. Otherwise, Day 1 is to take place 
as soon as Screening lab results are available.
Study Day 1 and first dose of study drug must take place ≤5 days from onset of first symptom. 
Subjects may be hospitalized as many as 9 days in the study (day 0 to 8) or more for the PK/PD sample as per 
Investigator discretion.
For subjects participating in the PK/PD subset,
Blood samples for estimating brequinar concentrations will be drawn (PK):
x
Day 1: Pre-dose (within 1 hour prior to study drug administration) and post dose at 1h, 2h, 4h, and 8h; note 
that the 8h sample is to be obtained prior to the next dose of dipyridamole;
x
Days 2 – 5 pre-dose and Day 8.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 40 of 72
Blood samples for nucleotide pool analysis will be drawn (PD): 
x
Days 1 – 5 pre-dose and Day 8. 
Aliquots of the NP/OP swab samples are to be stored at the testing laboratory for possible additional virological 
testing.
Screening visit and study visits on Days 1, 8, 15, 22 and 29 will be either in person or a combination of in-
person and virtual visit (telemedicine or other remote technique) or by visit to patient’s home by site team. 
Study visits on Day 4 and 12 may be virtual visits (telemedicine or other remote technique) or in person.
On Days 2, 3, 5, 6 and 7, the site will have a telephone call / or in-person communication with the subject for 
changes in concomitant medications and assessment of adverse events (same will also be captured by the subject 
using a patient diary card or these visits will be conducted in person).  
Note:
x
Study procedures are presented in detail in the Schedule of Events. 
x
Days 1, 8, 15 and 29 require sample collection for performing laboratory tests and will be conducted at the 
site or via home visit. 
x
Any in-person visit may also have telemedicine or telephone components if all study activities cannot be 
completed in person.
x
The visits that include bloodwork must be conducted at the study site or arrangements made for sample 
collection at the subject’s home or other appropriate location. 
x
Site staff (in case of an in-person visit) or subjects (in case of a remote visit) will assess respiratory rate, 
heart rate, body temperature and SpO2 (a thermometer and pulse oximeter are to be provided to subjects
who are home quarantined, leave the hospital or are unable to return for study visits).
x
Subjects will record details of concomitant medications, adverse events in the patient diary card (PDC). 
x
Subjects will complete a symptom assessment form on designated days daily during the study period (days 
1 – 8, 12, 15, 22, and 29).
x
In case the subject is hospitalized during the course of study, the activities specified in scheduled visits / 
time points will be carried out within the hospital facility. 
x
Study completion or the reason for study discontinuation will be recorded in the source document and the 
eCRF.
DSMB Meeting:
A Data Safety Monitoring Board (DSMB) will meet to review the safety and scientific conduct of the study. At 
a minimum, the DSMB will review the protocol and study design prior to study start, after the end of the first 
part of the study prior to the expansion phase, and at the end of the study. 
At each interim meeting the DSMB members will determine whether to stop the study, amend the protocol, or 
continue the study per protocol. The study enrollment will not be suspended for routine DSMB meetings.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 41 of 72
The DSMB will be convened and enrollment suspended if Cohort-Level Stopping Criteria are met. The DSMB 
may allow the enrollment to resume following their review if safety criteria are met.
9.3 
Hospitalization 
Subjects may be hospitalized for approximately 9 days (day 0 to 8) in the study as per Investigator discretion
for the PK/PD blood sample draws. Subjects may leave after this period (if medically discharged) after the Day 
8 blood work has been drawn. Extended stays beyond study Day 8 are permitted if the facility is a dedicated 
COVID-19 unit or other relevant hospital type or if per the Investigator the extended stay facilitates study 
procedures; this continuation will not be considered as an SAE. However, prolongation of hospitalization due 
to increase in disease severity or any other safety concerns related to the subjects will be considered as an SAE.
Hospitalization for the purpose of PK/PD sample collection may be done at Investigator’s discretion, in this 
case hospitalization may be for selected few days and may not be for entire 8 days duration. Appropriate 
documentation of the same will be done in source file.
9.4 
Unscheduled Visits and Early Discontinuation Visit 
An Unscheduled Visit is allowed at any time, for any reason, if in the Investigator’s opinion it is warranted. If 
the Unscheduled Visit is due to an AE, the Investigator will determine whether additional visits are needed. 
If a subject is discontinued from the study during an Unscheduled Visit, the Unscheduled Visit will be referred 
to as an Early Discontinuation Visit and all procedures scheduled for End of Study visit will be performed. 
If the Unscheduled Visit is not an Early Discontinuation Visit (i.e., the subject will continue to take part in the 
study), then the reason for unscheduled visit is documented and required procedures at the discretion of 
investigator considering the reason for visit will be performed.
If the Investigator determines that the subject’s condition has worsened to the degree that it is unsafe for the 
subject to continue in the study, the subject may be discontinued from the study as treatment failure and a 
standard of care treatment may be advised at the Investigator’s discretion.
In case of ongoing AEs, telephonic safety follow up will be continued until resolution or stabilization of AEs 
or up to 30 days after administration of last dose of IMP, whichever is earlier.
9.5 
Sample Collection Procedure 
Blood collection for PK analysis: 
PK blood samples will be collected through an indwelling intravenous cannula (Venflon or similar) placed in 
the forearm vein of the subjects for up to 24 hours or may also be collected through a fresh vein puncture at 
each time point. A 10 mL of blood per sample will be obtained using syringe/adaptor and transferred in to pre-
labelled vacutainers containing K2EDTA as anticoagulant. Filled vacutainers will be placed on wet ice bath 
(below 10 0C) during sample collection activity and until storage of plasma.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 42 of 72
Time of collection of each blood sample (as displayed in the calibrated digital clock) will be recorded in 24-
hour clock format (hh:mm) on the PK blood sample collection log and same will be transcribed to eCRFs. 
If an intravenous indwelling cannula is placed, maintain this as long as possible by injecting 0.5 mL of 5 IU/mL 
of heparin in normal saline solution or per hospital’s usual practice to maintain the cannula patentcy. When
sampling through the cannula, collect study blood samples after discarding the first 0.5 mL of heparinised blood 
from the cannula. If insertion of cannula is not possible, alternatively blood samples may be drawn by a fresh 
venipuncture or in case of blockade in an existing cannula, extra heparinised saline will be injected to stimulate 
the cannula and later blood samples will be collected after discarding the heparinised blood or central line. If 
the time window does not allow, it is recommended to directly use a disposable syringe for extraction, and 
appropriately dispose of the retained needle after blood collection.
The blood samples will be withdrawn using syringe or adaptor and transferred into pre-chilled (maintained at 
temperature below 10 °C), pre-labelled (mentioning Site number, Protocol number, Subject number, Period 
number, Sampling time point and Sample ID) sample collection tubes containing K2EDTA as an anticoagulant 
kept on wet ice bath (below 10 0C) until centrifugation. Immediately following blood collection, the vacutainers 
are to be gently inverted 5 - 7 times to mix the anticoagulant.
It is recommended that collected blood samples be placed on wet ice bath (below 10 0C) from the point of 
collection until storage of plasma.
Blood collection for PD analysis:
PD (nucleotide pools) blood samples are to be collected in a K2EDTA vaccutainer. Approximately 10 mL blood 
sample per subject pre-dose on days 1-5 and on day 8 is required to process for the isolating the PBMCs in
order to analyse the intracellular nucleotide content.
Freshly collected blood samples are to be shipped once daily in 2-8 °C shipment condtions to Bioneeds  
laboratory for further  processing. The blood should  reach the laboratory within 24-36 hours.
Blood samples will be collected through an indwelling intravenous cannula (Venflon) placed in the forearm 
vein of the subjects or through a fresh vein puncture. The filled vacutainer tube is slowly inverted 2-3 times to 
ensure the collected blood  mixes with the anticoagulant. This will prevent partial clotting of the samples which 
is generally seen due to improper mixing. No centrifugation will be done at investigation site. 
NP/OP Sample Collection for qPCR
The Laboratory Manual will provide details regarding collection, processing, storage and shipment for qPCR 
samples.
9.6 
Sample Size  
No statistical powering has been performed for this study. The number of subjects is designed to provide 
information on the safety, tolerability, and efficacy of the IMP tested in this study. In Part 1, approximately 64 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 43 of 72
subjects will be randomized to up to 4 cohorts of 5 consecutive days of one of the following regimens in addition 
to SOC in 2:1:1 ratio as shown below:
Treatment Arm
Day 1
Day 2
Day 3
Day 4
Day 5
Brequinar + 
Dipyridamole 
(N=8)
BRQ XX mg OD 
DPY 75 mg TID
BRQ XX mg OD 
DPY 75 mg TID
BRQ XX mg OD 
DPY 75 mg TID
BRQ XX mg OD 
DPY 75 mg TID
BRQ XX mg OD 
DPY 75 mg TID
Brequinar  
(N=4)
BRQ XX mg OD 
BRQ XX mg OD 
BRQ XX mg OD
BRQ XX mg OD 
BRQ XX mg OD 
Placebo 
(N=4)
PBO XX mg OD
PBO XX mg OD
PBO XX mg OD
PBO XX mg OD
PBO XX mg OD
The brequinar dose will start at 50 mg and may be escalated to 100 mg, 150 mg, and 200 mg if safety criteria 
are met for each cohort (see Safety Criteria below).
The hospital pharmacist is to be unblinded. Bulk supplies of investigational medicinal product (IMP) of 
brequinar 50 mg, brequinar 100 mg, dipyridamole 75 mg, brequinar placebo 50 mg and brequinar placebo 100 
mg will be supplied to the unblinded hospital pharmacist. 
The unblinded hospital pharmacist is to prepare the assigned IMP for each individual subject at that institution 
and create an appropriately labeled bottle/zip lock bag of study medication sufficient for a 5-day treatment 
course. The randomization assignment will be provided via an IWRS.
Alternatively, the hospital pharmacist and study team may decide to distribute IMP on a daily basis for 5 days 
for brequinar and dipyridamole while the subject is hospitalized, depending on the most convenient method.
9.7 
Patient identification and Randomisation 
Randomization will be carried out using SAS® (SAS Institute Inc., USA) version 9.4 or higher. Randomization 
will be done in blocks using PROC PLAN such that the design is unstructured. The treatment allocation will be 
determined according to the randomization schedule and randomization schedule will be done per cohort.
Screening and Randomization Numbering
Each subject will be assigned a unique number that will serve to identify laboratory specimens and all 
documents, and if randomized throughout the study.  If a subject fails to qualify for allocation to the study i.e. 
is a screen failure, the subject’s unique number will not be used for another subject.
Screening number will be a combination of center number, project number and subject number. The center 
number will be assigned by Veeda to the investigative site (e.g. A, B, C, D) and subsequent sites are assigned 
consecutive alphabet numbers. Upon signing the informed consent form, the subject will be assigned a screening 
number by the Investigator. At each site the first subject consented is assigned screening number e.g. A-21-
0372-001, and subsequent subjects are assigned consecutive numbers (e.g., the second subject consented is 
assigned screening number A-21-0372-002, the third subject is assigned screening number A-21-0372-003). 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 44 of 72
Once a screening number is assigned to a subject, that number will not be reused.
If the subject is deemed eligible for enrollment into the study and will commence dosing, then a randomization 
number will be assigned via IWRS as defined in the randomization plan. Subjects will be randomized with the 
next qualifying subject given the next available randomization number. 
A source document maintained at the site will link the screening number to the randomization assignment 
number (once assigned) and the same will be reflected in screening and enrollment log of Investigator site file.
The assigned subject number will be recorded in the CRF of the subject. 
The personnel involved in dispensing of study drug and verification of dispensed study drugs will be
accountable for ensuring compliance to randomization schedule. 
9.8 
Blinding 
Instructions provided in this section are a general description of operational procedures. Investigators are 
instructed to always refer to latest version of respective study plans/manuals for detailed and latest information.
The intent of blinding is to limit the occurrence of conscious and unconscious bias in the conduct and 
interpretation of the clinical study. The essential aim of blinding, therefore, is to prevent identification of the 
treatments by the Investigator and others associated with the conduct of the study until all such opportunities 
for bias have passed.
Due to unavailability of a matching dipyridamole placebo, subjects in the brequinar-dipyridamole treatment 
arm will have a daily dose of one brequinar capsule of appropriate strength and three 75 mg dipyridamole tablets 
whereas subjects in the SOC + brequinar only arm will receive only brequinar capsule(s) daily at the appropriate 
strength. Subjects in the SOC + brequnar placebo arm will receive only brequinar placebo capsule(s) daily at 
the appropriate strength. No dipyridamole placebo tablets will be provided to the subjects assigned to the 
brequinar only or brequninar placebo treatment arms.  
The Sponsor will provide investigational medicinal product (IMP) bulk drug supplies to the ThermoFisher 
depot. ThermoFisher will supply each site with bulk supplies of brequinar 50 mg and 100 mg capsules (50 count 
bottles) and dipyridamole (100 count bottles). An unblinded independent site staff member (e.g., hospital 
pharmacist) will dispense the IMP for each subject according to the assigned cohort and randomization 
schedule, and perform IMP accountability by collecting used and unused products. The unblinded pharmacist 
will not participate in the clinical trial assessments in order to minimize potential bias, and will be instructed 
not to discuss the IMP with assessors and other blinded study personnel. 
The unblinded pharmacist should use an opaque bottle or envelope to ensure that the blinded study team is not 
able to see the IMP. The subjects will be instructed not to reveal the contents of the bottle(s)/envelope(s) to the 
blinded investigator or study staff.  
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 45 of 72
The blinded investigational staff performing the assessments and data analysts (with the exception of the 
biostatistician who will undertake the generation of the randomisation scheme) will remain blinded to the 
identity of the treatment assignments for individual subjects from the time of randomization until database lock, 
using the following methods:  
x
Randomization data will be kept strictly confidential until the time of unblinding, and will not be 
accessible by anyone else involved in the study.  
x
Only the unblinded pharmacist or designate will be involved in dispensing, administering and collecting 
the study medication.  
x
Unblinding of blinded study personnel will be permitted only in the case of patient in emergency 
condition and at the conclusion of the study.   
Data 
that 
may 
potentially 
unblind 
the 
intervention 
assignment 
(i.e., 
study 
intervention 
preparation/accountability data, intervention allocation or other specific laboratory data) will be handled with 
special care to ensure that the integrity of the blinding is maintained and the potential for bias is minimized.  
Site specific randomization schedule, drug dispensing logs, drug accountability forms and other papers 
identifying treatment allocation are kept in a separate binder in a locked cupboard to which the investigators 
does not have access. Trial staff is provided training in the importance of maintaining blinding, and trial 
medication delegates/trial coordinators are also helped to set up systems at the clinic. 
Every effort must be made to limit the number of unblinded study personnel to ensure the integrity of this study.  
In the event of a Quality Assurance audit after the study has been unblinded, the auditor(s) will be allowed 
access to unblinded study intervention records at the site(s) to verify that randomization/dispensing has been 
done accurately. 
9.8.1 Unblinding of treatment assignment 
If necessary, the Investigator may be required to unblind a participant if an adverse event (AE) meets criteria in 
order to fulfill expedited regulatory reporting requirements. In this event, Investigator will inform the same to 
sponsor or its designee/study medical monitor if possible to discuss the particular situation, before breaking the 
blinding unless this could delay emergency treatment of the participant. Telephone contact with the medical 
monitor will be available 24 hours per day, 7 days per week. The Sponsor/CRO PV and/or safety review team 
will access the AE report and conclude whether unblinding is required. Once Sponsor/CRO PV and/or safety 
review team conclude that study participant requires the unblinding, Investigator will ask unblinded study 
personnel to provide the treatment sequence.  
Investigators are instructed to always refer to latest version of respective unblinding procedure manuals for 
detailed and latest information.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 46 of 72
9.8.2 Emergency unblinding of treatment assignment 
Most often, study drug discontinuation and knowledge of the possible treatment assignments are sufficient to 
treat a study participant who presents with an emergency condition. While the responsibility to break the 
intervention code in emergency situations resides solely with the evaluating investigator, it is recommended 
that the investigator contact the sponsor or its designee/study medical monitor if possible to discuss the 
particular situation, before breaking the blinding unless this could delay emergency treatment of the participant. 
Telephone contact with the medical monitor will be available 24 hours per day, 7 days per week. If a 
participant’s intervention assignment is unblinded, the sponsor must be notified within 24 hours after breaking 
the blind.  
The investigator will inform the participant how to contact his/her backup in cases of emergency when he/she 
is unavailable. The investigator will provide protocol number, study drug name if available, participant number, 
and instructions for contacting the sponsor (or any entity to which it has delegated responsibility for emergency 
code breaks) to the participant in case emergency unblinding is required at a time when the investigator and 
backup are unavailable.  
An assessment will be done by the appropriate site personnel and the Study Lead after an emergency unblinding 
to assess whether or not study drug should be discontinued for a given participant.  
In general, randomization codes will be disclosed fully only if the study is completed and the clinical database 
is closed.
9.9 
Study Duration 
Study duration will be approximately 34 days including a maximum screening period of 5 days. 
9.10Treatment  
All subjects will receive standard of care (SOC) including treatment for COVID-19 signs and/or symptoms as 
required. Study encounters may be conducted remotely or at the study site depending on visit requirements, site 
facilities and subject and study team preferences. 
9.11Clinical Safety Measures 
It is the responsibility of the investigator to ensure that adequate medical supervision and care is available for 
the study subjects during the study to ensure their utmost safety and well being. 
x
Demography (subject reported / measured height and weight, age, sex and race/ethnicity): At screening 
x
Medical history (relevant within 30 days or ongoing) / History of current illness (date of symptom onset or 
change in baseline co-morbidity thought to be due to COVID-19 infection): At screening 
x
Physical Examination (subject self-reported / examiner evaluated): At screening 
x
Vital signs (body temperature, respiratory rate, heart rate, SpO2) assessment: At screening, Day 4 (±8 hrs), 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 47 of 72
Day 8 (±8 hrs), Day 12 (± 1 day), Day 15 (±1 day), Day 22 (±1 day), End of study [EoS; Day 29 (±2 day)]. 
Note: If subject is hospitalized, Vital signs assessment will be done on daily basis by site team during 
hospitalization through Day 8 then following the Vital signs visits as listed above. 
x
Hematology, biochemistry and urine analysis: At screening, Day 1 unless same day as Screening visit, Day 
8 (±8 hrs), Day 15 (±1 day), End of study [EoS; Day 29 (±2 day)]. 
x
HCV, HbSAg, HIV Test: At screening 
x
Serum pregnancy test (Women of child bearing potential (WOCBP)): At screening. 
x
Urine pregnancy test (WOCBP): End of study [EoS; Day 29 (±2 day)]. 
Note: WOCBP: A premenopausal female capable of becoming pregnant
x
Rapid antigen test / SARS-CoV-2 RT-PCR Qualitative (in a clinically relevant specimen (Naso-Oro-
Pharyngeal as appropriate)): Screening 
Note: Test need not be repeated in those with possession of confirmed positive report. Date of positive report 
must be ≤5 days prior to randomization.
x
RT-PCR Quantitative Viral (in a clinically relevant specimen (Naso-Oro-Pharyngeal as appropriate)): Day 
1 (Prior to dosing), Day 4 (±8 hrs), Day 8 (±8 hrs), Day 12 (±1 day), Day 15 (±1 day), Day 22 (±1 day) and 
End of study [EoS; Day 29 (±2 day)] 
x
Ordinal Scale Assessment: Screening, Day 8 (±8 hrs), Day 15 (±1 day), Day 22 (±1 day) and End of study 
[EoS; Day 29 (±2 day)] 
x
Adverse events/ Serious Adverse Events: Adverse events/ Serious Adverse Events will be recorded from 
the time of first study drug administration till end of study safety assessments. Other medical events not 
related to disease condition under study and occurring before IMP administration, but after signing the 
informed consent form will be recorded on the medical history/current medical conditions of case report 
form. 
x
In addition to protocol-specific laboratory tests and/or clinical examinations at scheduled time points, 
additional tests/clinical examination may be conducted to evaluate subject safety at any time during the 
study, at the discretion of the Investigator (can be done in local laboratory or nearby 
clinic/hospital/institution). 
x
Medication taken prior to first dosing: All prescription medications and over-the-counter drugs (including 
vitamins) taken within 30 days prior to screening must be recorded in the eCRF as Medication history. 
x
Concomitant medications: Medications taken from time of signing of Informed Consent form until study 
completion (i.e. End of study) will be captured as concomitant medications. 
x
Prohibited medications: Any other antiviral medications or medication with antiviral potential.
Note:  
x
It is recommended that general precautions need to be taken by the staff caring for COVID patients during
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 48 of 72
the trial. 
x
In case the subject is hospitalized during the course of study, the activities specified in scheduled visits / 
time points will be carried out within the hospital facility.
9.12Discontinuation/ Termination of Study 
Investigator reserves the right to discontinue the study for safety reasons at any time. Ethics Committee (EC) 
and/or Regulatory Authority may ask to terminate the study, if there are major violations of ethical 
considerations or due to any serious adverse event(s). Reasons for termination of study will be provided to 
subjects. In case sponsor/PI decides to terminate the study, reason for the same will be notified to Central 
Licensing Authority within thirty working days of such termination and/or notified to EC as applicable. 
Note: In case of IMP termination, ongoing subjects will continue with standard treatment based on PI’s 
discretion.
Discontinuation of the trial at one particular centre: 
The sponsor may stop this trial at one particular centre for any of the following reasons or more: 
x
Serious and/or persistent non-compliance with the protocol 
x
False documentation in the source 
x
Inadequate co-operation with the sponsor, or its representatives 
x
Non-compliance with GCP and/or regulatory requirements 
x
The investigator requests discontinuation. 
10.0
STUDY TREATMENT 
10.1 Investigational Medicinal Product and Combination Product Dosage 
1. Brequinar 50 mg capsules (used for the 50 mg and 150 mg doses) 
2. Brequinar 100 mg capsules (used for the 100 mg, 150 mg and 200 mg doses)
3. Dipyridamole 75 mg tablets 
4. Brequinar Placebo 50 mg and 100 mg capsules 
Note: 
x
The subjects will take the study medication as directed on study days 1 – 5.  
x
Treatment assignment will be randomized, assessor-blind. 
x
IMP dispensing will be performed by an unblinded pharmacist. 
x
Study assessments will be performed by blinded Investigator or other designed blinded site personnel.
x
Brequinar and brequinar placebo doses will be administered once daily. 
x
Dipyridamole doses will be given thrice daily. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 49 of 72
x
The 150 mg brequinar or brequinar placebo dose will be given as 1 capsule of 100 mg and 1 capsule of 50 
mg; the 200 mg brequinar or brequinar placebo dose will be given as 2 capsules of  brequinar or  placebo 
100 mg. 
10.1.1 Assessment of Compliance 
Compliance for dosing at home will be captured using a patient diary card. 
10.2 Procurement, Storage and Accountability Procedures for Investigational Products 
10.2.1 Receipt and storage of investigational products 
Adequate supplies of investigational medicinal products for dosing will be distributed to the sites in bulk from 
the chosen depot. Investigational medicinal products will be stored per the storage condition supplied by 
sponsor. Certificates of analysis (COA) containing required product information will be received from sponsor. 
The hospital pharmacist will receive bulk supplies of IMP (brequinar 50 mg, brequinar 100 mg, dipyridamole 
75 mg and brequinar placebo 50 mg and 100 mg) and will be unblinded to treatment. For each individual subject, 
the hospital pharmacist will use the IWRS to assign the randomization subject numbers. Hospital pharmacist 
will create an opaque, labeled zip lock bag or bottle for IMPs as assigned for individual subjects either per day 
or for all 5 days in the requisite packaging.  
10.2.2 Accountability of investigational products 
Sites will maintain accountability of IMPs received, stored, administered and returned to CRO/ destroyed at 
site. Only subjects enrolled in the study should be administered IMP per this protocol. Investigator/ designee 
supervising the dosing will be responsible for compliance to randomization schedule at site. Overall 
responsibility of IMP accountability at the site lies with the Investigator. 
10.2.3 Handling of Unused Investigational products 
Unused IMPs will be returned to the CRO or destroyed locally (per IMP plan).  
10.2.4 Maintenance of Dispensing Record 
A copy of site-specific dispensing record will be maintained in the Site Investigator File as well as in Central 
Investigator File.
10.2.5 Concomitant medication 
Any allowable concomitant medication being taken by the subject should be continued on same dose during the 
study. Any change in the dose needs to be documented and subjects can continue in the study if the investigator 
deems proper. Administration of the following medications is not permitted after screening until after the end 
of each subject’s study participation.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 50 of 72
Prohibited Medications: 
The following concomitant medications, products or procedures will not be allowed while enrolled in the study: 
x
Hydroxychloroquine 
x
Ivermectin 
x
Immunomodulators such as tocilizumab  
x
Antiviral drugs or drugs with antiviral potential including but not limited to remdesivir 
The use of any of the above mentioned medications/procedure will result in withdrawal of the subject from the 
study. 
Note: This list of drug is not exhaustive. However, any drug which is not mentioned above and having a possible 
on study drug efficacy and safety, should be confirmed with Medical Monitor/Medical Expert.
Permissible Medications: Other than those prohibited. 
Standard treatment [(Standard Of Care (SOC)] provided in all the arms will be per the latest updated version of 
CLINICAL MANAGEMENT PROTOCOL for COVID-19 (in adults) released by Government of India 
Ministry of Health and Family Welfare Directorate General of Health Services (EMR Division). 
If drug therapy other than that specified in the protocol is required prior to or during the study period, decisions 
shall be taken by the investigator to continue or discontinue the subject based on the following: 
x
The pharmacology and pharmacokinetic of the non-study medication. 
x
The likelihood of a drug–drug interaction. 
x
The time and duration of administration of the non-study medicine. 
The start and stop date of concomitant medication use during the study should be recorded in source data. All 
such instances will be recorded and reported in the final report with details of start date, stop date and reason 
for medication use. 
11.0
EFFICACY ASSESSMENT 
Efficacy will primarily be assessed by reduction in SARS-CoV-2 RNA levels as measured by the quantitative 
RTPCR test for SARS COV2 in brequinar-dipyridamole treated subjects compared to brequinar-only and 
placebo-treated subjects through Day 29. 
Symptom improvement will be defined in the SAP. Clinical improvement for the ordinal scale will be defined 
as defined as a 2-point or greater improvement on an 8-point WHO ordinal scale in every subject measured on 
each designated day (i.e Screening, Days 1, 4, 8, 12, 15, 22, 29), until Day 29 from the date of randomization. 
This scale has been used in the current COVID-19 outbreak.    
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 51 of 72
Ordinal Scale for Clinical Improvement 
Patient State
Descriptor
Score
Uninfected
No clinical or virological evidence of infection
0
Ambulatory
No limitaion of activities
1
Limitation of activities
2
Hospitalized Mild 
disease
Hospitalized, no oxygen therapy
Oxygen by mask or nasal prongs
3
4
Hospitalized Severe 
Disease
Non-invasive ventilation or high-flow oxygen
5
Intubation and mechanical ventilation
6
Ventilation + additional organ support – pressors, RRT, ECMO
7
Dead
Death
8
12.0
SAFETY ASSESSMENT  
The study will include the following evaluations of safety and tolerability according to the time points provided 
in the 3.2 Schedule of Activities.
12.1 Demographic Characteristics  
Demographic data (subject reported / measured height and weight, age, sex and race/ethnicity) will be captured 
as specified in the 3.2 Schedule of Activities. 
12.2 Medical and Medication History 
The Investigator or his/her designee will obtain a detailed medical history and medication history as specified 
in the 3.2 Schedule of Activities.
Medical history includes clinically significant diseases within 30 days or ongoing and history of current illness 
(date of symptom onset or change in baseline co-morbidity thought to be due to COVID-19 infection).
Information on all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the participant within 30 days prior to baseline visit will be recorded 
on the CRF.  
Concomitant medications administered from screening to randomization will be recorded as a medication 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 52 of 72
history on the CRF.  
12.3 Physical Examination 
This evaluation will include an examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and basic nervous system evaluation. 
Information about the physical examination must be present in the source documentation at the study site. If 
any abnormalities are noted during the study, the participant may be referred to another doctor. The investigator 
should use his or her clinical judgment for appropriate treatment and/or medical referral. 
Clinically significant findings/abnormalities prior to the signing of ICF must be included in the relevant medical 
history/current medical conditions section of the CRF. Significant findings after the start of the IMPs that meet 
the definition of an AE must be recorded in the Adverse Event section of the CRF. Physical examination should 
be done at specified in the 3.2 Schedule of Activities. Changes from baseline abnormalities should be recorded 
in participant notes. New or worsened clinically significant abnormalities should be recorded as adverse events 
on the Adverse Event CRF. 
12.4 Vital Signs 
Vital signs will include measurements of body temperature, respiratory rate, heart rate and SpO2 taken with the 
participant in a seated position after resting for 5 minutes. Vital signs will be measured at specified in the 3.2 
Schedule of Activities. If the subject needs to be assessed remotely due to COVID-19 restrictions or for other 
reasons, the subject is to be provided with a pulse oximeter and digital thermometer. 
12.5 Abnormal Vital Sign Values  
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be reported as an adverse 
event if it meets any of the following criteria:  
x
Is accompanied by clinical symptoms  
x
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment 
discontinuation)  
x
Results in a medical intervention (e.g., potassium supplementation for hypokalemia)  
x
Is clinically significant in the investigator’s judgment  
x
Requires a change in concomitant therapy (i.e. addition of, interruption of, discontinuation of, or any other 
change in a concomitant medication, therapy or treatment) 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific judgment should be 
exercised in deciding whether an isolated vital sign abnormality should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood pressure), 
only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event CRF. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 53 of 72
Observations of the same clinically significant vital sign abnormality from visit to visit should not be repeatedly 
recorded on the Adverse Event CRF, unless the etiology changes. The initial severity of the event should be 
recorded, and the severity or seriousness should be updated any time the event worsens. 
12.6 Clinical Safety Laboratory Assessments 
Clinical laboratory tests will be performed at specified in the 3.2 Schedule of Activities. (Refer to section 26.0: 
for the list of clinical laboratory tests). 
The investigator must review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the CRF. The laboratory reports must be filed with the 
source documents. 
All laboratory tests with values considered clinically significantly abnormal during the study or within 30 days 
after the last dose of study intervention should be documented as AE. The abnormal test should be repeated 
until the values return to normal or baseline or are no longer considered clinically significant. 
x
If such values do not return to normal/baseline within a period of time judged reasonable by the investigator, 
the etiology should be identified and the sponsor notified. 
x
If laboratory values from non-protocol specified laboratory assessments performed at the institution’s local 
laboratory require a change in participant management or are considered clinically significant by the 
investigator (e.g., SAE or AE or dose modification), then the results must be recorded in the CRF. 
12.7 Other safety evaluations as appropriate and as indicated in the schedule of activities 
x
Pregnancy test (Serum and Urine): At specified in the 3.2 Schedule of Activities.
12.8  Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result should be reported as 
an adverse event if it meets any of the following criteria:  
x
Is accompanied by clinical symptoms  
x
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment 
discontinuation)  
x
Results in a medical intervention (e.g., potassium supplementation for hypokalemia)  
x
Is clinically significant in the investigator’s judgment 
x
Requiring a change in concomitant therapy (i.e. addition of, interruption of, discontinuation of, or any other 
change in a concomitant medication, therapy or treatment) 
It is the responsibility of the investigator to review all laboratory findings. Medical and scientific judgment 
should be exercised in deciding whether an isolated laboratory abnormality should be classified as an adverse 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 54 of 72
event. The investigator must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline phosphatase 
and bilirubin 5 × ULN associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the adverse event CRF.  
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality itself 
should be recorded on the adverse event CRF, along with a descriptor indicating if the test result is above or 
below the normal range (e.g., “elevated potassium,” as opposed to “abnormal potassium”).  
Observations of the same clinically significant laboratory abnormality from visit to visit should not be 
repeatedly recorded on the adverse event CRF, unless the etiology changes. The initial severity of the event 
should be recorded, and the severity or seriousness should be updated any time the event worsens. 
For each laboratory abnormality reported as an AE, the following laboratory values should be reported in the 
laboratory section of the CRF: the value indicative of the onset of each toxicity grade; the most abnormal value 
observed during the AE, and the value supporting recovery to Grade ≤1 or to baseline values. The CTCAE 
version 5 scale will be used to grade AEs including laboratory AEs. 
12.9 Handling and Reporting of Adverse Events 
An adverse event is any untoward medical occurrence (including a symptom or disease or an abnormal 
laboratory finding) during treatment with an investigational drug or a pharmaceutical product in a subject that 
does not necessarily have a relationship with the treatment being given.  
*Abnormalities based on laboratory parameters, vital signs, and 12-Lead ECG will be called AE, if they are 
associated with at least one of the following: 
x
Interruption or stoppage of the study medication  
x
Associated with signs or symptoms  
x
Requiring treatment 
x
Considered clinically significant by the investigator 
Safety Criteria: 
An independent, unblinded study physician (from CRO) will assess each cohort for safety. A cohort will be 
declared safe are as soon as all results are available for the Day 15 visit if the following conditions are met: 
x
No toxic deaths (deaths judged by the investigator to be related to either study drug); 
x
Not more than 1 toxic SAE (SAEs judged by the investigator to be related to either study drug); 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 55 of 72
x
No Grade 3 or higher toxicities (including laboratory AEs as per CTCAE version 5.0 or higher) (AEs judged 
by the investigator to be related to either study drug); 
x
<4 subjects with any grade toxicity (AEs judged by the investigator to be related to either study drug). 
In addition to the cohort-level safety, the independent study physician (from CRO) will determine if any subjects 
meet Individual Stopping Criteria:  
x
Subjects who develop a Grade 3 toxicity that is assessed by the investigator to be related to the study drug 
are to be permanently discontinued from study treatment but will continue in the study for safety 
assessments. 
x
Subjects who develop a Grade 4 toxicity, regardless of relatedness to study drug, are to be permanently 
discontinued from study treatment but will continue in the study for safety assessments. 
In addition to the individual subject-level safety, the independent study physician (from CRO) will determine 
if a cohort meets Cohort-level Stopping Criteria prior to completing the 16 subjects, in which case no additional 
subjects will be enrolled into that cohort and no higher brequinar doses will be assessed: 
x
≥3 brequinar-treated or combination-treated subjects meet the individual stopping criteria. 
x
≥5 brequinar-treated or combination-treated subjects develop a Grade 3 or higher AE regardless of 
relationship to study drug.  
Adverse Drug Reaction is a noxious and unintended response to a medicinal product related to any dose. The 
phrase responses to a medicinal product means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.  Regarding marketed 
medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally 
used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function.  
An Unexpected Adverse Drug Reaction (UADR) is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information [e.g., investigator's brochure for an unapproved 
investigational medicinal product or company core data sheet or package insert for marketed product]. 
Subjects will be monitored throughout the study period for adverse events. Subjects will be instructed to bring 
to the notice of study personnel any adverse event that may occur during the entire study period.  
The following information is to be recorded for each adverse event individually in Adverse Event Reporting 
Form. 
x
Type of adverse event* 
x
Is it serious or non-serious? 
x
Date of onset/reporting 
x
Date of onset and resolution 
x
Severity (as per section 12.12)
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 56 of 72
x
Association with the study medication (as per section 12.13)
x
Action taken 
x
Outcome of adverse event (as per section 12.14)
x
Further details of the AE, if any. 
*The investigator should attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis should be documented as the AE/SAE and not the individual 
signs/symptoms. 
For the recording of signs and symptoms, the subject will be required to report spontaneously any AEs as well 
as the intensity of these events. In addition, each subject will be asked by the investigator for AEs during vital 
signs and physical examination. All AEs including both observed and volunteered ones will be recorded in the 
Adverse Event Reporting Form, irrespective of its association with study medications. All findings considered 
clinically relevant and reportable as AE by investigator will be reported on the “Adverse event” page in the 
CRF and in the subject's medical records.  
Each AE will be evaluated for duration, severity and action taken, outcome and association with study 
medication. 
Adverse events/ Serious Adverse Events will be recorded from signing informed consent form through the end 
of the study safety assessments. Other medical events not related to study screening occurring before first dose 
administration, but after signing the informed consent form will be recorded on the medical history/current 
medical conditions of case report form.  
12.10 Serious Adverse Events (SAEs) 
A serious adverse event is any untoward medical occurrence during a study which satisfies one or more of the 
following conditions: 
x
resulting in death or 
x
permanent disability, or  
x
hospitalisation of the trial subject, or 
x
prolongation of hospitalisation, or 
x
significant disability, or  
x
incapacity, congenital anomaly, birth defect ,or  
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 57 of 72
x
life threatening event. 
The term ‘Life threatening’ refers to an event in which the subject was at immediate risk of death at the time of 
event. It does not refer to an event which may have caused death if it was more severe. 
The Investigator will be responsible to report all SAE to the central regulatory (e.g. DCGI-Central Licensing 
Authority), Sponsor’s representative and respective Ethics Committee within 24 hours of SAE 
occurrence/knowledge of occurrence if required. Investigator will be responsible for reporting the detailed 
report to the local regulatory (e.g. DCGI), chairman of the Ethics Committee and the head of the institution 
where the trial has been conducted within 14 days of SAE occurrence if required. Each AE will be evaluated 
for duration, severity, action taken, outcome and association with Investigational Medicinal Product. The study 
may be suspended or terminated depending upon the seriousness of SAEs. 
12.11 Reporting and Follow-up
The investigator must complete SAE form, verify the accuracy of the information recorded in corresponding 
source documents, and send a copy (by fax /mail) to sponsor/representative/CRO.
Investigator: 
The investigator shall report all serious adverse events (SAE) to the central licensing authority (DCGI), the 
Sponsor/CRO and chairperson of ethics committee within 24 hour of SAE occurrence, if required.  
The investigator shall report all SAE after due analysis to the central licensing authority (DCGI), chairperson 
of ethics committee and head of the institution where the trial has been conducted within fourteen days of SAE 
occurrence, if required. Subsequent follow-up information shall be reported to all stakeholders as mentioned 
above. 
In case, Investigator fails to report any SAE within stipulated period, the investigator shall have to furnish the 
reason for the delay to the satisfaction of central licensing authority along with the report of SAE. 
Sponsor or Sponsor’s Representative:
In case of SAE the Sponsor and/or CRO will be responsible for reporting the due analysis report of SAE to 
chairman of the Ethics Committee, the central licensing authority and the head of the institution where the trial 
has been conducted within 14 days of SAE occurrence, if required. 
Note: In case if SAE occurrence time and reporting time by subject to investigator is not same, investigator may 
fail to report such serious adverse event within the stipulated period. In such case Investigator shall have to 
furnish the reason for the delay to the satisfaction of the central licensing authority along with the report of the 
serious adverse event.  
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 58 of 72
Name of the sponsor representative:  
Barbara Powers, MSN, Ph.D. 
E-mail: bpowers@clearcreekbio.com
Sponsor Medical Monitor: 
John Pottage, MD 
E-mail: John.pottagemd@gmail.com
CRO contact details: 
Veeda Clinical Research Ltd. 
E-mail: safety@veedacr.com
Fax: +91-79-3001 3010 
Follow-up of Adverse Events: 
All AEs (serious or not) will be followed to resolution (the subject's health has returned to his/her baseline status 
or all variables have returned to normal or clinically acceptable level), an outcome is reached, stabilization (the 
Investigator does not expect any further improvement or worsening of the event), or the event is otherwise 
explained regardless of whether the subject is still participating in the study. Where appropriate, medical tests 
and examinations will be performed to document resolution of event(s). 
The Investigator should institute any supplemental investigations of SAE based on their clinical judgment of 
likely causative factors.  
If required, a follow-up report including all relevant new or reassessed information (e.g., concomitant treatment, 
medical history) obtained on the SAE will be prepared and same will be marked “Follow-up report”. Follow up 
reports are to be sequentially numbered to allow tracking. These reports will be sent to the sponsor/CRO. 
Adverse events occurring between informed consent and the last visit  
The investigator should follow up on all AEs which occurred from signature of study-specific informed consent 
until the last visit of the subject, at which point the outcome assessment is documented in the CRF. 
Ongoing serious adverse events at the time of last visit 
For any SAEs still ongoing at the time of last visit considered to be related to IMP, the investigator should 
continue to follow-up until the SAE has resolved or has stabilized / is judged permanent for SAEs, and for up 
to 30 days after the last visit of subject for non-related SAEs. Where appropriate, medical tests and examinations 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 59 of 72
will be performed to document resolution of event(s). The investigator should send SAE follow-up reports 
including all relevant new or reassessed information (e.g., concomitant treatment, medical history) obtained on 
the SAE /pregnancy to the sponsor/CRO. 
If a subject dies during participation in the study and an autopsy is performed, a copy of the report must be 
submitted. 
Serious adverse events occurring after the last visit 
Any SAEs experienced after the last visit should only be reported to sponsor if the investigator suspects a causal 
relationship to study treatment. The investigator must report the SADR to recipients as per the ‘SAE Reporting’ 
section 12.10.
Pregnancy Reporting: 
Pregnancy recorded for any trial participant after study drug administration should be reported immediately to 
the sponsor/representative. The subject will be withdrawn from the trial and every effort will be made to gather 
information regarding the pregnancy outcome until 8 weeks post-partum/termination of pregnancy. It will be 
the responsibility of the Investigator to obtain this information. Pregnancy recorded after screening but before 
randomization will be reported and subject will be withdrawn from the study and further follow up will not be 
done. In case of pregnancy, separate pregnancy form should be filled. Cases of pregnancy exposure associated 
with SAE and/or abnormal pregnancy outcome should be reported as per SAE reporting timelines. If any 
congenital anomaly is observed in offspring then the follow up should be conducted till six months after birth, 
if applicable. 
Ethics Committee Timelines for Reporting of SAE:  
In case of SAE, the Ethics Committee shall forward its report along with its opinion on the financial 
compensation (if any) to the licensing authority within 30 days of the occurrence of the SAE, if required.
12.12 Classification of Severity of Adverse Event 
Adverse event will be assessed for onset time, occurrence (single or repeat) and intensity. In terms of grade,  
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL*. 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation 
of hospitalisation indicated; disabling; limiting self care ADL**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 60 of 72
Grade 5: Death related to AE.
*Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
12.13Causality Assessment/Association with the Study Medication
Every effort will be made to obtain all the required information to determine whether the Adverse Event is 
related or unrelated to the study procedure or Investigational Medicinal Product (causal relationship).
In terms of relationship
Causality term 
Assessment criteria
Definite*
x
Event or laboratory test abnormality, with  plausible time relationship to drug intake 
x
Cannot be explained by disease or other drugs 
x
Response to withdrawal plausible (pharmacologically, pathologically) 
x
Event definitive pharmacologically or phenomenologically (i.e. an objective and 
specific medical disorder or a recognised  pharmacological phenomenon) 
x
Re-challenge satisfactory, if necessary 
Probable*
x
Event or laboratory test abnormality, with reasonable time relationship to drug 
intake 
x
Unlikely to be attributed to disease or other drugs 
x
Response to withdrawal clinically reasonable 
x
Re-challenge not required 
Possible*
x
Event or laboratory test abnormality, with  reasonable time relationship to drug 
intake 
x
Could also be explained by disease or other drugs 
x
Information on drug withdrawal may be lacking or unclear 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 61 of 72
Unlikely#
x
Event or laboratory test abnormality, with a time to drug intake that makes a 
relationship improbable (but not impossible) 
x
Disease or other drugs provide plausible explanations 
Not Related#
x
The AE is clearly NOT related to the study treatment
Note: #Unlikely and Not Related will be considered as Not Related. 
*Definite, Probable and Possible will be considered as Related. 
12.14 Outcome Categories 
The outcome of adverse event will be categorized as following: 
x
Recovered/ Resolved 
x
Recovering/ Resolving  
x
Recovered with sequelae/ Resolved with sequelae  
x
Not recovered/ Not Resolved 
x
Fatal 
x
Unknown 
13.0
SAMPLE PROCESSING AND TRANSFER PROCEDURES 
Clinical Laboratory Samples: 
All clinical laboratory blood and urine samples will be transferred to the central laboratory in controlled 
temperature and in pre validated laboratory kits which will be supplied to all the sites by the central laboratory. 
In case of emergency, samples can be sent to local laboratory for safety assessment at the discretion of the 
investigator. 
Pharmacokinetic (PK) samples: 
After collection of PK blood samples from all subjects at each time point, they will be centrifuged at 4000 RPM 
for 10 minutes at 5 ± 3 °C to separate plasma. For precaution purpose, the blood samples will be kept on wet 
ice bath (below 10 0C) both before centrifugation and after separation.  
The separated plasma will be transferred to pre-labeled polypropylene tubes in 2 aliquots:  
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 62 of 72
For Brequinar and Dipyridamol PK: 
Aliquot 1: Approximately 1.7 mL of plasma
Aliquot 2: Approximately 1.2 mL of plasma
Aliquot will be stored upright in a box containing dry ice or in a freezer at a temperature –15 °C or colder for 
interim storage at different investigator sites until shipment to Veeda Clinical Research Ltd., Ahmedabad, for 
analysis.
Note: Entire activity from blood sample collection to storage in a freezer should be completed within 60 minutes 
time.
During shipment the samples will be packed in thermocol boxes containing adequate amount of dry ice. The 
temperature will be monitored using calibrated data logger during shipment. Samples will then be stored at -78 
± 8 °C until completion of analysis at Veeda Clinical Research Ltd., Ahmedabad.   
Shipment for each aliquot will be carried out separately.
A designated person from bioanalytical department will receive the samples at Veeda Clinical Research Ltd., 
Ahmedabad or designate on arrival. The condition of the samples will be examined on arrival at Veeda Clinical 
Research Ltd., Ahmedabad and if any of the samples are not in a frozen condition, clinical facility and\or 
Sponsor will be informed for the same. After receiving the samples at Veeda Clinical Research Ltd., 
Ahmedabad, the samples will be stored at –78 ± 8 °C until completion of analysis.
Pharmacodynamic (PD) samples:
The PD blood samples will be centrifuged at 3500 RPM for 30 minutes at 5 ± 3°C to separate plasma. For 
precaution purpose, the blood samples will be kept on wet ice bath (below 10 0C) both before centrifugation. 
The plasma samples separated  are  to be transfeered to pre-labeled cryovials in 2 aliquots 
Aliquot 1: 2.5 mL of plasma- Primary Sample
Aliquot 2: 2.5 mL of plasma- Backup sample
Both the aliquots will be stored upright in a box containing dry ice or in a freezer at a temperature –20°C for 
interim storage at different investigator sites until shipment to Bioneeds India Private Limited, Bengaluru for 
analysis.
During shipment, primary aliquot and backup aliquots are to be separately shipped  in dry ice with data logger 
to Bioneeds, Bnagalore with necessary sample shipment documents.
Note: Samples of patients enrolled in Arm 3 (SOC + Placebo) of each cohort will not be analysed.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 63 of 72
qPCR Samples 
The qPCR samples are to be collected, processed, stored, and shipped as per the instructions in the Laboratory 
Manual.
14.0
BIOANALYTICAL PROCEDURES 
The Bioanalytical procedures will be performed at Bioanalytical facility of Veeda Clinical Research Ltd. 
Validated analytical method will be used for the PK analysis of the plasma samples.  
14.1 Method Validation 
Bioanalytical method will be validated at Veeda clinical research Ltd., which is in accordance with the 
regulatory guidelines on validation of bioanalytical methods.  
Method validations of Brequinar and Dipyridamol will be carried out by using analytical method developed at 
Veeda Clinical Research Ltd. This analytical methods will be validated for the sensitivity, specificity, matrix 
effect, linearity, ruggedness, accuracy and precision (repeatability and reproducibility), percent recovery and 
stability of samples (bench-top stability, autosampler stability, short-term, long-term stability of stock solution 
and internal standard) and effect of concomitant medications, if any. 
14.2 Assay of Samples 
The Brequinar and Dipyridamol will be quantified using a validated method. All available plasma samples of 
all subjects in the study will be analyzed as per approved protocol irrespective of withdrawn or dropped out 
from the study.  
The analysis of subject’s samples will be done using calibration curve with quality control samples, distributed 
throughout each batch. The details for the preparation of the calibration curve and quality control samples and 
the analytical batch acceptance criteria will be discussed in the respective in-house procedure. The analyst will 
not have access to the randomization schedule until analysis is completed. 
Note: Samples of patients enrolled in Arm 3 (SOC + Placebo) of each cohort will not be analysed. 
14.3 Incurred Study Sample Re-analysis 
Incurred Study Sample Re-analysis will be performed to ensure method reproducibility as per SOP (VIN-BRD-
092). 
15.0
STATISTICAL ANALYSIS 
15.1 Statistical Analysis Plan 
A statistical analysis plan (SAP) will be prepared and finalized prior to the database lock. Detailed description 
of the statistical methodology, population and handling of missing data will be described in this document. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 64 of 72
Mock tables and listings will be provided with the SAP. 
15.2 Sample Size Estimation 
There is no prospective powering in this study. The sample size was chosen to provide an adequate number of 
subjects to provide reasonable safety and efficacy data for this type of study.
15.3 Study Population for Analysis 
¾ Intent-to-treat population:  
Intent-to-treat (ITT) analysis set will include all the subjects who undergo randomization. 
¾ Safety Population: 
The safety population will include all randomized subjects who receive at least one dose of the study 
product. 
15.4 Analysis of Efficacy Data 
All statistical analysis will be done using SAS® Version 9.4 or higher (SAS Institute Inc., USA). 
For continuous variables, the summary statistics will be the number of observations, mean, standard 
deviation, median, minimum and maximum values. Categorical values will be summarized using 
frequencies and percentages. 
Primary Endpoints:  
x
Frequencies of grade 3 and 4 toxicities and serious adverse events (SAEs) considered by the investigator to 
be related to the combination, brequinar alone or placebo alone.
Because the primary study endpoint is a safety parameter no formal statistical testing will be performed for 
this parameter. 
Secondary Endpoints: 
For subjects treated with the brequinar-dipyridamole combination compared to subjects treated with the 
brequinar and to subjects treated with the placebo combination through Day 29, to determine: 
x
SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29 will be analyzed using analysis of 
covariance (ANCOVA) test; 
x
Time to symptom improvement through Day 29 will be analyzed using Kaplan-Meier time-to-event 
analysis; 
x
Percentage of subjects requiring hospital admission/re-admission as an in-patient for >24 hours through Day 
29 will be analyzed using Fisher exact / chi square test;
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 65 of 72
x
Percentage of subjects requiring medical attended visits, e.g., hospitalization, emergency room visits, Urgent 
Care/Family Doctor visits through Day 29 will be analyzed using Fisher exact / chi square test ; 
x
Percentage of subjects requiring supplemental support such as oxygen through Day 29 will be analyzed 
using Fisher exact / chi square test..   
Exploratory Endpoints:
x
Brequinar’s pharmacokinetic profile in a subset of patients that have received brequinar as a part of therapy 
and have consented to provide PK samples will  be analyzed descriptively. 
x
Effect on intracellular nucleotide pools of UTP/CTP/ATP/GTP in the subset of patients who received 
brequinar-dipyridamole combination with comparison to brequinar alone and placebo alone will be analyzed 
using an appropriate statistical method. 
15.5 Safety Analysis 
All safety analysis will be conducted using the safety population set.  
Frequency distribution or summary statistics of all demographics variable and baseline characteristics will be 
generated by treatment arm.  
The evaluation of the drug safety will be based on clinical AEs, vital signs, physical examination, concomitant 
medications and laboratory abnormalities reported during the study and incidence of adverse events and 
treatment emergent adverse events in each arm during the study. All safety presentations will include subjects
who receive at least one dose of the study medication and will group subjects by treatment received. Frequency 
distributions and individual listings of all adverse events will be generated. Changes in clinical laboratory test 
results from baseline will be listed. 
A treatment emergent adverse event is defined as any event not present prior to the initiation of the treatments 
or any event already present that worsens in either intensity or frequency following exposure to the treatments. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) terms using the 
version that is current at the time the first subjects is enrolled and will be summarized by system organ class 
(SOC) and preferred term within SOC. The Common Terminology Criteria for Adverse Events CTCAE 5.0 
will be used to grade the severity of adverse events.  
Adverse Events will be summarized by treatment and overall. AE summary tables will include counts of subjects
and the number of events. If a subject experiences more than one episode of a particular AE, that subject will 
be conducted only once for that event. If a subject has more than one AE that coded to the same preferred term, 
the subject will be counted only once for that preferred term. Similarly, if a subject has more than one AE within 
a SOC, the subject will be counted only once in that SOC. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 66 of 72
16.0
AMENDMENT TO THE PROTOCOL 
Any significant change in the study procedure or study design will only be effected upon mutual agreement 
between the Sponsor, CRO and Investigator and after obtaining a favorable opinion from the Ethics Committee 
and regulatory authority(ies). All such changes will be documented in the amended version of the protocol and 
a list of changes with reference to the previous version will be generated and submitted to the IEC and regulatory 
authorities as soon as possible. In cases where there is an immediate safety hazard to the subjects, the amended 
protocol will be effective immediately and approval of the IEC will be obtained as soon as possible. 
17.0
SOURCE DATA ACCESSIBILITY 
Quality Assurance (QA) auditors and study monitors of Veeda Clinical Research Ltd. as well as sponsor’s 
monitors, IEC and Regulatory agency(ies) will have access to raw data during inspection and audits. 
18.0
STUDY MONITORING 
Monitoring procedures developed by Veeda will be followed in order to comply with GCP guidelines and to 
ensure acceptability of the study data for national registration purposes. During the course of the study, a 
monitor from Veeda will perform site visits to review protocol compliance, compare CRFs to individual 
subject's medical records, assess drug accountability, and ensure that the study is being conducted according to 
pertinent regulatory requirements. CRF entries will be verified with source documentation. 
The Sponsor or its representative may visit the study facilities at any time in order to maintain current and 
personal knowledge of the study through review of the records, comparison with source documents, observation 
and discussion of the conduct and progress of the study.  
This clinical trial is to be conducted at Investigator sites and the Investigators should permit the different 
stakeholders for monitoring/ auditing/ inspections at their site. 
19.0
QUALITY CONTROL AND QUALITY ASSURANCE AUDITS 
Auditing procedures developed by Veeda will be followed in order to comply with GCP guidelines and to 
ensure accuracy, completeness and authenticity of the data generated, recorded and reported and acceptability 
of the study data for international registration purposes. 
 
The raw data generated during the course of the study as well as reports will undergo a random quality assurance 
process for conformance to this protocol and all the governing SOPs by the Monitors and the auditors of Veeda 
Clinical Research Ltd, respectively. The final report will contain a statement of quality assurance duly signed 
by the Head, Quality Assurance department. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 67 of 72
20.0
ETHICS 
20.1 Ethics Committee 
This protocol and corresponding informed consent Document (ICD) (containing information about the study to 
be given to subjects) to be used to obtain written informed consent of study subjects will be reviewed by IEC 
and subjects will not be enrolled into the study until IEC approves the protocol and ICD. 
The study will be conducted according to the current version of the IEC approved protocol, Relevant SOPs, 
[New Drugs & Clinical Trial Rules, 2019 of CDSCO (Central Drugs Standard Control Organization), Ministry 
of health and family welfare, Government of India], [Ethical guidelines for biomedical research on human 
participants, ICMR (Indian Council of Medical Research (2006)], [ICH (The International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use) E6 (R2) ‘Guideline for Good 
Clinical Practice’ 2016], Declaration of Helsinki – Brazil, October 2013].  
20.2 Written Informed Consent 
Investigator or designated study personnel before initiation of any study related procedure will inform the 
subject (in a language best understood by the subject) through an oral presentation regarding the purpose, 
procedures to be carried out, information on the investigational medicinal products, potential hazards, benefits 
and rights of the study subjects with maintaining adequate social distancing. Subjects will be encouraged to ask 
questions and clarify their doubts regarding any aspect of the study and the same would be documented in the 
source notes with sign and date. The ample time after completion of ICF discussion will be given to the subjects
to think and take an informed and voluntary decision. Investigator will ensure that the entire process of informed 
consent is followed as per local regulatory requirement for each subject at the respective site maintaining the 
confidentiality of subject’s personal information and all relevant records will be maintained in source file. The 
responsibility for taking informed consent must remain with that of a medically qualified person and cannot be 
delegated to a non-medically qualified person.  
Subject (or legally acceptable representative) should be present during the entire informed consent process and 
will also append his/her signatures on the informed consent form. If subject or subject’s legally acceptable 
representative is unable to read/write, an impartial witness should be present during the entire informed consent 
process, and will append his/her signatures on the informed consent form. In both the above cases, subjects will 
be required to give a thumb impression on the informed consent form. Only those subjects who are able to 
understand the ICF and able to communicate with the study personnel will be enrolled in the study. 
The subjects will give their written consent for participation in the trial by signing or by putting a thumb 
impression on the informed consent form, which will also be signed by the Investigator or his/her designate. 
If any new information becomes available during the course of the study that may be relevant to the subject’s 
willingness to continue participating in the trial, the Investigator must inform the subject in a timely manner, 
and a revised written informed consent must be obtained. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 68 of 72
Investigator will ensure that all the subject are handed over a signed and dated copy of the informed consent 
form immediately once the informed consent process is completed. 
21.0
DATA HANDLING AND RECORD KEEPING 
All clinical data generated during the conduct of the study will be entered in the source notes and will be 
transcribed in the respective CRF. All raw data and transcribed data forms compiled by the study personnel 
assisting in the study will be checked for completeness. All data related to the project will be in the custody of 
the Investigator or Project Manager until transferred to archives.  
All raw data generated during the conduct of the project compiled by the study personnel assisting in the study 
will be checked for completeness. Biostatistics department after receipt of the raw data will perform a statistical 
analysis and statistical data will be generated which will be further sent for compilation of the final clinical 
study report of the study. 
22.0
STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS 
The final report will be compiled and sent as per eCTD (Module 5) format. All copies of supplementary 
documents such as approved final version of Protocol along with all appendices, IEC approval letter, List of 
IEC members, CVs of Investigators, all subject CRFs, adverse event form (if any), Investigational Product 
Accountability records, Randomization list, Summary report of statistical analysis, protocol deviations, 
demographics and baseline characteristics and safety data will be submitted to sponsor with the final study 
report. 
23.0
ARCHIVING 
All data generated in connection with this study, together with the copy of this protocol and the audited final 
report will be archived according to the ICH guideline for good clinical practice and regulatory requirement and 
the TMF plan agreed with the Sponsor. Subject files, original source notes with Signed informed consent form 
and Patient Information Sheet (PIS), CRFs (If paper CRF has been used) and the Site Investigator File will be 
retained at individual study site as per applicable regulatory guidelines. 
All other data generated will be retained at Veeda as mentioned in Research Service Agreement. The sponsor 
will then arrange for the maintenance of these documents.   
24.0
INSURANCE POLICY 
The sponsor has a clinical trial insurance policy to cover the risks to subjects and/or any other eventualities 
pertaining to study. 
25.0
CONFIDENTIALITY OF DATA 
The data identifying each subject by name will be kept confidential and will be accessible to the study personnel 
and if necessary, to the QA auditors, IEC, Sponsor representative and Regulatory agency(ies). 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 69 of 72
Information related to COVID-19 infection may be highly sensitive in nature with a lot of scope for 
stigmatization, discrimination, violence etc. Maintaining confidentiality of research related data and its 
publication is important to protect the privacy of individuals and avoid any discrimination against them. 
26.0
PUBLICATION POLICY 
The results of the study including all data obtained will be the property of sponsor of this study. For any 
publication pertaining to the data or results of the study, a written approval of the sponsor will be obtained prior 
to communicating for publication and the manuscript will be sent for sponsor’s approval, if the sponsor asks to 
do so. 
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 70 of 72
27.0
REFERENCES 
1. CLINICAL MANAGEMENT PROTOCOL: COVID-19 released by Government of India Ministry of 
Health and Family Welfare Directorate General of Health Services (EMR Division). Version 6. Released 
on: 24.05.21
2. WHO R&D Blueprint novel Coronavirus COVID-19 Therapeutic Trial Synopsis. February 18, 2020, 
Geneva, Switzerland 
3. Declaration of Helsinki, Fortaleza, Brazil, October 2013. 
4. International Council on Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use- Good Clinical Practice (ICH-GCP) E6 (R2). 
5. Ethical Guidelines for Biomedical Research On Human Participants, Indian Council of Medical Research, 
2017.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 71 of 72
28.0
CLINICAL LABORATORY TESTS
HEMATOLOGY
Hemoglobin
Absolute WBC Counts (Neutrophils, Lymphocyte, Eosinophils, Monocyte, Basophils)
Complete Blood Counts, hematocrit, RBC count and indices
White blood cell (WBC) count, Differential Leucocyte count, Platelet count
BIOCHEMICAL PARAMETERS
SGOT (AST)
Alkaline Phosphatase
Serum Magnesium
SGPT (ALT)
Random Blood Glucose
Serum Potassium 
Total Bilirubin
Serum Cholesterol
Total Protein
Direct Bilirubin
Serum Triglyceride 
Indirect Bilirubin
Serum Creatinine
Blood urea nitrogen (BUN)
Creatinine clearance 
Pregnancy test by β-hCG Method
(for all females of child bearing 
potential)
Urea
SEROLOGY
HIV 
HbsAg 
(Hepatitis 
B 
surface 
antigen)
HCV antibodies
URINE ANALYSIS
Color
Glucose
WBC
Odor
Bilirubin
Epithelial Cells
Clarity
Blood
Casts
Specific gravity
Ketones
Crystals
pH
Urobilinogen
Bacteria
Protein
Nitrite
x
Any laboratory test, if required for adverse event management, may be performed at a local clinical 
laboratory at the discretion of Investigator.
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 01; Dated: 24 Sep 2021
Supersedes: None; Date of Supersedes: NA
Confidential                                                                                                                                                      Page 72 of 72
SIGNATURE(S) OF INVESTIGATOR(S) 
I, the undersigned, have read and understood this protocol, entitled 
“The CRISIS-04 Study: A phase II, randomized, assessor-blind, multicenter, multi-dose, placebo-
controlled study assessing the safety and anti-coronavirus response of brequinar combined with 
dipyridamole in patients with mild to moderate SARS-CoV-2 infection.”
and hereby agree to conduct the study in accordance with this protocol and to comply with all the requirements 
regarding the obligations of Investigators and all other pertinent requirements of the Ethical guidelines for 
biomedical research on human participants (ICMR) 2017 guidelines, New Drugs and Clinical Trial Rules (2019) 
of India, ICH (Step 5) ‘Guidance on Good Clinical Practice’ ICH Guidance E6 (R2), Declaration of Helsinki 
(Brazil, 2013) and with procedures oriented to Good Laboratory Practice and applicable regulatory guidelines. 
I agree to comply with all relevant SOPs required for the conduct of this study. I further agree to ensure that all 
associates assisting in the conduct of this study are informed regarding their obligations. 
___________________________________________           Date: ____________________
Investigator
Name:       
Address:   _________________________________________________________________
__________________________________________________________________________
__________________________________________________________________________
__________________________________________________________________________
Tel. No.:  ________________________________________
Fax: ____________________________________________
E-mail: __________________________________________
		



Confidential 
Confidential                                                                                                                                                      Page 1 of 80 
 
PROJECT NO.: 21-VIN-0372 
Protocol Number 
21-VIN-0372 
Protocol Title 
The CCB-CRISIS-04 Study: A phase II, randomized, assessor-blind, multicenter, 
multi-dose, placebo-controlled study assessing the safety and anti-coronavirus 
response of brequinar combined with dipyridamole in patients with mild to 
moderate SARS-CoV-2 infection. 
Study Phase 
II 
US IND Number 
149291 
Sponsor Study Code CCB-CRISIS-04 
Regulatory 
Submission 
DCGI 
Version Number 
2.1 
Protocol Date 
29 Dec 2021 
Supersedes 
02 
Date of Supersedes 
30 Sep 2021 
Sponsor 
Clear Creek Bio, Inc. 
585 Massachusetts Ave., 4th Floor 
Cambridge, MA 02139 USA 
Contract Research 
Organization 
(CRO) 
Veeda Clinical Research Ltd., 
Shivalik Plaza, Near I.I.M.,  
Ambawadi, Ahmedabad – 380 015, India 
Phone: +91-79-3001 3000 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of Sponsor (or 
under its control), and therefore provided to you in confidence as an Investigator or consultant, for review 
by you, your staff and an applicable Institutional Ethics Committee. By accepting this document you agree 
that this information will not be disclosed to others without written authorization from Sponsor except to the 
extent necessary to obtain informed consent from those persons (including their legally acceptable 
representatives as applicable) to whom the drug may be administered. 
 
	
		


RAVI ALAMCHANDANI 
2021.12.29 17:26:54 +05'30'
SUMIT ARORA 
2021.12.29 18:37:49 +05'30'
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 3 of 80
1.2 
Quality Assurance statement 
The contents of the protocol were reviewed for compliance with the applicable VIN SOPs, pertinent 
requirements of the Ethical guidelines for biomedical research on human participants (ICMR) 2017 guidelines, 
New Drugs and Clinical Trial Rules (2019) of India, ICH (Step 5) ‘Guidance on Good Clinical Practice’ ICH 
Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013) and with procedures oriented to Good Laboratory 
Practice and applicable regulatory guidelines.
Authorized signatory
Date
Name
:
Ms. Amee Kanuga
Head - Quality Assurance 
Address
:
Veeda Clinical Research Ltd.
Shivalik Plaza-A,
Near I.I.M., Opp. AMA, Ambawadi,
Ahmedabad – 380015,
Gujarat, India
Tel. No.
:
+91-79-30013000
Email ID
:
Amee.Kanuga@veedacr.com
Digitally signed by 
AMEE MILIND KANUGA 
Date: 2021.12.30 
09:16:53 +05'30'
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 4 of 80
1.3 
Sponsor’s Review & Approval
I, on behalf of Clear Creek Bio, Inc. have read, understood and approve this protocol. We agree to comply with 
all requirements of the Ethical guidelines for biomedical research on human participants (ICMR) 2017 
guidelines, New Drugs and Clinical Trial Rules (2019) of India, ICH (Step 5) ‘Guidance on Good Clinical 
Practice’ ICH Guidance E6 (R2), Declaration of Helsinki (Brazil, 2013) and with procedures oriented to Good 
Laboratory Practice guideline and other applicable regulatory guidelines.
Authorized signatory
Date
Name
:
Vikram Sheel Kumar, MD
Address
:
Clear Creek Bio, Inc.
585 Massachusetts Ave., 4th Floor
Cambridge, MA 02139 USA
Tel. No.
:
+1-671-899-8944
E-mail
:
kumar@clearcreekbio.com
	
		



Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 5 of 80
 
TABLE OF CONTENTS 
1.0
AUTHORIZATION OF PROTOCOL.................................................................................................... 2
1.1
Protocol Preparation and Authorization........................................................................................... 2
1.2
Quality Assurance statement............................................................................................................ 3
1.3
Sponsor’s Review & Approval ........................................................................................................ 4
2.0
LIST OF ABBREVIATIONS................................................................................................................. 8
3.0
PROTOCOL SUMMARY....................................................................................................................11
3.1
Synopsis .........................................................................................................................................11
3.2
Schedule of Activities ....................................................................................................................25
4.0
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................................28
4.1
Clinical Facilities ...........................................................................................................................28
4.2
Biostatistics Services and Quality Assurance ................................................................................28
4.3
Medical Experts .............................................................................................................................28
5.0
BACKGROUND INFORMATION......................................................................................................29
5.1
Introduction....................................................................................................................................29
5.2
Safety of brequinar.........................................................................................................................30
5.3
Safety of Dipyridamole..................................................................................................................31
5.4
Brequinar COVID-19 Studies........................................................................................................31
5.5
Adverse Reactions..........................................................................................................................33
5.6
Rationale ........................................................................................................................................34
5.7
Hypothesis......................................................................................................................................35
6.0
STUDY OBJECTIVE ...........................................................................................................................35
Primary Objective: ................................................................................................................................... 35
7.0
STUDY ENDPOINTS ..........................................................................................................................36
8.0
SELECTION AND WITHDRAWAL OF PATIENTS ........................................................................37
8.1
Inclusion Criteria............................................................................................................................37
8.2
Exclusion Criteria ..........................................................................................................................38
8.3
Withdrawal Criteria........................................................................................................................38
9.0
STUDY PROCEDURE.........................................................................................................................40
9.1
Study Design..................................................................................................................................40
9.2
Study Procedure .............................................................................................................................41
9.3
Hospitalization ...............................................................................................................................43
9.4
Unscheduled Visits and Early Discontinuation Visit.....................................................................43
9.5
Sample Collection Procedure.........................................................................................................43
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 6 of 80
9.6
Sample Size....................................................................................................................................44
9.7
Patient identification and Randomisation ......................................................................................45
9.8
Blinding..........................................................................................................................................46
9.8.1Unblinding of treatment assignment...............................................................................................47
9.8.2Emergency unblinding of treatment assignment.............................................................................47
9.9
Study Duration ...............................................................................................................................48
9.10 Treatment .......................................................................................................................................48
9.11 Clinical Safety Measures ...............................................................................................................48
9.12 Discontinuation/ Termination of Study..........................................................................................49
10.0 STUDY TREATMENT ........................................................................................................................50
10.1 Investigational Medicinal Product and Combination Product Dosage ..........................................50
10.1.1 Assessment of Compliance ........................................................................................................... 50
10.2 Procurement, Storage and Accountability Procedures for Investigational Products .....................50
10.2.1 Receipt and storage of investigational products ..........................................................................50
10.2.2 Accountability of investigational products..................................................................................51
10.2.3 Handling of Unused Investigational products .............................................................................51
10.2.4 Maintenance of Dispensing Record.............................................................................................51
10.2.5 Concomitant medication..............................................................................................................51
11.0 EFFICACY ASSESSMENT.................................................................................................................52
12.0 SAFETY ASSESSMENT.....................................................................................................................53
12.1 Demographic Characteristics .........................................................................................................53
12.2 Medical and Medication History....................................................................................................53
12.3 Physical Examination.....................................................................................................................53
12.4 Vital Signs......................................................................................................................................54
12.5 Abnormal Vital Sign Values..........................................................................................................54
12.6 Clinical Safety Laboratory Assessments........................................................................................54
12.7 Other safety evaluations as appropriate and as indicated in the schedule of activities..................55
12.8 Abnormal Laboratory Values.........................................................................................................55
12.9 Handling and Reporting of Adverse Events ..................................................................................56
12.10Serious Adverse Events (SAEs).....................................................................................................58
12.11Reporting and Follow-up ...............................................................................................................59
12.12Classification of Severity of Adverse Event..................................................................................61
12.13Causality Assessment/Association with the Study Medication .....................................................61
12.14Outcome Categories.......................................................................................................................62
13.0 SAMPLE PROCESSING AND TRANSFER PROCEDURES ...........................................................63
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 7 of 80
14.0 BIOANALYTICAL PROCEDURES...................................................................................................64
14.1 Method Validation .........................................................................................................................64
14.2 Assay of Samples...........................................................................................................................64
14.3 Incurred Study Sample Re-analysis ...............................................................................................65
15.0 STATISTICAL ANALYSIS.................................................................................................................65
15.1 Statistical Analysis Plan.................................................................................................................65
15.2 Sample Size Estimation .................................................................................................................65
15.3 Study Population for Analysis .......................................................................................................65
15.4 Analysis of Efficacy Data ..............................................................................................................65
15.5 Safety Analysis ..............................................................................................................................66
16.0 AMENDMENT TO THE PROTOCOL................................................................................................67
17.0 SOURCE DATA ACCESSIBILITY ....................................................................................................67
18.0 STUDY MONITORING.......................................................................................................................67
19.0 QUALITY CONTROL AND QUALITY ASSURANCE AUDITS ....................................................67
20.0 ETHICS.................................................................................................................................................68
20.1 Ethics Committee...........................................................................................................................68
20.2 Written Informed Consent .............................................................................................................68
21.0 DATA HANDLING AND RECORD KEEPING.................................................................................69
22.0 STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS ........................................................69
23.0 ARCHIVING ........................................................................................................................................69
24.0 INSURANCE POLICY ........................................................................................................................69
25.0 CONFIDENTIALITY OF DATA.........................................................................................................70
26.0 PUBLICATION POLICY.....................................................................................................................70
27.0 REFERENCES......................................................................................................................................71
28.0 CLINICAL LABORATORY TESTS...................................................................................................72
29.0 LIST OF CHANGES IN THE PROTOCOL FROM VERSION 02 TO VERSION 2.1......................73
SIGNATURE(S) OF INVESTIGATOR(S) ...................................................................................................80
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 8 of 80
2.0 LIST OF ABBREVIATIONS
AE
:
Adverse Event
ANOVA
:
Analysis of Variance
β-hCG
:
Beta-human Chorionic Gonadotropin
BA
:
Bioavailability
CBC
:
Complete Blood Count
CFR
:
Code of Federal Regulations
COA
:
Certificate of Analysis
COVID 19
:
Corona virus disease 2019
CRF
:
Case Report Form
CRO
:
Contract Research Organization
CRP
:
C-reactive protein
CTCAE
:
Common Terminology Criteria for Adverse Events
CYP
:
Cytochrome P
DCGI
:
Drug Controller General of India
EC
:
Ethics Committee
ECG
:
Electrocardiogram
ECMO
:
Extracorporeal membrane oxygenation
gm
:
Gram 
GCP
:
Good Clinical Practice
GGT
:
Gamma glutamyl transpeptidase
GLP
:
Good Laboratory Practice
HbsAg
:
Hepatitis B surface Antigen
HCV
:
Hepatitis C Virus
HIV
:
Human Immunodeficiency Virus
Hrs.
:
Hours
IB
:
Investigator Brochure
ICD
:
Informed Consent Document
ICH
:
International Council for Harmonization of Technical Requirements for Registration of 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 9 of 80
Pharmaceuticals for Human Use
ICMR
:
Indian Council of Medical Research
IMP
:
Investigational Medicinal Product
ITT
:
Intent-To-Treat
IU
:
International Unit
IUD
:
Intrauterine Device
Kg
:
Kilograms 
Ltd.
:
Limited
Mg
:
milligram
mg/dL
:
milligram/deciliter 
mL
:
Milliliter
No.
:
Number
OTC
:
Over the Counter
P/A
:
Postero-anterior 
PK
:
Pharmacokinetic
PP
:
Per protocol
PO2
:
Partial pressure of oxygen
PCO2
:
Partial pressure of carbon dioxide
QA
:
Quality Assurance
qPCR
Quantitative polymerase chain reaction to test SARS-CoV-2 viral load
RLD
:
Reference Listed Drug
RT-PCR
Reverse transcription polymerase chain reaction
SAE
:
Serious Adverse Event
SD
:
Standard Deviation
SGOT
:
Serum Glutamate Oxaloacetate Transaminase
SGPT
:
Serum Glutamate Pyruvate Transaminase
SOP
:
Standard Operating Procedure
TEAEs
:
Treatment Emergent Adverse Events
t1/2
:
The time required for the drug concentration to decrease by 50 percent from the 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 10 of 80
maximum concentration.
U
:
Units
UDS
:
Urine Drug Scan
UPT
:
Urine Pregnancy Test
USV
:
Unscheduled Visit
WBC
:
White Blood Cell
WOCBP
:
Women of child bearing potential
0C
:
Degree Celsius
0F
:
Degree Fahrenheit
%
:
Percent
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 11 of 80
3.0 PROTOCOL SUMMARY 
3.1 
Synopsis 
Title of Study:
The CCB-CRISIS-04 Study: A phase II, randomized, assessor-blind, multicenter, 
multi-dose, placebo-controlled study assessing the safety and anti-coronavirus 
response of brequinar combined with dipyridamole in patients with mild to moderate 
SARS-CoV-2 infection.
Sponsor:
Clear Creek Bio, Inc.
Clinical Study 
Centre(s):
Clinical facilities will be the clinics/ hospitals at different investigator sites across 
India.
Bio-analytical 
Study centre:
For PK analysis:
Veeda Clinical Research Ltd.
Rev. Sur. No. 12/1, Insignia, Corporate House,
Nr. Grand Bhagvati Hotel, 
Sindhu Bhavan Road, 
S. G. Highway, Bodakdev, Ahmedabad - 380054, Gujarat, India.
Phone: +91-79-67773000
Statistical Centre: 
Veeda Clinical Research Ltd. 
Shivalik Plaza, Near I.I.M., Ambawadi,
Ahmedabad–380 015, India
Phone: +91-79-3001 3000
Fax: +91-79-3001 3010
Type of Study:
Phase II study
Rationale:
Brequinar is a potent DHODH inhibitor that blocks de novo pyrimidine synthesis in the 
host and has been previously studied in more than 1,000 cancer, psoriasis, and organ 
transplant patients. 
Brequinar has potent in vitro antiviral activity against many RNA viruses including 
SARS-CoV-2. The in vitro antiviral activity of brequinar against SARS-CoV-2 is likely 
due to DHODH inhibition and shows nanomolar potency and a high selectivity index 
in inhibiting viral replication these studies. Brequinar has also been studied in two 
clinical trials in patients with confirmed SARS-CoV-2 infection. In these two studies, 
25 were hospitalized (15 treated with brequinar) and 115 were non-hospitalized (56 
treated with brequinar). Results in these 71 COVID-19 patients demonstrated that 
brequinar 100 mg x 5 days was safe and well-tolerated in these populations. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 12 of 80
Brequinar’s antiviral activity was demonstrated in the out-patient study as shown by 
decreased viral load compared to placebo at days 12, 15, 22 and 29 and a shorter 
duration of viral shedding. The strong safety data in 71 COVID-19 subjects treated 
with daily brequinar at 100 mg for 5 days provides strong support for the further 
investigation of brequinar in the treatment of COVID-19.
The antiviral effects of brequinar may be blunted in vivo by pyrimidine salvage. One 
approach to enhancing the antiviral effect of brequinar is to block the pyrimidine 
salvage pathway by combining brequinar with a pyrimidine salvage inhibitor. 
Dipyridamole has been shown in vitro to block pyrimidine salvage and may potentiate 
the antiviral activities of DHODH inhibition on RNA viruses (Liu et al., 2020). 
Blocking pyrimidine salvage via dipyridamole shows improved in vitro antiviral 
efficacy of de novo pyrimidine synthesis inhibition via DHODH inhibition and will be 
used in this study in combination with brequinar to enhance brequinar’s antiviral 
activity. 
Dipyridamole is a well-tolerated, FDA-approved medication that is a nucleoside 
transport inhibitor and PDE3 inhibitor that inhibits blood clot formation and causes 
vasodilation. Dipyridamole was first approved by the US FDA in 1961 for prevention 
of thromboembolism in patients who have had cardiac valve replacement. It has also 
been widely prescribed in combination with aspirin to prevent stroke.
The CCB-CRISIS-04 trial will study subjects who have mild to moderate COVID-19
infection confirmed by a positive SARS-CoV-2 RT-PCR qualitative test / rapid antigen 
test and have mild/moderate signs and/or symptoms ongoing at study entry. The 
purpose of this study is to determine if the antiviral activity of brequinar can be 
improved by combining brequinar with dipyridamole in patients infected with SARS-
CoV-2.
Investigational 
Product and 
Combination 
Product Dosage:
1. Brequinar 50 mg capsules (used for the 50 mg and 150 mg doses)
2. Brequinar 100 mg capsules (used for the 100 mg, 150 mg and 200 mg doses)
3. Dipyridamole 75 mg tablets
4. Brequinar Placebo 50 mg and 100 mg capsules
Note:
x
The subjects will take the study medication as directed on study days 1 – 5.
x
Treatment assignment will be randomized, assessor-blind.
x
IMP dispensing will be performed by unblinded pharmacist.
x
Study assessments will be performed by blinded Investigator or designate blinded 
site personnel.
x
Brequinar and brequinar placebo doses will be administered once daily.
x
Dipyridamole doses will be given thrice daily.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 13 of 80
x
The 150 mg brequinar or brequinar placebo dose will be given as 1 capsule of 100 
mg and 1 capsule of 50 mg; the 200 mg brequinar or brequinar placebo dose will 
be given as 2 capsules of  brequinar or brequinar placebo 100 mg.
Study Design:
The first part of the study will be a phase II, randomized, assessor-blind, multicenter,
multi-dose, placebo-controlled study in approximately 64 subjects with mild to 
moderate COVID-19 infection confirmed by a positive SARS-CoV-2 RT-PCR 
qualitative test /rapid antigen test and who have at least mild to moderate signs and/or 
symptoms ongoing at study entry. 
Approximately 32 subjects (50% of subjects per arm per cohort) at selected sites will 
be invited to participate in the “PK” arm of the study until approximately 8 subjects in 
each cohort have been recruited after providing written informed consent for the same.
PK includes brequinar and dipyridamole plasma concentrations. 
If a particular cohort meets study stopping criteria (as defined in section “Safety 
Criteria”) or is found to be unsafe by DSMB members, then the study will not proceed 
with enrollment of subsequent cohorts. 
An expansion cohort of approximately 48 subjects will be added to the cohort with the 
highest brequinar dose that meets safety criteria.
Safety data of cohort 1 to cohort 4 (or highest dose cohort evaluated) will be submitted 
to the regulators and their approval will be obtained prior to commencing recruitment 
in the expansion cohort.
All subjects will receive SOC as per relevant guidelines for treatment of patients with 
mild to moderate COVID-19 infection. 
Subjects will be randomized to one of the following cohorts in Part 1:
Cohort 1:
x
Arm 1: 5 days of standard of care (SOC) + brequinar 50 mg OD + dipyridamole 
75 mg TID (N = 8) 
x
Arm 2: 5 days of SOC + brequinar 50 mg OD (N = 4).
x
Arm 3: 5 days of SOC + brequinar placebo 50 mg OD (N = 4).
Cohort 2:
If the 50 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-
defined in the protocol the brequinar dose will be escalated to 100 mg.  
x
Arm 1: 5 days of standard of care (SOC) + brequinar 100 mg OD +
dipyridamole 75 mg TID (N = 8) 
x
Arm 2: 5 days of SOC + brequinar 100 mg OD (N = 4).
x
Arm 3: 5 days of SOC + brequinar placebo 100 mg OD (N = 4).
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 14 of 80
Cohort 3:
If the 100 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-
defined in the protocol the brequinar dose will be escalated to 150 mg:  
x
Arm 1: 5 days of standard of care (SOC) + brequinar 150 mg (100 mg + 50 mg) 
OD + dipyridamole 75 mg TID (N = 8) 
x
Arm 2: 5 days of SOC + brequinar 150 mg (100 mg + 50 mg) OD (N = 4)
x
Arm 3: 5 days of SOC + brequinar placebo 150 mg (100 mg + 50 mg) OD (N 
= 4).
Cohort 4:
If the 150 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-
defined in the protocol the brequinar dose will be escalated to 200 mg:  
x
Arm 1: 5 days of standard of care (SOC) + brequinar 200 mg (100 mg +100
mg) OD + dipyridamole 75 mg TID (N = 8) 
x
Arm 2: 5 days of SOC + brequinar 200 mg (100 mg +100 mg) OD (N = 4)
x
Arm 3: 5 days of SOC + brequinar placebo 200 mg (100 mg +100 mg) OD (N 
= 4).
Expansion Cohort:
Approximately forty-eight (48) subjects will be added to the cohort with the highest 
brequinar dose that meets safety criteria in a 2 : 1 ratio of active treatment 
(approximately 32 SOC + brequinar + dipyridamole treated and 16 SOC + brequinar 
monotherapy group). Additional sites may be added if required to meet enrollment of 
the expansion cohort in an efficient manner.
Study Duration:
Study duration will be approximately 34 days including a maximum screening period 
of 5 days.
Objectives: 
Primary Objective:
x
To characterize the safety and tolerability of the brequinar-dipyridamole 
combination in COVID-19 subjects as measured by frequencies of grade 3 and 4 
toxicities and serious adverse events (SAEs) considered by the investigator to be 
related to the combination.
Secondary Objectives:
For subjects treated with the brequinar-dipyridamole combination compared to subjects 
treated with brequinar and to subjects treated with placebo through Day 29, to 
determine:
x
Reduction of SARS-CoV-2 levels using qPCR through Day 29 and at days 4, 8, 12, 
15, 22, and 29;
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 15 of 80
x
Reduction in time to symptom improvement;
x
Reduction in percentage of subjects requiring hospital admission/re-admission as 
an in-patient for >24 hours;
x
Reduction in percentage of subjects requiring medical attended visits, e.g., 
hospitalization, emergency room visits, Urgent Care/Family Doctor visits;
x
Reduction in percentage of subjects requiring supplemental support such as 
oxygen.  
Exploratory Objectives:
x
To 
determine 
brequinar-dipyridamole 
combination 
and
brequinar’s 
pharmacokinetic profile in a subset of subjects agreeing to participate in the PK 
aspect of the study.
Study Endpoints:
Primary Endpoints: 
x
Frequencies of grade 3 and 4 toxicities and serious adverse events (SAEs) 
considered by the investigator to be related to the combination, brequinar alone or 
placebo alone.
Secondary Endpoints:
x
qPCR SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29;
x
Time to symptom improvement through Day 29;
x
Percentage of subjects requiring hospital admission/re-admission as an in-patient
for >24 hours through Day 29;
x
Percentage of subjects requiring medical attended visits, e.g., hospitalization, 
emergency room visits, Urgent Care/Family Doctor visits through Day 29;
x
Percentage of subjects requiring supplemental support such as oxygen through Day 
29.
Exploratory Endpoints (PK):
x
Analysis of brequinar’s pharmacokinetic profile in a subset of patients that have 
received brequinar as a part of therapy and have consented to provide PK samples.
Study Procedure:
To be eligible for screening, subjects must have a documented positive SARS-CoV-2
test result within 5 days of first dose of study drug and have at least one ongoing 
symptom consistent with SARS-CoV-2 infection rated as at least mild to moderate in 
the opinion of the investigator. The subject’s earliest symptom must have an onset date 
within 5 days of first dose of study drug.
Subjects will undergo screening (day -4 to 0) for confirming eligibility for participation
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 16 of 80
in the study. Study Day 1 includes randomization visit. 
Subjects will be randomized to a cohort as described above.
Screening activities as well as randomization can take place on the same day as a 
combined Screening/Day 1 visit, if the site team is able to obtain Screening lab results 
on the same day. Otherwise, Day 1 is to take place as soon as Screening lab results are 
available.
Study Day 1 and first dose of study drug must take place ≤5 days from onset of first 
symptom. 
Subjects may be hospitalized as many as 9 days in the study (day 0 to 8) or more for 
the PK sample as per Investigator discretion.
For subjects participating in the PK subset, 
Blood samples for estimating brequinar concentrations will be drawn (PK):
x
Day 1: Pre-dose (within 1 hour prior to study drug administration) and post dose at 
1h, 2h, 4h, and 8h; note that the 8h sample is to be obtained prior to the next dose 
of dipyridamole.
x
Days 2 – 5 pre-dose and Day 8.
Aliquots of the NP/OP swab samples are to be stored at the testing laboratory for 
possible additional virological testing.
Screening visit and study visits on Days 1, 8, 15, 22 and 29 will be either in person or 
a combination of in-person and virtual visit (telemedicine or other remote technique) 
or by visit to patient’s home by site team. 
Study visits on Day 4 and 12 may be virtual visits (telemedicine or other remote 
technique) or in person.
On Days 2, 3, 5, 6 and 7, the site will have a telephone call / or in-person 
communication with the subject for changes in concomitant medications and 
assessment of adverse events (same will also be captured by the subject using a patient 
diary card or these visits will be conducted in person).
Note:
x
Study procedures are presented in detail in the Schedule of Events. 
x
Days 1, 8, 15 and 29 require sample collection for performing laboratory tests and 
will be conducted at the site or via home visit. 
x
Any in-person visit may also have telemedicine or telephone components if all 
study activities cannot be completed in person.
x
The visits that include bloodwork must be conducted at the study site or 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 17 of 80
arrangements made for sample collection at the subject’s home or other appropriate 
location. 
x
Site staff (in case of an in-person visit) or subjects (in case of a remote visit) will 
assess respiratory rate, heart rate, body temperature and SpO2 (a thermometer and 
pulse oximeter are to be provided to subjects who are home quarantined, leave the 
hospital or are unable to return for study visits).
x
Subjects will record details of concomitant medications, adverse events in the 
patient diary card (PDC). 
x
Subjects will complete a symptom assessment form on designated days during the 
study period (days 1 – 8, 12, 15, 22, and 29).
x
In case the subject is hospitalized during the course of study, the activities specified 
in scheduled visits / time points will be carried out within the hospital facility. 
x
Study completion or the reason for study discontinuation will be recorded in the 
source document and the eCRF.
DSMB Meeting:
A Data Safety Monitoring Board (DSMB) will meet to review the safety and scientific 
conduct of the study. At a minimum, the DSMB will review the protocol and study 
design prior to study start, after the end of the first part of the study prior to the 
expansion phase, and at the end of the study.
At each interim meeting the DSMB members will determine whether to stop the study, 
amend the protocol, or continue the study per protocol. The study enrollment will not 
be suspended for routine DSMB meetings.
The DSMB will be convened and enrollment suspended if Cohort-Level Stopping 
Criteria are met. The DSMB may allow the enrollment to resume following their review 
if safety criteria are met.
Hospitalization:
Subjects may be hospitalized for approximately 9 days (days 0 to 8) in the study as per
Investigator discretion for the PK blood sample draws. Subjects may leave after this 
period (if medically discharged) after the Day 8 blood work has been drawn. Extended 
stays beyond study Day 8 are permitted if the facility is a dedicated COVID-19 unit or 
other relevant hospital type or if per the Investigator the extended stay facilitates study 
procedures; this continuation will not be considered as an SAE. However, prolongation 
of hospitalization due to increase in disease severity or any other safety concerns related 
to the subjects will be considered as an SAE.
Hospitalization for the purpose of PK sample collection may be done at Investigator’s 
discretion, in this case hospitalization may be for selected few days and may not be for 
entire 8 days duration. Appropriate documentation of the same will be done in source 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 18 of 80
file.
Treatment:
All subjects will receive standard of care (SOC) including treatment for COVID-19 
signs and/or symptoms as required. Study encounters may be conducted remotely or at
the study site depending on visit requirements, site facilities and subject and study team 
preferences.
Clinical Safety 
Measures:
It is the responsibility of the investigator to ensure that adequate medical supervision 
and care is available for the study subjects during the study to ensure their utmost safety 
and well being.
x
Demography (subject reported / measured height and weight, age, sex and 
race/ethnicity): At screening
x
Medical history (relevant within 30 days or ongoing) / History of current illness
(date of symptom onset or change in baseline co-morbidity thought to be due to 
COVID-19 infection): At screening
x
Physical Examination (subject self-reported / examiner evaluated): At screening
x
Vital signs (body temperature, respiratory rate, heart rate, SpO2) assessment: At 
screening, Day 4 (±8 hrs), Day 8 (±8 hrs), Day 12 (± 1 day), Day 15 (±1 day), Day 
22 (±1 day), End of study [EoS; Day 29 (±2 day)].
Note: If subject is hospitalized, vital signs assessment will be done on daily basis 
by site team during hospitalization through Day 8 then following the Vital signs 
visits as listed above.
x
Hematology, biochemistry and urine analysis: At screening, Day 1 unless same day 
as Screening visit, Day 8 (±8 hrs), Day 15 (±1 day), End of study [EoS; Day 29 (±2 
day)].
x
HCV, HbSAg, HIV Test: At screening
x
Serum pregnancy test (Women of child bearing potential (WOCBP)): At screening.
x
Urine pregnancy test (WOCBP): End of study [EoS; Day 29 (±2 day)].
Note: WOCBP: A premenopausal female capable of becoming pregnant
x
Rapid antigen test / SARS-CoV-2 RT-PCR Qualitative (in a clinically relevant 
specimen (Naso-Oro-Pharyngeal as appropriate)): Screening
Note: Test need not be repeated in those with possession of confirmed positive 
report. Date of positive report must be ≤5 days prior to randomization.
x
RT-PCR Quantitative Viral (in a clinically relevant specimen (Naso-Oro-
Pharyngeal as appropriate)): Day 1 (Prior to dosing), Day 4 (±8 hrs), Day 8 (±8 
hrs), Day 12 (±1 day), Day 15 (±1 day), Day 22 (±1 day) and End of study [EoS; 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 19 of 80
Day 29 (±2 day)]
x
Ordinal Scale Assessment: Screening, Day 8 (±8 hrs), Day 15 (±1 day), Day 22 (±1 
day) and End of study [EoS; Day 29 (±2 day)]
x
Adverse events/ Serious Adverse Events: Adverse events/ Serious Adverse Events 
will be recorded from the time of first study drug administration till end of study 
safety assessments. Other medical events not related to disease condition under 
study and occurring before IMP administration, but after signing the informed 
consent form will be recorded on the medical history/current medical conditions of 
case report form.
x
In addition to protocol-specific laboratory tests and/or clinical examinations at 
scheduled time points, additional tests/clinical examination may be conducted to 
evaluate subject safety at any time during the study, at the discretion of the 
Investigator (can be done in local laboratory or nearby clinic/hospital/institution).
x
Medication taken prior to first dosing: All prescription medications and over-the-
counter drugs (including vitamins) taken within 30 days prior to screening must be 
recorded in the eCRF as Medication history.
x
Concomitant medications: Medications taken from time of signing of Informed 
Consent form until study completion (i.e. End of study) will be captured as 
concomitant medications.
x
Prohibited medications: Any other antiviral medications or medication with 
antiviral potential.
Note: 
x
It is recommended that general precautions need to be taken by the staff caring for
COVID patients during the trial.
x
In case the subject is hospitalized during the course of study, the activities specified 
in scheduled visits / time points will be carried out within the hospital facility. 
Sample Size:
In Part 1, approximately 64 subjects will be randomized to up to 4 cohorts of 5 
consecutive days of one of the following regimens in addition to SOC in 2:1:1 ratio as 
shown below:
Treatment 
Arma
Day 1
Day 2
Day 3
Day 4
Day 5
Brequinar + 
Dipyridamole
(N=8)
BRQ XX mg OD
DPY 75 mg TID
BRQ XX mg OD
DPY 75 mg TID
BRQ XX mg OD
DPY 75 mg TID
BRQ XX mg OD
DPY 75 mg TID
BRQ XX mg OD
DPY 75 mg TID
Brequinar
(N=4)
BRQ XX mg OD
BRQ XX mg OD
BRQ XX mg OD
BRQ XX mg OD
BRQ XX mg OD
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 20 of 80
Placebo
(N=4)
PBO XX 
mgPlacebo OD
PBO XX 
mgPlacebo OD
PBO XX 
mgPlacebo OD
PBO XX 
mgPlacebo OD
PBO XX
mgPlacebo OD
aAll subjects in the study will also receive standard of care (SOC).
The brequinar dose will start at 50 mg and may be escalated to 100 mg, 150 mg, and 
200 mg if safety criteria are met for each cohort (see Safety Criteria below).
The hospital pharmacist is to be unblinded. Bulk supplies of investigational medicinal 
product (IMP) of brequinar 50 mg, brequinar 100 mg, dipyridamole 75 mg, brequinar 
placebo 50 mg and brequinar placebo 100 mg will be supplied to the unblinded hospital 
pharmacist. 
The unblinded hospital pharmacist is to prepare the assigned IMP for each individual 
subject at that institution and create an appropriately labeled bottle/zip lock bag of study 
medication sufficient for a 5-day treatment course. Randomization code will be 
supplied using an IWRS.
Alternatively, the hospital pharmacist and study team may decide to distribute IMP on
a daily basis for each of the 5 days for brequinar and dipyridamole while the subject is 
hospitalized, depending on the most convenient method.
Inclusion 
Criteria:
Subjects will be eligible if they meet all of the following 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. Subjects between ≥18 and ≤65 years of age. 
3. Subjects found positive for SARS-CoV-2 either by rapid antigen test or by reverse 
transcription polymerase chain reaction (RT-PCR) using ICMR-validated kit.
Note: Test need not be repeated in those with possession of confirmed positive 
report but positive result test date must be ≤5 days of first dose of study drug.
4. Mild or Moderate COVID-19 as per latest updated version of CLINICAL 
MANAGEMENT PROTOCOL for COVID-19 (in Adults) released by 
Government of India Ministry of Health and Family Welfare Directorate General 
of Health Services (EMR Division).
5. The effects of brequinar on the developing human fetus are unknown. For this 
reason, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately. Men and women 
treated or enrolled on this protocol must also agree to use adequate contraception 
for the duration of study participation, and for 90 days after completion of brequinar 
administration.
6. Male subjects must agree to refrain from sperm donation and female subjects must 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 21 of 80
agree to refrain from ovum donation from initial study drug administration until 90 
days after the last dose of brequinar.
7. At least one non-respiratory COVID-19 symptom characterized as mild to 
moderate by the Investigator including but not limited to fatigue, chills, fever, body 
aches, nasal congestion, nausea, vomiting, or other sign or symptom commonly 
associated with COVID-19 in the opinion of the investigator. Symptom onset must 
be ≤5 days prior to first dose. Subject must have one or more signs/symptoms 
present at first dose.
8. Willing to participate in the PK subset if at one of the identified sites.
9. Able to swallow capsules.
Exclusion 
Criteria:
Subjects will not be eligible for this study if any of the following in present at the time 
of study inclusion: 
1. Have an oxygen saturation of <90% while breathing ambient air.
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 subject.
3. Nursing women or women of childbearing potential (WOCBP) with a positive 
pregnancy test.
4. Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide) or 
other agents known to cause bone marrow suppression leading to 
thrombocytopenia.
5. Ongoing treatment with aspirin and or dipyridamole, famotidine or cimetidine. 
Remdesivir and ivermectin are prohibited through Study Day 8. Steroids are 
permitted per the guidelines.
6. Platelets ≤125,000 cell/mm3.
7. Hemoglobin <10 gm/dL.
8. Absolute neutrophil count <1000 cells/mm3.
9. Renal dysfunction, i.e., creatinine clearance <30 mL/min.
10. AST or ALT >3 x ULN, or total bilirubin >ULN. Gilbert’s Syndrome is allowed.
11. Bleeding disorders or blood loss requiring transfusion in the six weeks preceding 
enrollment.
12. Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks of first 
dose.
13. HIV, Chronic hepatitis B infection, active hepatitis C infection, active liver disease 
and/or cirrhosis per subject report.
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).
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 22 of 80
PK Sample 
Collection and 
Processing:
Blood collection and processing for PK analysis:
Brequinar/Dipyridamole PK blood samples are to be collected either through an 
indwelling intravenous cannula (Venflon or similar) or may also be collected through 
a fresh vein puncture at each time point.
For PK samples, collect a 10 mL sample using syringe/adaptor and transfer to a pre-
labelled vacutainer containing K2EDTA as anticoagulant. Immediately following blood 
collection, gently invert the vacutainer 5 - 7 times to mix the anticoagulant. Place the 
filled vacutainer on wet ice bath (below 10 0C) during sample collection activity until 
storage of plasma.
Centrifuge the PK blood sample at 4000 RPM for 10 minutes at 5 ± 3°C to separate 
plasma. Keep the samples on wet ice bath (below 10 0C) both before centrifugation and 
after separation. 
Transfer the separated plasma to pre-labeled polypropylene tubes in 2 aliquots: 
Aliquot 1: Approximately 1.7 mL of plasma
Aliquot 2: Approximately 1.2 mL of plasma
Aliquots are to be stored upright in a box containing dry ice or in a freezer at a 
temperature –15 °C or colder for interim storage at the sites until shipment to Veeda 
Clinical Research Ltd., Ahmedabad.
Note: Entire activity from blood sample collection to storage in a freezer should be 
completed within 60 minutes time.
Ship each aliquot separately. During shipment the samples are to be packed in 
thermocol boxes containing an adequate amount of dry ice. The temperature will be 
monitored using calibrated data logger during shipment. Samples will be stored at -78
± 8°C until completion of analysis at Veeda Clinical Research Ltd., Ahmedabad.
Shipment for the backup Aliquot 2 will be carried out after confirmation of receipt of 
Aliquot 1.
A designated person or designate from bioanalytical department will take receipt of the
samples at Veeda Clinical Research Ltd., Ahmedabad. The condition of the samples is 
to be examined on arrival at Veeda Clinical Research Ltd., Ahmedabad. If any of the 
samples are not in a frozen condition, clinical facility and\or Sponsor is to be informed. 
After receiving the samples at Veeda Clinical Research Ltd., Ahmedabad, the samples 
will be stored at -78 ± 8 °C until completion of analysis.
Note: Samples of patients enrolled in Arm 3 (SOC + Placebo) of each cohort will not 
be analysed.
Quantitative PCR 
(qPCR)
Obtain a NP/OP swab sample to be processed as outlined in the laboratory manual and 
sent to a central lab for analysis of quantitative PCR.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 23 of 80
Drug Analysis:
Plasma concentration of brequinar and dipyridamole will be quantified at the 
Bioanalytical facility of Veeda Clinical Research Ltd.
Safety Criteria:
An independent, unblinded study physician (from CRO) will assess each cohort for 
safety. A cohort will be declared safe are as soon as all results are available for the Day 
15 visit if the following conditions are met:
x
No toxic deaths (deaths judged by the investigator to be related to either study 
drug);
x
Not more than 1 toxic SAE (SAEs judged by the investigator to be related to 
either study drug);
x
No Grade 3 or higher toxicities (including laboratory AEs as per CTCAE 
version 5.0 or higher) (AEs judged by the investigator to be related to either 
study drug);
x
<4 subjects with any grade toxicity (AEs judged by the investigator to be related 
to either study drug).
In addition to the cohort-level safety, the independent study physician (from CRO) will
determine if any subjects meet Individual Stopping Criteria: 
x
Subjects who develop a Grade 3 toxicity that is assessed by the investigator to 
be related to the study drug are to be permanently discontinued from study 
treatment but will continue in the study for safety assessments.
x
Subjects who develop a Grade 4 toxicity, regardless of relatedness to study 
drug, are to be permanently discontinued from study treatment but will continue 
in the study for safety assessments.
In addition to the individual subject-level safety, the independent study physician (from 
CRO) will determine if a cohort meets Cohort-level Stopping Criteria prior to 
completing the 16 subjects, in which case no additional subjects will be enrolled into 
that cohort and no higher brequinar doses will be assessed:
x
≥3 brequinar-treated or combination-treated subjects meet the individual 
stopping criteria;
x
≥5 brequinar-treated or combination-treated subjects develop a Grade 3 or 
higher AE regardless of relationship to study drug.
Statistical 
methods:
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, 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 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 24 of 80
appropriate.  Any statistical testing will be considered exploratory and descriptive. All 
computations will be performed using SAS® (Version 9.4 or higher). Safety and 
tolerability will be assessed in terms of AEs, SAEs, and safety laboratory data. 
Adverse event data will be descriptively evaluated. All AEs will be reported in data 
listings. The incidence of treatment-emergent adverse events, defined as TEAEs 
occurring after first dose will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and 
relationship to study treatment. All laboratory results and other clinical measures will 
be summarized using appropriate descriptive statistics.
Ethical Issues:
The study will commence only after a written approval is obtained from the 
Institutional Ethics Committee and applicable regulatory authorities. The trial will be 
conducted as per the biomedical research on human participants (ICMR) 2017 
guidelines, New Drugs and Clinical Trial Rules (2019) of India, ICH (Step 5) 
‘Guidance on Good Clinical Practice’ ICH Guidance E6 (R2), Declaration of Helsinki 
(Brazil, 2013) and with procedures oriented to Good Laboratory Practice and 
applicable regulatory guidelines.
	
		


Protocol for clinical study of Brequinar
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 25 of 80
3.2 
Schedule of Activities 
Windows are relative to time of first dose
Procedures
Screeninga/
Day 1
(Day -4 to 0)
Day 2, 3
(± 8 hrs)
Day 4
(± 8 hrs)
Day     
5, 6, 7
(±8 hrs)
Day 8
(±8 hrs)
Day 12
(±1 day)
Day 15
(±1 day)
Day 22
(±1 day)
Final Visitk
Day 29
(±2 days)
Type of visitg
IPVf
TCf
TM
TC
IPV+TM
TM
IPV+TM IPV+TM
IPV+TM
Informed Consent (note Date and Time)
X
AE/Concomitant Medications (dose, route, duration or 
ongoing)
X
X
X
X
X
X
X
X
X
Medical history (relevant within 30 days or ongoing)/ 
History of current illness (date of symptom onset or 
change in baseline co-morbidity thought to be due to 
COVID-19 infection)
X
Demographics (subject reported/ measured height and 
weight, age, sex, race/ethnicity)
X
Check for Physical Exam abnormalities (subject self-
reported/examiner evaluated)
X
Pregnancy Test (WOCBP) (serum at Screen and urine at 
D29)
X
X
Hematology / Biochemistry / Urine Analysisj
X
Xm
X
X
X
HCV, HbSAg, HIV Test
X
Vital Signsb
X
X
X
X
X
X
X
Symptom Assessmentc
X
X
X
X
X
X
X
X
X
Rapid antigen test/SARS-CoV-2 RT-PCR Qualitatived
X
RT-PCR Quantitative Viral Loadl
X
X
X
X
X
X
X
PK Sampling (subset of subjects)h
X
X
X
X
X
Hospitalized Days 0 to 8i
Day 0
X
X
X
X
Hospital/Healthcare utilization Status
X
X
X
Ordinal Scale Assessment
X
X
X
X
X
Confirm Eligibility
3
Randomize subject and dispense Study Medication
X
Study drug administration (Days 1 – 5 only)f
X
X
X
X
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 26 of 80
Windows are relative to time of first dose
Procedures
Screeninga/
Day 1
(Day -4 to 0)
Day 2, 3
(± 8 hrs)
Day 4
(± 8 hrs)
Day     
5, 6, 7
(±8 hrs)
Day 8
(±8 hrs)
Day 12
(±1 day)
Day 15
(±1 day)
Day 22
(±1 day)
Final Visitk
Day 29
(±2 days)
Type of visitg
IPVf
TCf
TM
TC
IPV+TM
TM
IPV+TM IPV+TM
IPV+TM
Drug Accountability (Unblinded pharmacist)
X
PDC distribution
X
X
X
X
PDC collection and review
X
X
X
X
Symptom assessment form distribution
X
X
X
X
Symptom assessment form collection and review
X
X
X
X
a.
Day -4 to 0 includes screening activities.
b.
Vital signs (include heart rate, respiratory rate, body temperature, SpO2) assessment will be done at screening, Day 4 (±8 hrs), Day 8 (±8 hrs), Day 12 (± 1 
day), Day 15 (±1 day), Day 22 (±1 day), End of study [EoS; Day 29 (±2 day)]. Subjects who leave the hospital will be provided with a thermometer and 
pulse oximeter with heart rate monitoring capability. Training will be provided during the first home visit. Vital signs parameters will be observed and 
recorded by study staff via telemedicine or in-person visit (IPV) (at the study site or home visit).
Note: If subject is hospitalized, vital signs assessment will be done on daily basis by site team during hospitalization through day 8 then following the Vital 
signs visits as listed above.
c.
Symptom Assessment will capture respiratory symptoms as well as sore throat, cough, GI symptoms (vomiting, diarrhea), fatigue, anosmia, dysgeusia, 
other (specify), etc. Severity None, Mild, Moderate, or Severe will be collected. Longest symptom(s) onset date must be within 5 days of first dose.
d.
Documentation of a positive SARS-CoV-2 result from Rapid antigen test/RT-PCR or other regulatory agency-approved test is required to qualify for 
Screening. Test need not be repeated in those with possession of confirmed positive report. Date of positive report must be ≤5 days prior to randomization.
e.
Day 1 PK baseline sample must be obtained prior to dosing. 
f.
Subject will take study drug once daily Days 1 – 5 and record doses in a medication diary. Note that some visits/visit activities post hospital discharge may 
be conducted via telephone, telemedicine, or digital media other than serum pregnancy test and chemistry/hematology/PK sample collections. These labs 
may be collected at the clinical site or another designated out-patient facility/laboratory or collected via home visit.
g.
IPV= in-person visit (subject’s home or at clinical site, may also include TM or TC if all study visit activities cannot be completed by the in-person 
personnel); TC = Telephone Call with site and subject; TM = Telemedicine with site and subject. 
h.
PK Sampling: For PK, day 1 samples will be drawn pre-dose, and after dosing at 1h, 2h, 4h, and 8h (Note: 8h sample is to be obtained prior to the next dose 
of dipyridamole), and pre-dose days 2, 3, 4, 5 and on day 8. One 10 mL sample is required for PK at each timepoint.
i.
Subjects hospitalization will be based on the discretion of the Investigator. Hospitalization for the purpose of PK sample collection can be done at 
Investigator’s discretion, in this case hospitalization may be for selected few days and may not be for entire 8 days duration. Subjects may leave the hospital 
after the Day 8 samples have been obtained if medically able to be discharged. In case the subject is hospitalized during the course of study, the activities 
specified in scheduled visits / time points will be carried out within the hospital facility.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 27 of 80
j.
Sample collection for performing laboratory tests on days 1, 8, 15 and 29 will be conducted at the site or via home visit.
k.
If a study subject is discontinued from the study during an unscheduled visit, the unscheduled visit will be referred to as an Early Discontinuation Visit and 
all procedures scheduled for End of Study Visit will be performed.
l.
RT-PCR Quantitative Viral will be done at Day 1 (Prior to dosing), Day 4 (±8 hrs), Day 8 (±8 hrs), Day 12 (±1 day), Day 15 (±1 day), Day 22 (±1 day) and 
End of study [EoS; Day 29 (±2 day)]
m. Day 1 unless same day as Screening visit.
Note:
x
If the unscheduled visit is not an Early Discontinuation Visit (i.e., the study subject will continue to take part in the study), then the reason for unscheduled 
visit is to be documented and required procedures at the discretion of investigator considering the reason for visit, will be performed.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 28 of 80
4.0 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
4.1 
Clinical Facilities 
Clinical facilities will be the clinics/ hospitals of investigators’ site.
4.2 
Biostatistics Services and Quality Assurance 
Biostatistics
:
Dr. Ghanshyam Patel
Quality Assurance
:
Mrs. Amee Kanuga
Authorised Signatory
:
Dr. Sumit Arora  
Veeda clinical research Ltd.,
Shivalik Plaza, Near I.I.M., Ambawadi, Ahmedabad – 380 015, India.
Phone No.: +91-79-3001 3000
4.3 
Medical Experts 
Veeda’s Medical Expert:
Sponsor’s Medical Expert:
Dr. Ravi Alamchandani
Veeda Clinical Research Ltd.,
Shivalik Plaza, 
Near I.I.M., Ambawadi, 
Ahmedabad – 380 015, India.
Phone No.: +91-79-3001 3000
E-mail: Ravi.A1950@veedacr.com
John Pottage, MD
Phone No: +1-610-761-0840
E-mail: John.pottagemd@gmail.com
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 29 of 80
5.0 BACKGROUND INFORMATION 
5.1 
Introduction 
Coronaviruses are large group of viruses that cause illness in humans and animals. Rarely, animal coronaviruses 
can evolve and infect people and then spread between people such as has been seen with MERS and SARS. 
The current outbreak of novel coronavirus disease (COVID-19) was initially noticed in Wuhan city in Hubei 
Province of China in mid December, 2019 has now spread to 215 countries/territories/areas worldwide. WHO 
(under International Health Regulations) has declared this outbreak as a “Public Health Emergency of 
International Concern” (PHEIC) on 30th January 2020. WHO subsequently declared COVID- 19 a pandemic 
on 11th March, 2020.
Pathophysiology of COVID 19: 
Most adult patients with COVID-19 predominantly have a respiratory tract infection associated with SARS-
CoV-2 infection. However, in a small proportion of cases, the disease can progress to a more severe stage 
characterized by a dysregulated immune response with hyperinflammation with subsequent development of 
ARDS.  
Clinical Features: 
COVID-19 patients reporting to various COVID-19 treatment facilities have reported the following signs and 
symptoms: 
x
Fever, 
x
cough, 
x
general weakness/ fatigue, 
x
headache, 
x
myalgia, 
x
sore throat, coryza, 
x
dyspnoea, 
x
anorexia/nausea/vomiting, 
x
diarrhoea, 
x
altered mental status. 
x
loss of smell (anosmia) or loss of taste (ageusia) preceding the onset of respiratory symptoms has also been 
reported. 
Older people and immune-suppressed patients in particular may present with atypical symptoms such as fatigue, 
reduced alertness, reduced mobility, diarrhoea, loss of appetite, delirium, and absence of fever.  
Diagnosis of COVID 19: 
COVID-19 diagnosis is currently based on using a reverse transcriptase polymerase chain reaction (RT-PCR) 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 30 of 80
assay to detect viral RNA in respiratory samples. The high specificity of RT-PCR removes the need for lower 
respiratory tract samples to diagnose COVID-19 when a nasopharyngeal swab is positive for a patient with 
recent onset of the disease.  
5.2 
Safety of brequinar 
Introduction: 
Brequinar is an orally available and potent inhibitor of dihydroorotate dehydrogenase (DHODH). DHODH 
catalyzes the fourth step in pyrimidine synthesis, the conversion of dihydroorotate (DHO) to orotate. DHODH 
inhibitors, including brequinar, inhibit de novo pyrimidine synthesis thereby leading to a depletion of the 
cellular pool of uridine, cytidine, and thymidine ribonucleotides and deoxyribonucleotides. Brequinar has 
previously been evaluated for the treatment of hematologic malignancies, autoimmune disorders and COVID 
19. There are other DHODH inhibitors that have been approved for use in the treatment of rheumatoid arthritis 
and multiple sclerosis. 
Brequinar has been shown to have significant in vitro antiviral activity against several RNA viruses, including 
SARS-CoV-2, the cause of COVID-19 disease. As RNA viruses cannot synthesize their own ribonucleotides, 
they depend upon the host intracellular pool of ribonucleotides as the source for viral gene expression and 
replication. By transiently depleting the pool of host of pyrimidines, DHODH inhibition denies a virus of its 
source of ribonucleotide building blocks and thereby suppresses viral replication. This antiviral strategy 
targeting a host rather than viral protein also is less likely to select for resistant viruses. 
Preclinical study data: 
Initial nonclinical pharmacology studies of brequinar confirmed that its mechanism of action is the inhibition 
of de novo pyrimidine synthesis. Further studies with partially purified enzymes isolated from L1210 cells 
showed that brequinar inhibited DHODH activity, the fourth biochemical step in pyrimidine synthesis
Clinical study data: 
Brequinar has been studied under FDA IND 149,291 in 138 patients in two studies as an antiviral for coronavirus 
disease 2019 (COVID-19); 71 of these patients were treated with brequinar. Brequinar was administered as a 
single daily dose for five consecutive days with standard of care (SOC) in these COVID-19 studies.
Brequinar has also been previously studied in more than 1,000 patients in 30 clinical trials for treatment of solid 
tumors, psoriasis, and organ transplant. More recently Clear Creek Bio has studied brequinar use for acute 
myeloid leukemia (AML). In the oncology, psoriasis and organ transplant studies brequinar was administered 
as a single dose and as multiple courses with once weekly, twice weekly, single dose every 3 weeks, daily times 
5 every 4 weeks, and daily times 21 days regimens. The maximum single intravenous dose of 3250 mg/m2 was 
administered in an oncology study; the maximum oral dose of 950 mg/m2 twice weekly was also dosed during 
an oncology study. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 31 of 80
5.3 
Safety of Dipyridamole 
Introduction: 
Dipyridamole was first approved for use in 1961 as an adjunct to coumarin anticoagulants in the prevention of 
postoperative thromboembolic complications of cardiac valve replacement. The primary therapeutic actions of 
dipyridamole relate to its activity in (1) inhibiting platelet function and aggregation and (2) vasodilatation. 
Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in 
vivo; the inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5−1.9 μg/mL). This 
inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-receptor 
thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate 
(cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as 
platelet activating factor (PAF), collagen and adenosine diphosphate (ADP). 
Dipyridamole also inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is 
weak, therapeutic levels of dipyridamole inhibit cyclic-3',5'-guanosine monophosphate-PDE (cGMP-PDE), 
thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now 
identified as nitric oxide). 
Preclinical study data: 
In addition to the effects upon platelet function, dipyridamole can cause vasodilatation.  
Hemodynamics: 
In dogs intraduodenal doses of dipyridamole of 0.5 to 4.0 mg/kg produced dose-related decreases in systemic 
and coronary vascular resistance leading to decreases in systemic blood pressure and increases in coronary 
blood flow. Onset of action was in about 24 minutes and effects persisted for about 3 hours. 
Similar effects were observed following intravenous dipyridamole in doses ranging from 0.025 to 2.0 mg/kg. 
In man the same qualitative hemodynamic effects have been observed. However, acute intravenous 
administration of dipyridamole may worsen regional myocardial perfusion distal to partial occlusion of 
coronary arteries. 
5.4 
Brequinar COVID-19 Studies 
CCB-CRISIS-01 in Hospitalized Patients 
The CRISIS-01 trial studied standard of care (SOC) and SOC with 5 days of brequinar administration in patients 
hospitalized for treatment of COVID-19. This was a phase 1 randomized, open label, multi-center study 
designed to enroll approximately 24 subjects. All subjects received SOC per institutional guidelines for 
treatment of patients with SARS-CoV-2 infection. In addition to SOC, the brequinar group received brequinar 
100 mg as an oral capsule once daily for 5 days. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 32 of 80
A total of 25 subjects were randomized in study CRISIS-01 at 5 sites. Two subjects assigned to the SOC plus 
brequinar group were randomized but withdrew consent and were never treated with brequinar. The modified 
Intent-to-Treat (mITT) population which was used for all study analyses included all 23 randomized subjects 
who had at least one post-randomization assessment, and who received at least one dose of study medication if 
randomized to the SOC plus brequinar group. A total of 15 subjects were exposed to SOC plus brequinar and 8 
subjects had SOC treatment only. 
Brequinar was generally safe and well-tolerated in this population. No subjects discontinued study drug 
treatment due to an AE. No subjects died. 4 subjects (17.4%) experienced a total of 6 SAEs (1 in the SOC + 
brequinar group and three in the SOC only group). 12 subjects (52.2%) experienced a total of 28 treatment 
emergent AEs (TEAEs); 10/15 subjects (66.7%) reported 22 TEAEs in the SOC plus brequinar group; 2/8 
(25.0%) reported 6 TEAEs in the SOC only group. The most common TEAE was hyperglycaemia reported in 
3 subjects (20.0%) in the SOC plus brequinar group. Increased ALT was experienced by 2 subjects (13.3%) in 
the SOC plus brequinar group in subjects who had also received remdesivir. No other AEs were reported for 
more than one subject in either treatment group.
CCB-CRISIS-02 in Non-Hospitalized Patients 
The CRISIS-02 trial: A phase 2, randomized, double blind, placebo-controlled, multi-center study assessing the 
safety and anti-coronavirus response of suppression of host nucleotide synthesis in out-patient adults with 
SARS-CoV-2.
The CRISIS-02 trial studied outpatients (non-hospitalized patients) who had a positive SARS-CoV-2 RT-PCR 
test using a saliva sample and were symptomatic. Subjects were randomized to receive SOC + 5 days of 
brequinar or SOC + 5 days of placebo. The purpose of this study was to determine if the in vitro antiviral activity 
of brequinar translated to patients infected with SARS-CoV-2 by measuring the effect of treatment with 
brequinar on SARS-CoV-2 RNA levels (henceforth called “viral load”). 
The study enrolled 115 subjects (56 in the SOC plus brequinar group and 59 in the SOC plus placebo group). 
All subjects received SOC for treatment of patients with COVID-19 infection. In addition to SOC, the subjects 
self-administered one capsule of brequinar or placebo once daily for 5 days. Subjects were randomly assigned 
in a 1:1 ratio to SOC plus brequinar or SOC plus placebo. 
The median decrease in viral load was higher in the SOC plus brequinar group beginning at Day 12 (Days 12, 
15, 22, and 29). None of the comparisons to placebo reached statistical significance. None of the other efficacy 
endpoints showed a difference between the SOC plus brequinar compared to the SOC plus placebo treatments. 
There was no effect in reducing the time to clinical symptom resolution, however the majority of patients had 
very mild disease making improvements difficult to assess. 
Brequinar was safe and well-tolerated in this population. No subjects discontinued study drug treatment or 
discontinued from the study due to an AE. No subjects died. One subject in the brequinar plus SOC group 
(1.8%) experienced one non-study-drug-related SAE (admitted to hospital for COVID-19 pneumonia). A total 
of 23 subjects (52.2%) experienced a total of 28 TEAEs; 10/56 subjects (17.9%) reported 22 TEAEs in the SOC 
plus brequinar group; 13/59 (22.0%) reported 6 TEAEs in the SOC plus placebo group. AEs were experienced 
by one subject only with the exceptions of nausea and rash each of which were experienced by two subjects. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 33 of 80
The majority of AEs were mild or moderate; there was one subject (1.8%) with a non-related Grade 3 AE in the 
SOC plus brequinar group (COVID-19 pneumonia) and 3 subjects with Grade 3 AEs in the SOC plus placebo 
group (chills, pain, injury and breast pain); all of the related AEs were considered Mild (Grade 1) by the 
investigators. There were no Grade 4 or higher AEs in either treatment group.
A total of 6 subjects had AEs considered possibly related to treatment, 3 in each group. 
5.5 
Adverse Reactions 
 
Brequinar: 
As discussed above, brequinar is an investigational drug that has been given to 71 patients with COVID-19. 
Adverse events related to brequinar were mild to moderate and infrequent, and no subjects discontinued 
brequinar treatment due to a related adverse event in either of the two COVID-19 studies. 
Brequinar has also been given to more than 800 patients with various forms of cancer in more than 20 clinical 
trials and has also been tested in patients with psoriasis and those who have had a kidney or liver transplant. 
The most common side effects in cancer patients when given higher doses of brequinar have been: 
x
Thrombocytopenia, which may require replacement.  Low platelet count can lead to bruising, nose bleeds, 
vomiting blood, bloody diarrhea, blood in the urine, bloody gums, coughing up blood, and taking longer to 
stop bleeding from cuts.  
x
Stomatitis/mucositis. 
x
Other risks associated with brequinar include: 
o
Skin rash, 
o
Nausea, 
o
Vomiting, 
o
Diarrhea, 
o
Leukopenia, 
o
Anemia,  
o
Yellowing of the skin or whites of the eyes caused by high levels of the pigment bilirubin, 
o
Abnormal liver tests, 
o
Abnormal kidney function, 
o
Cardiac complications, and  
o
Fatigue  
Some of these side effects were severe enough in patients treated with brequinar to require hospitalization or 
caused death. In most cases, these side effects went away within about 2 weeks after patients stopped taking 
brequinar.  
Patients must be contact to study doctor/study staff if they experience any of the following: 
x
Discoloration/bruising of the skin or a rash of red/purple spots on your skin. These can be caused by bleeding 
in or under the skin, 
x
Nose bleed, 
x
Coughing up blood, 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 34 of 80
x
Blood in urine,
x
Bleeding gums,
x
Prolonged bleeding time from needle sticks, abrasions or lacerations,
x
Vomiting blood,
x
Rectal bleeding, 
x
Blood in stool, 
x
Any other unusual bleeding  
Dipyridamole:
Dipyridamole will be used in this study as a pyrimidine salvage inhibitor when co-administered with brequinar 
(see Rationale below). When used per the labeled indications of stroke prevention and inhibitor of blood clot 
formation, adverse reactions at therapeutic doses are usually minimal and transient. In combination with 
warfarin, the dipyridamole label reports dizziness (13.6%), abdominal distress (6.1%), headache (2.3%), and 
rash (2.3%). Reactions from uncontrolled studies include diarrhea, flushing, and pruritus. Angina pectoris has 
been reported rarely and there have been rare reports of liver dysfunction. In post-marketing reporting 
experience, there have been rare reports of hypersensitivity reactions (such as rash, urticaria, severe 
bronchospasm, and angioedema), larynx edema, fatigue, malaise, myalgia, arthritis, nausea, dyspepsia, 
paresthesia, hepatitis, thrombocytopenia, alopecia, cholelithiasis, hypotension, palpitation, and tachycardia. In 
the case of real or suspected overdose, symptoms may occur such as warm feeling, flushes, sweating, 
restlessness, and feeling of weakness and dizziness. There is an increased risk of thrombocytopenia when taking 
dipyridamole. There are no clinical data to suggest that dipyridamole is beneficial for treating COVID-19.
Co-Administration of Brequinar and Dipyridamole:
This combination has not previously been tested in the clinic. There is a potential for increased bleeding when 
taking either drug as well as the combination, and the risk compared to brequinar or dipyridamole when 
administered alone is unknown. To address any potential increased risk, careful attention will be paid to 
laboratory reports and any increased signs or symptoms of bleeding during this study.
5.6
Rationale
Rationale for the use of brequinar and dipyridamole in COVID-19 disease:
Brequinar is a potent DHODH inhibitor that blocks de novo pyrimidine synthesis in the host and has been 
previously studied in more than 1,000 cancer, psoriasis, and organ transplant patients. 
Brequinar has potent in vitro antiviral activity against many RNA viruses including SARS-CoV-2. The in vitro
antiviral activity of brequinar against SARS-CoV-2 is likely due to DHODH inhibition and shows nanomolar 
potency and a high selectivity index in inhibiting viral replication these studies. Brequinar has also been studied 
in two clinical trials in patients with confirmed SARS-CoV-2 infection. In these two studies, 25 were 
hospitalized (15 treated with brequinar) and 115 were non-hospitalized (56 treated with brequinar). Results in 
these 71 COVID-19 patients demonstrated that brequinar 100 mg x 5 days was safe and well-tolerated in these 
populations. Brequinar’s antiviral activity was demonstrated in the out-patient study as shown by decreased 
viral load compared to placebo at days 12, 15, 22 and 29 and a shorter duration of viral shedding. The strong 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 35 of 80
safety data in 71 COVID-19 subjects treated with daily brequinar at 100 mg for 5 days provides strong support 
for the further investigation of brequinar in the treatment of COVID-19.  
The antiviral effects of brequinar may be blunted in vivo by pyrimidine salvage. One approach to enhancing the 
antiviral effect of brequinar is to block the pyrimidine salvage pathway by combining brequinar with a 
pyrimidine salvage inhibitor. Dipyridamole has been shown in vitro to block pyrimidine salvage and may 
potentiate the antiviral activities of DHODH inhibition on RNA viruses (Liu et al., 2020). Blocking pyrimidine 
salvage via dipyridamole shows improved in vitro antiviral efficacy of de novo pyrimidine synthesis inhibition 
via DHODH inhibition and will be used in this study in combination with brequinar to enhance brequinar’s 
antiviral activity.  
Dipyridamole is a well-tolerated, FDA-approved medication that is a nucleoside transport inhibitor and PDE3 
inhibitor that inhibits blood clot formation and causes vasodilation. Dipyridamole was first approved by the US 
FDA in 1961 for prevention of thromboembolism in patients who have had cardiac valve replacement. It has 
also been widely prescribed in combination with aspirin to prevent stroke. There is no clinical evidence that 
dipyridamole used alone is effective for treating SARS-CoV-2.
The CCB-CRISIS-04 trial will study subjects who have mild to moderate COVID-19 infection confirmed by a
positive SARS-CoV-2 RT-PCR qualitative test / rapid antigen test and have mild/moderate signs and/or 
symptoms ongoing at study entry. The purpose of this study is to determine if the antiviral activity of brequinar 
can be improved by combining brequinar with dipyridamole in patients infected with SARS-CoV-2.
5.7 
Hypothesis 
Treatment with brequinar combined with dipyridamole in patients with SARS-CoV-2 viral infection will reduce 
viral load, decrease time to resolution of COVID-19-related clinical signs and/or symptoms and improve clinical 
outcomes compared with current standard care.
6.0 STUDY OBJECTIVE 
Primary Objective: 
x
To characterize the safety and tolerability of the brequinar-dipyridamole combination in COVID-19 subjects 
as measured by frequencies of grade 3 and 4 toxicities and serious adverse events (SAEs) considered by the 
investigator to be related to the combination.
Secondary Objectives:
For subjects treated with the brequinar-dipyridamole combination compared to subjects treated with brequinar 
and to subjects treated with placebo through Day 29, to determine: 
x
Reduction of qPCR SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29; 
x
Reduction in time to symptom improvement; 
x
Reduction in percentage of subjects requiring hospital admission/re-admission as an in-patient for >24 
hours;
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 36 of 80
x
Reduction in percentage of subjects requiring medical attended visits, e.g., hospitalization, emergency room 
visits, Urgent Care/Family Doctor visits;
x
Reduction in percentage of subjects requiring supplemental support such as oxygen.  
Exploratory Objectives:
x
To determine brequinar-dipyridamole combination and brequinar’s pharmacokinetic profile in a subset of
subjects agreeing to participate in the PK aspect of the study.
7.0 STUDY ENDPOINTS
Primary Endpoints: 
x
Frequencies of grade 3 and 4 toxicities and serious adverse events (SAEs) considered by the investigator to 
be related to the combination, brequinar alone or placebo alone.
Secondary Endpoints:
x
qPCR SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29;
x
Time to symptom improvement through Day 29;
x
Percentage of subjects requiring hospital admission/re-admission as an in-patient for >24 hours through Day 
29;
x
Percentage of subjects requiring medical attended visits, e.g., hospitalization, emergency room visits, Urgent 
Care/Family Doctor visits through Day 29;
x
Percentage of subjects requiring supplemental support such as oxygen through Day 29.  
Exploratory Endpoints (PK):
x
Analysis of brequinar’s pharmacokinetic profile in a subset of patients that have received brequinar as a part 
of therapy and have consented to provide PK samples.
Clinical improvement will be defined as a 2-point or greater improvement on an 8-point WHO ordinal scale in 
every subject measured on each designated day, from the date of randomization through day 29. This scale has 
been used in the current COVID-19 outbreak.   
Ordinal Scale for Clinical Improvement
Patient State
Descriptor
Score
Uninfected
No clinical or virological evidence of infection
0
Ambulatory
No limitaion of activities
1
Limitation of activities
2
Hospitalized
Hospitalized, no oxygen therapy
3
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 37 of 80
Mild disease
Oxygen by mask or nasal prongs
4
Hospitalized 
Severe Disease
Non-invasive ventilation or high-flow oxygen
5
Intubation and mechanical ventilation
6
Ventilation + additional organ support – pressors, RRT, ECMO
7
Dead
Death
8
8.0 SELECTION AND WITHDRAWAL OF PATIENTS
Subjects will be selected on the basis of the following inclusion and exclusion criteria.
8.1
Inclusion Criteria
Subjects will be eligible if they meet all of the following 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. Subjects between ≥18 and ≤65 years of age. 
3. Subjects found positive for SARS-CoV-2 either by rapid antigen test or by reverse transcription polymerase 
chain reaction (RT-PCR) using ICMR-validated kit.
Note: Test need not be repeated in those with possession of confirmed positive report but positive result test 
date must be ≤5 days of first dose of study drug.
4. Mild or Moderate COVID-19 as per latest updated version of CLINICAL MANAGEMENT PROTOCOL 
for COVID-19 (in Adults) released by Government of India Ministry of Health and Family Welfare 
Directorate General of Health Services (EMR Division).
5. The effects of brequinar on the developing human fetus are unknown. For this reason, women of child-
bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform 
her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to 
use adequate contraception for the duration of study participation, and for 90 days after completion of 
brequinar administration.
6. Male subjects must agree to refrain from sperm donation and female subjects must agree to refrain from 
ovum donation from initial study drug administration until 90 days after the last dose of brequinar.
7. At least one non-respiratory COVID-19 symptom characterized as moderate to severe by the Investigator 
including but not limited to fatigue, chills, fever, body aches, nasal congestion, nausea, vomiting, or other 
sign or symptom commonly associated with COVID-19 in the opinion of the investigator. Symptom onset 
must be ≤5 days prior to first dose. Subject must have one or more signs/symptoms present at first dose.
8. Willing to participate in the PK subset if at one of the identified sites.
9. Able to swallow capsules.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 38 of 80
8.2 
Exclusion Criteria
Subjects will not be eligible for this study if any of the following in present at the time of study inclusion:  
1. Have an oxygen saturation of <90% while breathing ambient air.
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 subject.
3. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test. 
4. Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide) or other agents known to cause 
bone marrow suppression leading to thrombocytopenia.
5. Ongoing treatment with aspirin and or dipyridamole, famotidine or cimetidine. Remdesivir and ivermectin 
are prohibited through Study Day 8. Steroids are permitted per the guidelines.
6. Platelets ≤125,000 cell/mm3.
7. Hemoglobin <10 gm/dL.
8. Absolute neutrophil count <1000 cells/mm3.
9. Renal dysfunction, i.e., creatinine clearance <30 mL/min.
10. AST or ALT >3 x ULN, or total bilirubin >ULN. Gilbert’s Syndrome is allowed.
11. Bleeding disorders or blood loss requiring transfusion in the six weeks preceding enrollment. 
12. Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks of first dose. 
13. HIV, Chronic hepatitis B infection, active hepatitis C infection, active liver disease and/or cirrhosis per 
subject report. 
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).
8.3 
Withdrawal Criteria 
Subjects may voluntarily withdraw from the study at any time without assigning any reason thereof by 
withdrawing their consent. They may be considered withdrawn if they state an intention to withdraw, or fail to 
return for visits, or become lost to follow up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must determine the primary reason for a patient’s 
premature withdrawal from the study and record this information in the CRF. For patients who are lost to follow-
up (i.e., those patients whose status is unclear because they fail to appear for study visits without stating an 
intention to withdraw), the investigator should show "due diligence" by documenting in the source documents 
steps taken to contact the patient, e.g., dates of telephone calls, other means of communication even though 
patient is unwilling to attend further visits etc.  
If study participation is discontinued, the final evaluation will be performed as completely as possible. Any 
comments (spontaneous or elicited) or complaints made by the patient and the reason for termination, date of 
stopping the study medication and the total amount of study medication must be recorded in the source 
documents or CRFs. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 39 of 80
Criteria for a withdrawal of patients from clinical study: 
The subject may be withdrawn from the trial at the discretion of the investigator or the sponsor, if judged non-
compliant with trial procedures or due to safety concern.  
A subject must in addition be withdrawn from treatment with IMP if the following applies: 
x
AE requiring permanent discontinuation of study drug. 
x
The subject suffers from significant intercurrent illness or undergoes surgery requiring study discontinuation 
during the course of the study. 
x
Any subject who requires the use of an unacceptable concomitant medicine. 
x
If the Investigator believes it is not in the subject’s best interest to continue.
x
The subject wishes to withdraw his/her consent. 
x
Any other justifiable reason, which should be adequately documented. 
x
Any subject whose condition worsens, requiring treatment with immunomodulators including but not 
limited to tocilizumab and / or antiviral drugs including but not limited to remdesivir as per the best 
judgement of the Investigator. 
x
Non-compliance: The participant may be withdrawn from the trial at the discretion of the Investigator if it 
is judged that participant is non-compliant to study assessment and schedule leading to safety concerns.  
x
Positive pregnancy test: A female participant with a positive pregnancy test will be withdrawn from the 
trial. 
The sponsor or its representative may be contacted for clarification as required on a case-by case basis.  
Handling of Withdrawals: 
In the case of premature discontinuation of study subject, the investigator should schedule a study 
discontinuation visit to complete all assessment according to End of Study / Early Termination visit 
requirements. All reasons for ending participation must be recorded in the source documents or in the CRF.  
If the subject discontinues because of an adverse event (serious or non-serious), the investigator must follow up 
patient’s recovery until resolution or stabilization of AEs or up to 30 days after administration of last dose of 
IMP, whichever is earlier. 
This visit should be documented in the appropriate section of the Case Report Form (CRF). The investigator 
will record the reason for study discontinuation, provide or arrange for appropriate follow-up for such subjects, 
and document the course of the subject’s condition. In addition, the investigator will report the subject’s 
withdrawal to the responsible study monitor immediately.   
Subjects withdrawn from investigational product treatment will be treated as routine subjects. The investigator 
will discuss the appropriate therapy with each subject who withdraws early from this study. Determination of 
the appropriate follow-on therapy will be left to the discretion of the investigator and investigator could treat 
such subjects as per his/her routine practice. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 40 of 80
9.0 STUDY PROCEDURE  
9.1 
Study Design 
The first part of the study will be a phase II, randomized, assessor-blind, multicenter, multi-dose, placebo-
controlled study in approximately 64 subjects with mild to moderate COVID-19 infection confirmed by a 
positive SARS-CoV-2 RT-PCR qualitative test /rapid antigen test and who have at least mild to moderate signs 
and/or symptoms ongoing at study entry.  
Approximately 32 subjects (50% of subjects per arm per cohort) at selected sites will be invited to participate 
in the “PK” arm of the study until approximately 8 subjects in each cohort have been recruited after providing 
written informed consent for the same. PK includes brequinar and dipyridamole plasma concentrations.  
If a particular cohort meets study stopping criteria (as defined in section “Stopping Criteria”) or is found to be 
unsafe by DSMB members, then the study will not proceed with enrollment of subsequent cohorts.  
An expansion cohort of approximately 48 subjects will be added to the cohort with the highest brequinar dose 
that meets safety criteria. 
Safety data of cohort 1 to cohort 4 (or highest dose cohort evaluated) will be submitted to the regulators and 
their approval will be obtained prior to commencing recruitment in the expansion cohort. 
All subjects will receive SOC as per relevant guidelines for treatment of patients with mild to moderate COVID-
19 infection.  
Subjects will be randomized to one of the following cohorts in Part 1: 
Cohort 1: 
x
Arm 1: 5 days of standard of care (SOC) + brequinar 50 mg OD + dipyridamole 75 mg TID (N = 8)  
x
Arm 2: 5 days of SOC + brequinar 50 mg OD (N = 4). 
x
Arm 3: 5 days of SOC + brequinar placebo 50 mg OD (N = 4). 
Cohort 2: 
If the 50 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-defined in the protocol the 
brequinar dose will be escalated to 100 mg.   
x
Arm 1: 5 days of standard of care (SOC) + brequinar 100 mg OD + dipyridamole 75 mg TID (N = 8)  
x
Arm 2: 5 days of SOC + brequinar 100 mg OD (N = 4). 
x
Arm 3: 5 days of SOC + brequinar placebo 100 mg OD (N = 4).
Cohort 3: 
If the 100 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-defined in the protocol the 
brequinar dose will be escalated to 150 mg:   
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 41 of 80
x
Arm 1: 5 days of standard of care (SOC) + brequinar 150 mg (100 mg + 50 mg) OD + dipyridamole 75 
mg TID (N = 8)  
x
Arm 2: 5 days of SOC + brequinar 150 mg (100 mg + 50 mg) OD (N = 4) 
x
Arm 3: 5 days of SOC + brequinar placebo 150 mg (100 mg + 50 mg) OD (N = 4). 
Cohort 4: 
If the 150 mg brequinar OD + dipyridamole 75 mg TID meets safety criteria as pre-defined in the protocol the 
brequinar dose will be escalated to 200 mg:   
x
Arm 1: 5 days of standard of care (SOC) + brequinar 200 mg (100 mg +100 mg) OD + dipyridamole 75 
mg TID (N = 8)  
x
Arm 2: 5 days of SOC + brequinar 200 mg (100 mg +100 mg) OD (N = 4) 
x
Arm 3: 5 days of SOC + brequinar placebo (100 mg + 100 mg) OD (N = 4). 
Expansion Cohort: 
Approximately forty-eight (48) subjects will be added to the cohort with the highest brequinar dose that meets 
safety criteria in a 2 : 1 ratio of active treatment (approximately 32 in SOC + brequinar + dipyridamole treated 
and 16 in SOC + brequinar monotherapy group). Additional sites may be added if required to meet enrollment 
of the expansion cohort in an efficient manner. 
9.2 
Study Procedure 
To be eligible for screening, subjects must have a documented positive SARS-CoV-2 test result within 5 days 
of first dose of study drug and have at least one ongoing symptom consistent with SARS-CoV-2 infection rated 
as at least mild to moderate in the opinion of the investigator. The subject’s earliest symptom must have an 
onset date within 5 days of first dose of study drug.
Subjects will undergo screening (day -4 to 0) for confirming eligibility for participation in the study. Study Day 
1 includes randomization visit. 
Subjects will be randomized to a cohort as described above.
Screening activities as well as randomization can take place on the same day as a combined Screening/Day 1 
visit, if the site team is able to obtain Screening lab results on the same day. Otherwise, Day 1 is to take place 
as soon as Screening lab results are available.
Study Day 1 and first dose of study drug must take place ≤5 days from onset of first symptom. 
Subjects may be hospitalized as many as 9 days in the study (day 0 to 8) or more for the PK sample as per 
Investigator discretion.
For subjects participating in the PK subset, 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 42 of 80
Blood samples for estimating brequinar concentrations will be drawn (PK):
x
Day 1: Pre-dose (within 1 hour prior to study drug administration) and post dose at 1h, 2h, 4h, and 8h; note 
that the 8h sample is to be obtained prior to the next dose of dipyridamole;
x
Days 2 – 5 pre-dose and Day 8.
Aliquots of the NP/OP swab samples are to be stored at the testing laboratory for possible additional virological 
testing.
Screening visit and study visits on Days 1, 8, 15, 22 and 29 will be either in person or a combination of in-
person and virtual visit (telemedicine or other remote technique) or by visit to patient’s home by site team. 
Study visits on Day 4 and 12 may be virtual visits (telemedicine or other remote technique) or in person.
On Days 2, 3, 5, 6 and 7, the site will have a telephone call / or in-person communication with the subject for 
changes in concomitant medications and assessment of adverse events (same will also be captured by the subject 
using a patient diary card or these visits will be conducted in person).  
Note:
x
Study procedures are presented in detail in the Schedule of Events. 
x
Days 1, 8, 15 and 29 require sample collection for performing laboratory tests and will be conducted at the 
site or via home visit. 
x
Any in-person visit may also have telemedicine or telephone components if all study activities cannot be 
completed in person.
x
The visits that include bloodwork must be conducted at the study site or arrangements made for sample 
collection at the subject’s home or other appropriate location. 
x
Site staff (in case of an in-person visit) or subjects (in case of a remote visit) will assess respiratory rate, 
heart rate, body temperature and SpO2 (a thermometer and pulse oximeter are to be provided to subjects
who are home quarantined, leave the hospital or are unable to return for study visits).
x
Subjects will record details of concomitant medications, adverse events in the patient diary card (PDC). 
x
Subjects will complete a symptom assessment form on designated days daily during the study period (days 
1 – 8, 12, 15, 22, and 29).
x
In case the subject is hospitalized during the course of study, the activities specified in scheduled visits / 
time points will be carried out within the hospital facility. 
x
Study completion or the reason for study discontinuation will be recorded in the source document and the 
eCRF.
DSMB Meeting:
A Data Safety Monitoring Board (DSMB) will meet to review the safety and scientific conduct of the study. At 
a minimum, the DSMB will review the protocol and study design prior to study start, after the end of the first 
part of the study prior to the expansion phase, and at the end of the study. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 43 of 80
At each interim meeting the DSMB members will determine whether to stop the study, amend the protocol, or 
continue the study per protocol. The study enrollment will not be suspended for routine DSMB meetings.
The DSMB will be convened and enrollment suspended if Cohort-Level Stopping Criteria are met. The DSMB 
may allow the enrollment to resume following their review if safety criteria are met.
9.3 
Hospitalization 
Subjects may be hospitalized for approximately 9 days (day 0 to 8) in the study as per Investigator discretion
for the PK blood sample draws. Subjects may leave after this period (if medically discharged) after the Day 8 
blood work has been drawn. Extended stays beyond study Day 8 are permitted if the facility is a dedicated 
COVID-19 unit or other relevant hospital type or if per the Investigator the extended stay facilitates study 
procedures; this continuation will not be considered as an SAE. However, prolongation of hospitalization due 
to increase in disease severity or any other safety concerns related to the subjects will be considered as an SAE.
Hospitalization for the purpose of PK sample collection may be done at Investigator’s discretion, in this case 
hospitalization may be for selected few days and may not be for entire 8 days duration. Appropriate 
documentation of the same will be done in source file.
9.4 
Unscheduled Visits and Early Discontinuation Visit 
An Unscheduled Visit is allowed at any time, for any reason, if in the Investigator’s opinion it is warranted. If 
the Unscheduled Visit is due to an AE, the Investigator will determine whether additional visits are needed. 
If a subject is discontinued from the study during an Unscheduled Visit, the Unscheduled Visit will be referred 
to as an Early Discontinuation Visit and all procedures scheduled for End of Study visit will be performed.
If the Unscheduled Visit is not an Early Discontinuation Visit (i.e., the subject will continue to take part in the 
study), then the reason for unscheduled visit is documented and required procedures at the discretion of 
investigator considering the reason for visit will be performed.
If the Investigator determines that the subject’s condition has worsened to the degree that it is unsafe for the 
subject to continue in the study, the subject may be discontinued from the study as treatment failure and a 
standard of care treatment may be advised at the Investigator’s discretion.
In case of ongoing AEs, telephonic safety follow up will be continued until resolution or stabilization of AEs 
or up to 30 days after administration of last dose of IMP, whichever is earlier.
9.5 
Sample Collection Procedure 
Blood collection for PK analysis: 
PK blood samples will be collected through an indwelling intravenous cannula (Venflon or similar) placed in 
the forearm vein of the subjects for up to 24 hours or may also be collected through a fresh vein puncture at 
each time point. A 10 mL of blood per sample will be obtained using syringe/adaptor and transferred in to pre-
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 44 of 80
labelled vacutainers containing K2EDTA as anticoagulant. Filled vacutainers will be placed on wet ice bath 
(below 10 0C) during sample collection activity and until storage of plasma.
Time of collection of each blood sample (as displayed in the calibrated digital clock) will be recorded in 24-
hour clock format (hh:mm) on the PK blood sample collection log and same will be transcribed to eCRFs. 
If an intravenous indwelling cannula is placed, maintain this as long as possible by injecting 0.5 mL of 5 IU/mL 
of heparin in normal saline solution or per hospital’s usual practice to maintain the cannula patentcy. When
sampling through the cannula, collect study blood samples after discarding the first 0.5 mL of heparinised blood 
from the cannula. If insertion of cannula is not possible, alternatively blood samples may be drawn by a fresh 
venipuncture or in case of blockade in an existing cannula, extra heparinised saline will be injected to stimulate 
the cannula and later blood samples will be collected after discarding the heparinised blood or central line. If 
the time window does not allow, it is recommended to directly use a disposable syringe for extraction, and 
appropriately dispose of the retained needle after blood collection.
The blood samples will be withdrawn using syringe or adaptor and transferred into pre-chilled (maintained at 
temperature below 10 °C), pre-labelled (mentioning Site number, Protocol number, Subject number, Period 
number, Sampling time point and Sample ID) sample collection tubes containing K2EDTA as an anticoagulant 
kept on wet ice bath (below 10 0C) until centrifugation. Immediately following blood collection, the vacutainers 
are to be gently inverted 5 - 7 times to mix the anticoagulant.
It is recommended that collected blood samples be placed on wet ice bath (below 10 0C) from the point of 
collection until storage of plasma.
NP/OP Sample Collection for qPCR
The Laboratory Manual will provide details regarding collection, processing, storage and shipment for qPCR 
samples.
9.6 
Sample Size  
No statistical powering has been performed for this study. The number of subjects is designed to provide 
information on the safety, tolerability, and efficacy of the IMP tested in this study. In Part 1, approximately 64 
subjects will be randomized to up to 4 cohorts of 5 consecutive days of one of the following regimens in addition 
to SOC in 2:1:1 ratio as shown below:
Treatment Arma
Day 1
Day 2
Day 3
Day 4
Day 5
Brequinar + 
Dipyridamole 
(N=8)
BRQ XX mg OD 
DPY 75 mg TID
BRQ XX mg OD 
DPY 75 mg TID
BRQ XX mg OD 
DPY 75 mg TID
BRQ XX mg OD 
DPY 75 mg TID
BRQ XX mg OD 
DPY 75 mg TID
Brequinar  
(N=4)
BRQ XX mg OD 
BRQ XX mg OD 
BRQ XX mg OD
BRQ XX mg OD 
BRQ XX mg OD 
Placebo 
(N=4)
PBO XX mg OD
PBO XX mg OD
PBO XX mg OD
PBO XX mg OD
PBO XX mg OD
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 45 of 80
aAll subjects will also received standard of care (SOC).
The brequinar dose will start at 50 mg and may be escalated to 100 mg, 150 mg, and 200 mg if safety criteria 
are met for each cohort (see Safety Criteria below).
The hospital pharmacist is to be unblinded. Bulk supplies of investigational medicinal product (IMP) of 
brequinar 50 mg, brequinar 100 mg, dipyridamole 75 mg, brequinar placebo 50 mg and brequinar placebo 100 
mg will be supplied to the unblinded hospital pharmacist. 
The unblinded hospital pharmacist is to prepare the assigned IMP for each individual subject at that institution 
and create an appropriately labeled bottle/zip lock bag of study medication sufficient for a 5-day treatment 
course. The randomization assignment will be provided via an IWRS.
Alternatively, the hospital pharmacist and study team may decide to distribute IMP on a daily basis for 5 days 
for brequinar and dipyridamole while the subject is hospitalized, depending on the most convenient method.
9.7 
Patient identification and Randomisation 
Randomization will be carried out using SAS® (SAS Institute Inc., USA) version 9.4 or higher. Randomization 
will be done in blocks using PROC PLAN such that the design is unstructured. The treatment allocation will be 
determined according to the randomization schedule and randomization schedule will be done per cohort.
Screening and Randomization Numbering
Each subject will be assigned a unique number that will serve to identify laboratory specimens and all 
documents, and if randomized throughout the study.  If a subject fails to qualify for allocation to the study i.e. 
is a screen failure, the subject’s unique number will not be used for another subject.
Screening number will be a combination of center number, project number and subject number. The center 
number will be assigned by Veeda to the investigative site (e.g. A, B, C, D) and subsequent sites are assigned 
consecutive alphabet numbers. Upon signing the informed consent form, the subject will be assigned a screening 
number by the Investigator. At each site the first subject consented is assigned screening number e.g. A-21-
0372-001, and subsequent subjects are assigned consecutive numbers (e.g., the second subject consented is 
assigned screening number A-21-0372-002, the third subject is assigned screening number A-21-0372-003). 
Once a screening number is assigned to a subject, that number will not be reused.
If the subject is deemed eligible for enrollment into the study and will commence dosing, then a randomization 
number will be assigned via IWRS as defined in the randomization plan. Subjects will be randomized with the 
next qualifying subject given the next available randomization number. 
A source document maintained at the site will link the screening number to the randomization assignment 
number (once assigned) and the same will be reflected in screening and enrollment log of Investigator site file.
The assigned subject number will be recorded in the CRF of the subject. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 46 of 80
The personnel involved in dispensing of study drug and verification of dispensed study drugs will be 
accountable for ensuring compliance to randomization schedule. 
9.8 
Blinding 
Instructions provided in this section are a general description of operational procedures. Investigators are 
instructed to always refer to latest version of respective study plans/manuals for detailed and latest information.
The intent of blinding is to limit the occurrence of conscious and unconscious bias in the conduct and 
interpretation of the clinical study. The essential aim of blinding, therefore, is to prevent identification of the 
treatments by the Investigator and others associated with the conduct of the study until all such opportunities 
for bias have passed.
Due to unavailability of a matching dipyridamole placebo, subjects in the brequinar-dipyridamole treatment 
arm will have a daily dose of one brequinar capsule of appropriate strength and three 75 mg dipyridamole tablets 
whereas subjects in the SOC + brequinar only arm will receive only brequinar capsule(s) daily at the appropriate 
strength. Subjects in the SOC + brequnar placebo arm will receive only brequinar placebo capsule(s) daily at 
the appropriate strength. No dipyridamole placebo tablets will be provided to the subjects assigned to the 
brequinar only or brequninar placebo treatment arms.  
The Sponsor will provide investigational medicinal product (IMP) bulk drug supplies to the ThermoFisher 
depot. ThermoFisher will supply each site with bulk supplies of brequinar 50 mg and 100 mg capsules (50 count 
bottles) and dipyridamole (100 count bottles). An unblinded independent site staff member (e.g., hospital 
pharmacist) will dispense the IMP for each subject according to the assigned cohort and randomization 
schedule, and perform IMP accountability by collecting used and unused products. The unblinded pharmacist 
will not participate in the clinical trial assessments in order to minimize potential bias, and will be instructed 
not to discuss the IMP with assessors and other blinded study personnel. 
The unblinded pharmacist should use an opaque bottle or envelope to ensure that the blinded study team is not 
able to see the IMP. The subjects will be instructed not to reveal the contents of the bottle(s)/envelope(s) to the 
blinded investigator or study staff.  
The blinded investigational staff performing the assessments and data analysts (with the exception of the 
biostatistician who will undertake the generation of the randomisation scheme) will remain blinded to the 
identity of the treatment assignments for individual subjects from the time of randomization until database lock, 
using the following methods:  
x
Randomization data will be kept strictly confidential until the time of unblinding, and will not be 
accessible by anyone else involved in the study.  
x
Only the unblinded pharmacist or designate will be involved in dispensing, administering and collecting 
the study medication.  
x
Unblinding of blinded study personnel will be permitted only in the case of patient in emergency 
condition and at the conclusion of the study.   
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 47 of 80
Data 
that 
may 
potentially 
unblind 
the 
intervention 
assignment 
(i.e., 
study 
intervention 
preparation/accountability data, intervention allocation or other specific laboratory data) will be handled with 
special care to ensure that the integrity of the blinding is maintained and the potential for bias is minimized.  
Site specific randomization schedule, drug dispensing logs, drug accountability forms and other papers 
identifying treatment allocation are kept in a separate binder in a locked cupboard to which the investigators 
does not have access. Trial staff is provided training in the importance of maintaining blinding, and trial 
medication delegates/trial coordinators are also helped to set up systems at the clinic. 
Every effort must be made to limit the number of unblinded study personnel to ensure the integrity of this study.  
In the event of a Quality Assurance audit after the study has been unblinded, the auditor(s) will be allowed 
access to unblinded study intervention records at the site(s) to verify that randomization/dispensing has been 
done accurately. 
9.8.1 Unblinding of treatment assignment 
If necessary, the Investigator may be required to unblind a participant if an adverse event (AE) meets criteria in 
order to fulfill expedited regulatory reporting requirements. In this event, Investigator will inform the same to 
sponsor or its designee/study medical monitor if possible to discuss the particular situation, before breaking the 
blinding unless this could delay emergency treatment of the participant. Telephone contact with the medical 
monitor will be available 24 hours per day, 7 days per week. The Sponsor/CRO PV and/or safety review team 
will access the AE report and conclude whether unblinding is required. Once Sponsor/CRO PV and/or safety 
review team conclude that study participant requires the unblinding, Investigator will ask unblinded study 
personnel to provide the treatment sequence.  
Investigators are instructed to always refer to latest version of respective unblinding procedure manuals for 
detailed and latest information.
9.8.2 Emergency unblinding of treatment assignment 
Most often, study drug discontinuation and knowledge of the possible treatment assignments are sufficient to 
treat a study participant who presents with an emergency condition. While the responsibility to break the 
intervention code in emergency situations resides solely with the evaluating investigator, it is recommended 
that the investigator contact the sponsor or its designee/study medical monitor if possible to discuss the 
particular situation, before breaking the blinding unless this could delay emergency treatment of the participant. 
Telephone contact with the medical monitor will be available 24 hours per day, 7 days per week. If a 
participant’s intervention assignment is unblinded, the sponsor must be notified within 24 hours after breaking 
the blind.  
The investigator will inform the participant how to contact his/her backup in cases of emergency when he/she 
is unavailable. The investigator will provide protocol number, study drug name if available, participant number, 
and instructions for contacting the sponsor (or any entity to which it has delegated responsibility for emergency 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 48 of 80
code breaks) to the participant in case emergency unblinding is required at a time when the investigator and 
backup are unavailable.  
An assessment will be done by the appropriate site personnel and the Study Lead after an emergency unblinding 
to assess whether or not study drug should be discontinued for a given participant.  
In general, randomization codes will be disclosed fully only if the study is completed and the clinical database 
is closed.
9.9 
Study Duration 
Study duration will be approximately 34 days including a maximum screening period of 5 days. 
9.10Treatment  
All subjects will receive standard of care (SOC) including treatment for COVID-19 signs and/or symptoms as 
required. Study encounters may be conducted remotely or at the study site depending on visit requirements, site 
facilities and subject and study team preferences. 
9.11Clinical Safety Measures 
It is the responsibility of the investigator to ensure that adequate medical supervision and care is available for 
the study subjects during the study to ensure their utmost safety and well being. 
x
Demography (subject reported / measured height and weight, age, sex and race/ethnicity): At screening 
x
Medical history (relevant within 30 days or ongoing) / History of current illness (date of symptom onset or 
change in baseline co-morbidity thought to be due to COVID-19 infection): At screening 
x
Physical Examination (subject self-reported / examiner evaluated): At screening 
x
Vital signs (body temperature, respiratory rate, heart rate, SpO2) assessment: At screening, Day 4 (±8 hrs), 
Day 8 (±8 hrs), Day 12 (± 1 day), Day 15 (±1 day), Day 22 (±1 day), End of study [EoS; Day 29 (±2 day)]. 
Note: If subject is hospitalized, Vital signs assessment will be done on daily basis by site team during 
hospitalization through Day 8 then following the Vital signs visits as listed above. 
x
Hematology, biochemistry and urine analysis: At screening, Day 1 unless same day as Screening visit, Day 
8 (±8 hrs), Day 15 (±1 day), End of study [EoS; Day 29 (±2 day)]. 
x
HCV, HbSAg, HIV Test: At screening 
x
Serum pregnancy test (Women of child bearing potential (WOCBP)): At screening. 
x
Urine pregnancy test (WOCBP): End of study [EoS; Day 29 (±2 day)]. 
Note: WOCBP: A premenopausal female capable of becoming pregnant
x
Rapid antigen test / SARS-CoV-2 RT-PCR Qualitative (in a clinically relevant specimen (Naso-Oro-
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 49 of 80
Pharyngeal as appropriate)): Screening 
Note: Test need not be repeated in those with possession of confirmed positive report. Date of positive report 
must be ≤5 days prior to randomization.
x
RT-PCR Quantitative Viral (in a clinically relevant specimen (Naso-Oro-Pharyngeal as appropriate)): Day 
1 (Prior to dosing), Day 4 (±8 hrs), Day 8 (±8 hrs), Day 12 (±1 day), Day 15 (±1 day), Day 22 (±1 day) and 
End of study [EoS; Day 29 (±2 day)] 
x
Ordinal Scale Assessment: Screening, Day 8 (±8 hrs), Day 15 (±1 day), Day 22 (±1 day) and End of study 
[EoS; Day 29 (±2 day)] 
x
Adverse events/ Serious Adverse Events: Adverse events/ Serious Adverse Events will be recorded from 
the time of first study drug administration till end of study safety assessments. Other medical events not 
related to disease condition under study and occurring before IMP administration, but after signing the 
informed consent form will be recorded on the medical history/current medical conditions of case report 
form. 
x
In addition to protocol-specific laboratory tests and/or clinical examinations at scheduled time points, 
additional tests/clinical examination may be conducted to evaluate subject safety at any time during the 
study, at the discretion of the Investigator (can be done in local laboratory or nearby 
clinic/hospital/institution). 
x
Medication taken prior to first dosing: All prescription medications and over-the-counter drugs (including 
vitamins) taken within 30 days prior to screening must be recorded in the eCRF as Medication history. 
x
Concomitant medications: Medications taken from time of signing of Informed Consent form until study 
completion (i.e. End of study) will be captured as concomitant medications. 
x
Prohibited medications: Any other antiviral medications or medication with antiviral potential.
Note:  
x
It is recommended that general precautions need to be taken by the staff caring for COVID patients during
the trial.
x
In case the subject is hospitalized during the course of study, the activities specified in scheduled visits / 
time points will be carried out within the hospital facility.
9.12Discontinuation/ Termination of Study 
Investigator reserves the right to discontinue the study for safety reasons at any time. Ethics Committee (EC) 
and/or Regulatory Authority may ask to terminate the study, if there are major violations of ethical 
considerations or due to any serious adverse event(s). Reasons for termination of study will be provided to 
subjects. In case sponsor/PI decides to terminate the study, reason for the same will be notified to Central 
Licensing Authority within thirty working days of such termination and/or notified to EC as applicable. 
Note: In case of IMP termination, ongoing subjects will continue with standard treatment based on PI’s 
discretion. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 50 of 80
Discontinuation of the trial at one particular centre: 
The sponsor may stop this trial at one particular centre for any of the following reasons or more: 
x
Serious and/or persistent non-compliance with the protocol 
x
False documentation in the source 
x
Inadequate co-operation with the sponsor, or its representatives 
x
Non-compliance with GCP and/or regulatory requirements 
x
The investigator requests discontinuation. 
10.0
STUDY TREATMENT 
10.1 Investigational Medicinal Product and Combination Product Dosage 
1. Brequinar 50 mg capsules (used for the 50 mg and 150 mg doses) 
2. Brequinar 100 mg capsules (used for the 100 mg, 150 mg and 200 mg doses)
3. Dipyridamole 75 mg tablets 
4. Brequinar Placebo 50 mg and 100 mg capsules 
Note: 
x
The subjects will take the study medication as directed on study days 1 – 5.  
x
Treatment assignment will be randomized, assessor-blind. 
x
IMP dispensing will be performed by an unblinded pharmacist. 
x
Study assessments will be performed by blinded Investigator or other designed blinded site personnel.
x
Brequinar and brequinar placebo doses will be administered once daily. 
x
Dipyridamole doses will be given thrice daily. 
x
The 150 mg brequinar or brequinar placebo dose will be given as 1 capsule of 100 mg and 1 capsule of 50 
mg; the 200 mg brequinar or brequinar placebo dose will be given as 2 capsules of  brequinar or  placebo 
100 mg. 
10.1.1 Assessment of Compliance 
Compliance for dosing at home will be captured using a patient diary card. 
10.2 Procurement, Storage and Accountability Procedures for Investigational Products 
10.2.1 Receipt and storage of investigational products 
Adequate supplies of investigational medicinal products for dosing will be distributed to the sites in bulk from
the chosen depot. Investigational medicinal products will be stored per the storage condition supplied by 
sponsor. Certificates of analysis (COA) containing required product information will be received from sponsor. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 51 of 80
The hospital pharmacist will receive bulk supplies of IMP (brequinar 50 mg, brequinar 100 mg, dipyridamole 
75 mg and brequinar placebo 50 mg and 100 mg) and will be unblinded to treatment. For each individual subject, 
the hospital pharmacist will use the IWRS to assign the randomization subject numbers. Hospital pharmacist 
will create an opaque, labeled zip lock bag or bottle for IMPs as assigned for individual subjects either per day 
or for all 5 days in the requisite packaging.  
10.2.2 Accountability of investigational products 
Sites will maintain accountability of IMPs received, stored, administered and returned to CRO/ destroyed at 
site. Only subjects enrolled in the study should be administered IMP per this protocol. Investigator/ designee 
supervising the dosing will be responsible for compliance to randomization schedule at site. Overall 
responsibility of IMP accountability at the site lies with the Investigator. 
10.2.3 Handling of Unused Investigational products 
Unused IMPs will be returned to the CRO or destroyed locally (per IMP plan).  
10.2.4 Maintenance of Dispensing Record 
A copy of site-specific dispensing record will be maintained in the Site Investigator File as well as in Central 
Investigator File.
10.2.5 Concomitant medication 
Any allowable concomitant medication being taken by the subject should be continued on same dose during the 
study. Any change in the dose needs to be documented and subjects can continue in the study if the investigator 
deems proper. Administration of the following medications is not permitted after screening until after the end 
of each subject’s study participation.
Prohibited Medications: 
The following concomitant medications, products or procedures will not be allowed while enrolled in the study: 
x
Hydroxychloroquine 
x
Ivermectin 
x
Immunomodulators such as tocilizumab  
x
Antiviral drugs or drugs with antiviral potential including but not limited to remdesivir 
The use of any of the above mentioned medications/procedure will result in withdrawal of the subject from the 
study. 
Note: This list of drug is not exhaustive. However, any drug which is not mentioned above and having a possible 
on study drug efficacy and safety, should be confirmed with Medical Monitor/Medical Expert.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 52 of 80
Permissible Medications: Other than those prohibited.
Standard treatment [(Standard Of Care (SOC)] provided in all the arms will be per the latest updated version of 
CLINICAL MANAGEMENT PROTOCOL for COVID-19 (in adults) released by Government of India 
Ministry of Health and Family Welfare Directorate General of Health Services (EMR Division).
If drug therapy other than that specified in the protocol is required prior to or during the study period, decisions 
shall be taken by the investigator to continue or discontinue the subject based on the following:
x
The pharmacology and pharmacokinetic of the non-study medication.
x
The likelihood of a drug–drug interaction.
x
The time and duration of administration of the non-study medicine.
The start and stop date of concomitant medication use during the study should be recorded in source data. All 
such instances will be recorded and reported in the final report with details of start date, stop date and reason 
for medication use.
11.0
EFFICACY ASSESSMENT
Efficacy will primarily be assessed by reduction in SARS-CoV-2 RNA levels as measured by the quantitative 
RTPCR test for SARS COV2 in brequinar-dipyridamole treated subjects compared to brequinar-only and 
placebo-treated subjects through Day 29.
Symptom improvement will be defined in the SAP. Clinical improvement for the ordinal scale will be defined 
as defined as a 2-point or greater improvement on an 8-point WHO ordinal scale in every subject measured on 
each designated day (i.e Screening, Days 1, 4, 8, 12, 15, 22, 29), until Day 29 from the date of randomization. 
This scale has been used in the current COVID-19 outbreak.   
Ordinal Scale for Clinical Improvement
Patient State
Descriptor
Score
Uninfected
No clinical or virological evidence of infection
0
Ambulatory
No limitaion of activities
1
Limitation of activities
2
Hospitalized Mild 
disease
Hospitalized, no oxygen therapy
Oxygen by mask or nasal prongs
3
4
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 53 of 80
Hospitalized Severe 
Disease
Non-invasive ventilation or high-flow oxygen
5
Intubation and mechanical ventilation
6
Ventilation + additional organ support – pressors, RRT, ECMO
7
Dead
Death
8
12.0
SAFETY ASSESSMENT  
The study will include the following evaluations of safety and tolerability according to the time points provided 
in the 3.2 Schedule of Activities. 
12.1 Demographic Characteristics  
Demographic data (subject reported / measured height and weight, age, sex and race/ethnicity) will be captured 
as specified in the 3.2 Schedule of Activities.
12.2 Medical and Medication History 
The Investigator or his/her designee will obtain a detailed medical history and medication history as specified 
in the 3.2 Schedule of Activities. 
Medical history includes clinically significant diseases within 30 days or ongoing and history of current illness 
(date of symptom onset or change in baseline co-morbidity thought to be due to COVID-19 infection).
Information on all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) used by the participant within 30 days prior to baseline visit will be recorded 
on the CRF.  
Concomitant medications administered from screening to randomization will be recorded as a medication 
history on the CRF.  
12.3 Physical Examination 
This evaluation will include an examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and basic nervous system evaluation. 
Information about the physical examination must be present in the source documentation at the study site. If 
any abnormalities are noted during the study, the participant may be referred to another doctor. The investigator 
should use his or her clinical judgment for appropriate treatment and/or medical referral. 
Clinically significant findings/abnormalities prior to the signing of ICF must be included in the relevant medical 
history/current medical conditions section of the CRF. Significant findings after the start of the IMPs that meet 
the definition of an AE must be recorded in the Adverse Event section of the CRF. Physical examination should 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 54 of 80
be done at specified in the 3.2 Schedule of Activities. Changes from baseline abnormalities should be recorded 
in participant notes. New or worsened clinically significant abnormalities should be recorded as adverse events 
on the Adverse Event CRF. 
12.4 Vital Signs 
Vital signs will include measurements of body temperature, respiratory rate, heart rate and SpO2 taken with the 
participant in a seated position after resting for 5 minutes. Vital signs will be measured at specified in the 3.2 
Schedule of Activities. If the subject needs to be assessed remotely due to COVID-19 restrictions or for other 
reasons, the subject is to be provided with a pulse oximeter and digital thermometer. 
12.5 Abnormal Vital Sign Values  
Not every vital sign abnormality qualifies as an adverse event. A vital sign result must be reported as an adverse 
event if it meets any of the following criteria:  
x
Is accompanied by clinical symptoms  
x
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment 
discontinuation)  
x
Results in a medical intervention (e.g., potassium supplementation for hypokalemia)  
x
Is clinically significant in the investigator’s judgment 
x
Requires a change in concomitant therapy (i.e. addition of, interruption of, discontinuation of, or any other 
change in a concomitant medication, therapy or treatment) 
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific judgment should be 
exercised in deciding whether an isolated vital sign abnormality should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood pressure), 
only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event CRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit should not be repeatedly 
recorded on the Adverse Event CRF, unless the etiology changes. The initial severity of the event should be 
recorded, and the severity or seriousness should be updated any time the event worsens. 
12.6 Clinical Safety Laboratory Assessments 
Clinical laboratory tests will be performed at specified in the 3.2 Schedule of Activities. (Refer to section 26.0:
for the list of clinical laboratory tests). 
The investigator must review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the CRF. The laboratory reports must be filed with the 
source documents. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 55 of 80
All laboratory tests with values considered clinically significantly abnormal during the study or within 30 days 
after the last dose of study intervention should be documented as AE. The abnormal test should be repeated 
until the values return to normal or baseline or are no longer considered clinically significant. 
x
If such values do not return to normal/baseline within a period of time judged reasonable by the investigator, 
the etiology should be identified and the sponsor notified. 
x
If laboratory values from non-protocol specified laboratory assessments performed at the institution’s local 
laboratory require a change in participant management or are considered clinically significant by the 
investigator (e.g., SAE or AE or dose modification), then the results must be recorded in the CRF. 
12.7 Other safety evaluations as appropriate and as indicated in the schedule of activities 
x
Pregnancy test (Serum and Urine): At specified in the 3.2 Schedule of Activities.
12.8  Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result should be reported as 
an adverse event if it meets any of the following criteria:  
x
Is accompanied by clinical symptoms  
x
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment 
discontinuation)  
x
Results in a medical intervention (e.g., potassium supplementation for hypokalemia)  
x
Is clinically significant in the investigator’s judgment 
x
Requiring a change in concomitant therapy (i.e. addition of, interruption of, discontinuation of, or any other 
change in a concomitant medication, therapy or treatment) 
It is the responsibility of the investigator to review all laboratory findings. Medical and scientific judgment 
should be exercised in deciding whether an isolated laboratory abnormality should be classified as an adverse 
event. The investigator must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline phosphatase 
and bilirubin 5 × ULN associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the adverse event CRF.  
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality itself 
should be recorded on the adverse event CRF, along with a descriptor indicating if the test result is above or 
below the normal range (e.g., “elevated potassium,” as opposed to “abnormal potassium”).  
Observations of the same clinically significant laboratory abnormality from visit to visit should not be 
repeatedly recorded on the adverse event CRF, unless the etiology changes. The initial severity of the event 
should be recorded, and the severity or seriousness should be updated any time the event worsens. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 56 of 80
For each laboratory abnormality reported as an AE, the following laboratory values should be reported in the 
laboratory section of the CRF: the value indicative of the onset of each toxicity grade; the most abnormal value 
observed during the AE, and the value supporting recovery to Grade ≤1 or to baseline values. The CTCAE 
version 5 scale will be used to grade AEs including laboratory AEs. 
12.9 Handling and Reporting of Adverse Events 
An adverse event is any untoward medical occurrence (including a symptom or disease or an abnormal 
laboratory finding) during treatment with an investigational drug or a pharmaceutical product in a subject that 
does not necessarily have a relationship with the treatment being given.  
*Abnormalities based on laboratory parameters, vital signs, and 12-Lead ECG will be called AE, if they are 
associated with at least one of the following: 
x
Interruption or stoppage of the study medication  
x
Associated with signs or symptoms  
x
Requiring treatment 
x
Considered clinically significant by the investigator 
Safety Criteria: 
An independent, unblinded study physician (from CRO) will assess each cohort for safety. A cohort will be 
declared safe are as soon as all results are available for the Day 15 visit if the following conditions are met: 
x
No toxic deaths (deaths judged by the investigator to be related to either study drug); 
x
Not more than 1 toxic SAE (SAEs judged by the investigator to be related to either study drug); 
x
No Grade 3 or higher toxicities (including laboratory AEs as per CTCAE version 5.0 or higher) (AEs judged 
by the investigator to be related to either study drug); 
x
<4 subjects with any grade toxicity (AEs judged by the investigator to be related to either study drug). 
In addition to the cohort-level safety, the independent study physician (from CRO) will determine if any subjects 
meet Individual Stopping Criteria:  
x
Subjects who develop a Grade 3 toxicity that is assessed by the investigator to be related to the study drug 
are to be permanently discontinued from study treatment but will continue in the study for safety 
assessments. 
x
Subjects who develop a Grade 4 toxicity, regardless of relatedness to study drug, are to be permanently 
discontinued from study treatment but will continue in the study for safety assessments. 
In addition to the individual subject-level safety, the independent study physician (from CRO) will determine 
if a cohort meets Cohort-level Stopping Criteria prior to completing the 16 subjects, in which case no additional 
subjects will be enrolled into that cohort and no higher brequinar doses will be assessed: 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 57 of 80
x
≥3 brequinar-treated or combination-treated subjects meet the individual stopping criteria. 
x
≥5 brequinar-treated or combination-treated subjects develop a Grade 3 or higher AE regardless of 
relationship to study drug.  
Adverse Drug Reaction is a noxious and unintended response to a medicinal product related to any dose. The 
phrase responses to a medicinal product means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.  Regarding marketed 
medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally 
used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function.  
An Unexpected Adverse Drug Reaction (UADR) is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information [e.g., investigator's brochure for an unapproved 
investigational medicinal product or company core data sheet or package insert for marketed product]. 
Subjects will be monitored throughout the study period for adverse events. Subjects will be instructed to bring 
to the notice of study personnel any adverse event that may occur during the entire study period.  
The following information is to be recorded for each adverse event individually in Adverse Event Reporting 
Form. 
x
Type of adverse event* 
x
Is it serious or non-serious? 
x
Date of onset/reporting 
x
Date of onset and resolution 
x
Severity (as per section 12.12)
x
Association with the study medication (as per section 12.13)
x
Action taken 
x
Outcome of adverse event (as per section 12.14)
x
Further details of the AE, if any. 
*The investigator should attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis should be documented as the AE/SAE and not the individual 
signs/symptoms. 
For the recording of signs and symptoms, the subject will be required to report spontaneously any AEs as well 
as the intensity of these events. In addition, each subject will be asked by the investigator for AEs during vital 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 58 of 80
signs and physical examination. All AEs including both observed and volunteered ones will be recorded in the 
Adverse Event Reporting Form, irrespective of its association with study medications. All findings considered 
clinically relevant and reportable as AE by investigator will be reported on the “Adverse event” page in the 
CRF and in the subject's medical records.  
Each AE will be evaluated for duration, severity and action taken, outcome and association with study 
medication. 
Adverse events/ Serious Adverse Events will be recorded from signing informed consent form through the end 
of the study safety assessments. Other medical events not related to study screening occurring before first dose 
administration, but after signing the informed consent form will be recorded on the medical history/current 
medical conditions of case report form.  
12.10 Serious Adverse Events (SAEs) 
A serious adverse event is any untoward medical occurrence during a study which satisfies one or more of the 
following conditions: 
x
resulting in death or 
x
permanent disability, or  
x
hospitalisation of the trial subject, or 
x
prolongation of hospitalisation, or 
x
significant disability, or  
x
incapacity, congenital anomaly, birth defect ,or  
x
life threatening event. 
The term ‘Life threatening’ refers to an event in which the subject was at immediate risk of death at the time of 
event. It does not refer to an event which may have caused death if it was more severe. 
The Investigator will be responsible to report all SAE to the central regulatory (e.g. DCGI-Central Licensing 
Authority), Sponsor’s representative and respective Ethics Committee within 24 hours of SAE 
occurrence/knowledge of occurrence if required. Investigator will be responsible for reporting the detailed 
report to the local regulatory (e.g. DCGI), chairman of the Ethics Committee and the head of the institution 
where the trial has been conducted within 14 days of SAE occurrence if required. Each AE will be evaluated 
for duration, severity, action taken, outcome and association with Investigational Medicinal Product. The study 
may be suspended or terminated depending upon the seriousness of SAEs. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 59 of 80
12.11Reporting and Follow-up
The investigator must complete SAE form, verify the accuracy of the information recorded in corresponding 
source documents, and send a copy (by fax /mail) to sponsor/representative/CRO.
Investigator:
The investigator shall report all serious adverse events (SAE) to the central licensing authority (DCGI), the 
Sponsor/CRO and chairperson of ethics committee within 24 hour of SAE occurrence, if required. 
The investigator shall report all SAE after due analysis to the central licensing authority (DCGI), chairperson 
of ethics committee and head of the institution where the trial has been conducted within fourteen days of SAE 
occurrence, if required. Subsequent follow-up information shall be reported to all stakeholders as mentioned 
above.
In case, Investigator fails to report any SAE within stipulated period, the investigator shall have to furnish the 
reason for the delay to the satisfaction of central licensing authority along with the report of SAE.
Sponsor or Sponsor’s Representative:
In case of SAE the Sponsor and/or CRO will be responsible for reporting the due analysis report of SAE to 
chairman of the Ethics Committee, the central licensing authority and the head of the institution where the trial 
has been conducted within 14 days of SAE occurrence, if required.
Note: In case if SAE occurrence time and reporting time by subject to investigator is not same, investigator may
fail to report such serious adverse event within the stipulated period. In such case Investigator shall have to 
furnish the reason for the delay to the satisfaction of the central licensing authority along with the report of the 
serious adverse event. 
Name of the sponsor representative: 
Barbara Powers, MSN, Ph.D.
E-mail: bpowers@clearcreekbio.com
Sponsor Medical Monitor:
John Pottage, MD
E-mail: John.pottagemd@gmail.com
CRO contact details:
Veeda Clinical Research Ltd.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 60 of 80
E-mail: safety@veedacr.com
Fax: +91-79-3001 3010
Follow-up of Adverse Events: 
All AEs (serious or not) will be followed to resolution (the subject's health has returned to his/her baseline status 
or all variables have returned to normal or clinically acceptable level), an outcome is reached, stabilization (the 
Investigator does not expect any further improvement or worsening of the event), or the event is otherwise 
explained regardless of whether the subject is still participating in the study. Where appropriate, medical tests 
and examinations will be performed to document resolution of event(s). 
The Investigator should institute any supplemental investigations of SAE based on their clinical judgment of 
likely causative factors.  
If required, a follow-up report including all relevant new or reassessed information (e.g., concomitant treatment, 
medical history) obtained on the SAE will be prepared and same will be marked “Follow-up report”. Follow up 
reports are to be sequentially numbered to allow tracking. These reports will be sent to the sponsor/CRO. 
Adverse events occurring between informed consent and the last visit  
The investigator should follow up on all AEs which occurred from signature of study-specific informed consent 
until the last visit of the subject, at which point the outcome assessment is documented in the CRF. 
Ongoing serious adverse events at the time of last visit 
For any SAEs still ongoing at the time of last visit considered to be related to IMP, the investigator should 
continue to follow-up until the SAE has resolved or has stabilized / is judged permanent for SAEs, and for up 
to 30 days after the last visit of subject for non-related SAEs. Where appropriate, medical tests and examinations 
will be performed to document resolution of event(s). The investigator should send SAE follow-up reports 
including all relevant new or reassessed information (e.g., concomitant treatment, medical history) obtained on 
the SAE /pregnancy to the sponsor/CRO. 
If a subject dies during participation in the study and an autopsy is performed, a copy of the report must be 
submitted. 
Serious adverse events occurring after the last visit 
Any SAEs experienced after the last visit should only be reported to sponsor if the investigator suspects a causal 
relationship to study treatment. The investigator must report the SADR to recipients as per the ‘SAE Reporting’ 
section 12.10.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 61 of 80
Pregnancy Reporting:
Pregnancy recorded for any trial participant after study drug administration should be reported immediately to 
the sponsor/representative. The subject will be withdrawn from the trial and every effort will be made to gather 
information regarding the pregnancy outcome until 8 weeks post-partum/termination of pregnancy. It will be
the responsibility of the Investigator to obtain this information. Pregnancy recorded after screening but before 
randomization will be reported and subject will be withdrawn from the study and further follow up will not be 
done. In case of pregnancy, separate pregnancy form should be filled. Cases of pregnancy exposure associated 
with SAE and/or abnormal pregnancy outcome should be reported as per SAE reporting timelines. If any 
congenital anomaly is observed in offspring then the follow up should be conducted till six months after birth, 
if applicable.
Ethics Committee Timelines for Reporting of SAE: 
In case of SAE, the Ethics Committee shall forward its report along with its opinion on the financial 
compensation (if any) to the licensing authority within 30 days of the occurrence of the SAE, if required.
12.12Classification of Severity of Adverse Event
Adverse event will be assessed for onset time, occurrence (single or repeat) and intensity. In terms of grade, 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL*.
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation 
of hospitalisation indicated; disabling; limiting self care ADL**.
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
*Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
12.13Causality Assessment/Association with the Study Medication
Every effort will be made to obtain all the required information to determine whether the Adverse Event is 
related or unrelated to the study procedure or Investigational Medicinal Product (causal relationship).
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 62 of 80
In terms of relationship 
Causality term 
Assessment criteria
Definite*
x
Event or laboratory test abnormality, with  plausible time relationship to drug intake 
x
Cannot be explained by disease or other drugs 
x
Response to withdrawal plausible (pharmacologically, pathologically) 
x
Event definitive pharmacologically or phenomenologically (i.e. an objective and 
specific medical disorder or a recognised  pharmacological phenomenon) 
x
Re-challenge satisfactory, if necessary 
Probable*
x
Event or laboratory test abnormality, with reasonable time relationship to drug 
intake 
x
Unlikely to be attributed to disease or other drugs 
x
Response to withdrawal clinically reasonable 
x
Re-challenge not required 
Possible*
x
Event or laboratory test abnormality, with  reasonable time relationship to drug 
intake 
x
Could also be explained by disease or other drugs 
x
Information on drug withdrawal may be lacking or unclear 
Unlikely#
x
Event or laboratory test abnormality, with a time to drug intake that makes a 
relationship improbable (but not impossible) 
x
Disease or other drugs provide plausible explanations 
Not Related#
x
The AE is clearly NOT related to the study treatment
Note: #Unlikely and Not Related will be considered as Not Related. 
*Definite, Probable and Possible will be considered as Related. 
12.14 Outcome Categories 
The outcome of adverse event will be categorized as following: 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 63 of 80
x
Recovered/ Resolved
x
Recovering/ Resolving 
x
Recovered with sequelae/ Resolved with sequelae 
x
Not recovered/ Not Resolved
x
Fatal
x
Unknown
13.0
SAMPLE PROCESSING AND TRANSFER PROCEDURES
Clinical Laboratory Samples:
All clinical laboratory blood and urine samples will be transferred to the central laboratory in controlled 
temperature and in pre validated laboratory kits which will be supplied to all the sites by the central laboratory. 
In case of emergency, samples can be sent to local laboratory for safety assessment at the discretion of the 
investigator.
Pharmacokinetic (PK) samples:
After collection of PK blood samples from all subjects at each time point, they will be centrifuged at 4000 RPM 
for 10 minutes at 5 ± 3 °C to separate plasma. For precaution purpose, the blood samples will be kept on wet 
ice bath (below 10 0C) both before centrifugation and after separation. 
The separated plasma will be transferred to pre-labeled polypropylene tubes in 2 aliquots: 
For Brequinar and Dipyridamol PK: 
Aliquot 1: Approximately 1.7 mL of plasma
Aliquot 2: Approximately 1.2 mL of plasma
Aliquot will be stored upright in a box containing dry ice or in a freezer at a temperature –15 °C or colder for 
interim storage at different investigator sites until shipment to Veeda Clinical Research Ltd., Ahmedabad, for 
analysis.
Note: Entire activity from blood sample collection to storage in a freezer should be completed within 60 minutes 
time.
During shipment the samples will be packed in thermocol boxes containing adequate amount of dry ice. The 
temperature will be monitored using calibrated data logger during shipment. Samples will then be stored at -78 
± 8 °C until completion of analysis at Veeda Clinical Research Ltd., Ahmedabad.   
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 64 of 80
Shipment for each aliquot will be carried out separately. 
A designated person from bioanalytical department will receive the samples at Veeda Clinical Research Ltd., 
Ahmedabad or designate on arrival. The condition of the samples will be examined on arrival at Veeda Clinical 
Research Ltd., Ahmedabad and if any of the samples are not in a frozen condition, clinical facility and\or 
Sponsor will be informed for the same. After receiving the samples at Veeda Clinical Research Ltd., 
Ahmedabad, the samples will be stored at –78 ± 8 °C until completion of analysis. 
Note: Samples of patients enrolled in Arm 3 (SOC + Placebo) of each cohort will not be analysed. 
qPCR Samples 
The qPCR samples are to be collected, processed, stored, and shipped as per the instructions in the Laboratory 
Manual.
14.0
BIOANALYTICAL PROCEDURES 
The Bioanalytical procedures will be performed at Bioanalytical facility of Veeda Clinical Research Ltd. 
Validated analytical method will be used for the PK analysis of the plasma samples.  
14.1 Method Validation 
Bioanalytical method will be validated at Veeda clinical research Ltd., which is in accordance with the 
regulatory guidelines on validation of bioanalytical methods.  
Method validations of Brequinar and Dipyridamol will be carried out by using analytical method developed at 
Veeda Clinical Research Ltd. This analytical methods will be validated for the sensitivity, specificity, matrix 
effect, linearity, ruggedness, accuracy and precision (repeatability and reproducibility), percent recovery and 
stability of samples (bench-top stability, autosampler stability, short-term, long-term stability of stock solution 
and internal standard) and effect of concomitant medications, if any. 
14.2 Assay of Samples 
The Brequinar and Dipyridamol will be quantified using a validated method. All available plasma samples of 
all subjects in the study will be analyzed as per approved protocol irrespective of withdrawn or dropped out 
from the study.  
The analysis of subject’s samples will be done using calibration curve with quality control samples, distributed 
throughout each batch. The details for the preparation of the calibration curve and quality control samples and 
the analytical batch acceptance criteria will be discussed in the respective in-house procedure. The analyst will 
not have access to the randomization schedule until analysis is completed. 
Note: Samples of patients enrolled in Arm 3 (SOC + Placebo) of each cohort will not be analysed. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 65 of 80
14.3 Incurred Study Sample Re-analysis 
Incurred Study Sample Re-analysis will be performed to ensure method reproducibility as per SOP (VIN-BRD-
092). 
15.0
STATISTICAL ANALYSIS 
15.1 Statistical Analysis Plan 
A statistical analysis plan (SAP) will be prepared and finalized prior to the database lock. Detailed description 
of the statistical methodology, population and handling of missing data will be described in this document. 
Mock tables and listings will be provided with the SAP. 
15.2 Sample Size Estimation 
There is no prospective powering in this study. The sample size was chosen to provide an adequate number of 
subjects to provide reasonable safety and efficacy data for this type of study.
15.3 Study Population for Analysis 
¾ Intent-to-treat population:  
Intent-to-treat (ITT) analysis set will include all the subjects who undergo randomization. 
¾ Safety Population: 
The safety population will include all randomized subjects who receive at least one dose of the study 
product. 
15.4 Analysis of Efficacy Data 
All statistical analysis will be done using SAS® Version 9.4 or higher (SAS Institute Inc., USA). 
For continuous variables, the summary statistics will be the number of observations, mean, standard 
deviation, median, minimum and maximum values. Categorical values will be summarized using 
frequencies and percentages. 
Primary Endpoints:  
x
Frequencies of grade 3 and 4 toxicities and serious adverse events (SAEs) considered by the investigator to 
be related to the combination, brequinar alone or placebo alone.
Because the primary study endpoint is a safety parameter no formal statistical testing will be performed for 
this parameter. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 66 of 80
Secondary Endpoints: 
For subjects treated with the brequinar-dipyridamole combination compared to subjects treated with the 
brequinar and to subjects treated with the placebo combination through Day 29, to determine: 
x
SARS-CoV-2 levels through Day 29 and at days 4, 8, 12, 15, 22, and 29 will be analyzed using analysis of 
covariance (ANCOVA) test; 
x
Time to symptom improvement through Day 29 will be analyzed using Kaplan-Meier time-to-event 
analysis; 
x
Percentage of subjects requiring hospital admission/re-admission as an in-patient for >24 hours through Day 
29 will be analyzed using Fisher exact / chi square test;
x
Percentage of subjects requiring medical attended visits, e.g., hospitalization, emergency room visits, Urgent 
Care/Family Doctor visits through Day 29 will be analyzed using Fisher exact / chi square test ; 
x
Percentage of subjects requiring supplemental support such as oxygen through Day 29 will be analyzed 
using Fisher exact / chi square test.   
Exploratory Endpoints:
x
Brequinar’s pharmacokinetic profile in a subset of patients that have received brequinar as a part of therapy 
and have consented to provide PK samples will be analyzed descriptively. 
15.5 Safety Analysis
All safety analysis will be conducted using the safety population set.  
Frequency distribution or summary statistics of all demographics variable and baseline characteristics will be 
generated by treatment arm.  
The evaluation of the drug safety will be based on clinical AEs, vital signs, physical examination, concomitant 
medications and laboratory abnormalities reported during the study and incidence of adverse events and 
treatment emergent adverse events in each arm during the study. All safety presentations will include subjects
who receive at least one dose of the study medication and will group subjects by treatment received. Frequency 
distributions and individual listings of all adverse events will be generated. Changes in clinical laboratory test 
results from baseline will be listed. 
A treatment emergent adverse event is defined as any event not present prior to the initiation of the treatments 
or any event already present that worsens in either intensity or frequency following exposure to the treatments. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) terms using the 
version that is current at the time the first subjects is enrolled and will be summarized by system organ class 
(SOC) and preferred term within SOC. The Common Terminology Criteria for Adverse Events CTCAE 5.0 
will be used to grade the severity of adverse events.  
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 67 of 80
Adverse Events will be summarized by treatment and overall. AE summary tables will include counts of subjects
and the number of events. If a subject experiences more than one episode of a particular AE, that subject will 
be conducted only once for that event. If a subject has more than one AE that coded to the same preferred term, 
the subject will be counted only once for that preferred term. Similarly, if a subject has more than one AE within 
a SOC, the subject will be counted only once in that SOC. 
16.0
AMENDMENT TO THE PROTOCOL 
Any significant change in the study procedure or study design will only be effected upon mutual agreement 
between the Sponsor, CRO and Investigator and after obtaining a favorable opinion from the Ethics Committee 
and regulatory authority(ies). All such changes will be documented in the amended version of the protocol and 
a list of changes with reference to the previous version will be generated and submitted to the IEC and regulatory 
authorities as soon as possible. In cases where there is an immediate safety hazard to the subjects, the amended 
protocol will be effective immediately and approval of the IEC will be obtained as soon as possible. 
17.0
SOURCE DATA ACCESSIBILITY 
Quality Assurance (QA) auditors and study monitors of Veeda Clinical Research Ltd. as well as sponsor’s 
monitors, IEC and Regulatory agency(ies) will have access to raw data during inspection and audits. 
18.0
STUDY MONITORING 
Monitoring procedures developed by Veeda will be followed in order to comply with GCP guidelines and to 
ensure acceptability of the study data for national registration purposes. During the course of the study, a 
monitor from Veeda will perform site visits to review protocol compliance, compare CRFs to individual 
subject's medical records, assess drug accountability, and ensure that the study is being conducted according to 
pertinent regulatory requirements. CRF entries will be verified with source documentation. 
The Sponsor or its representative may visit the study facilities at any time in order to maintain current and 
personal knowledge of the study through review of the records, comparison with source documents, observation 
and discussion of the conduct and progress of the study.  
This clinical trial is to be conducted at Investigator sites and the Investigators should permit the different 
stakeholders for monitoring/ auditing/ inspections at their site. 
19.0
QUALITY CONTROL AND QUALITY ASSURANCE AUDITS 
Auditing procedures developed by Veeda will be followed in order to comply with GCP guidelines and to 
ensure accuracy, completeness and authenticity of the data generated, recorded and reported and acceptability 
of the study data for international registration purposes. 
 
The raw data generated during the course of the study as well as reports will undergo a random quality assurance 
process for conformance to this protocol and all the governing SOPs by the Monitors and the auditors of Veeda 
Clinical Research Ltd, respectively. The final report will contain a statement of quality assurance duly signed 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 68 of 80
by the Head, Quality Assurance department. 
20.0
ETHICS 
20.1 Ethics Committee 
This protocol and corresponding informed consent Document (ICD) (containing information about the study to 
be given to subjects) to be used to obtain written informed consent of study subjects will be reviewed by IEC 
and subjects will not be enrolled into the study until IEC approves the protocol and ICD. 
The study will be conducted according to the current version of the IEC approved protocol, Relevant SOPs, 
[New Drugs & Clinical Trial Rules, 2019 of CDSCO (Central Drugs Standard Control Organization), Ministry 
of health and family welfare, Government of India], [Ethical guidelines for biomedical research on human 
participants, ICMR (Indian Council of Medical Research (2006)], [ICH (The International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use) E6 (R2) ‘Guideline for Good 
Clinical Practice’ 2016], Declaration of Helsinki – Brazil, October 2013].  
20.2 Written Informed Consent 
Investigator or designated study personnel before initiation of any study related procedure will inform the 
subject (in a language best understood by the subject) through an oral presentation regarding the purpose, 
procedures to be carried out, information on the investigational medicinal products, potential hazards, benefits 
and rights of the study subjects with maintaining adequate social distancing. Subjects will be encouraged to ask 
questions and clarify their doubts regarding any aspect of the study and the same would be documented in the 
source notes with sign and date. The ample time after completion of ICF discussion will be given to the subjects
to think and take an informed and voluntary decision. Investigator will ensure that the entire process of informed 
consent is followed as per local regulatory requirement for each subject at the respective site maintaining the 
confidentiality of subject’s personal information and all relevant records will be maintained in source file. The 
responsibility for taking informed consent must remain with that of a medically qualified person and cannot be 
delegated to a non-medically qualified person.  
Subject (or legally acceptable representative) should be present during the entire informed consent process and 
will also append his/her signatures on the informed consent form. If subject or subject’s legally acceptable 
representative is unable to read/write, an impartial witness should be present during the entire informed consent 
process, and will append his/her signatures on the informed consent form. In both the above cases, subjects will 
be required to give a thumb impression on the informed consent form. Only those subjects who are able to 
understand the ICF and able to communicate with the study personnel will be enrolled in the study. 
The subjects will give their written consent for participation in the trial by signing or by putting a thumb 
impression on the informed consent form, which will also be signed by the Investigator or his/her designate. 
If any new information becomes available during the course of the study that may be relevant to the subject’s 
willingness to continue participating in the trial, the Investigator must inform the subject in a timely manner, 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 69 of 80
and a revised written informed consent must be obtained. 
Investigator will ensure that all the subject are handed over a signed and dated copy of the informed consent 
form immediately once the informed consent process is completed. 
21.0
DATA HANDLING AND RECORD KEEPING 
All clinical data generated during the conduct of the study will be entered in the source notes and will be 
transcribed in the respective CRF. All raw data and transcribed data forms compiled by the study personnel 
assisting in the study will be checked for completeness. All data related to the project will be in the custody of 
the Investigator or Project Manager until transferred to archives.  
All raw data generated during the conduct of the project compiled by the study personnel assisting in the study 
will be checked for completeness. Biostatistics department after receipt of the raw data will perform a statistical 
analysis and statistical data will be generated which will be further sent for compilation of the final clinical 
study report of the study. 
22.0
STUDY REPORTS AND SUPPLEMENTARY DOCUMENTS 
The final report will be compiled and sent as per eCTD (Module 5) format. All copies of supplementary 
documents such as approved final version of Protocol along with all appendices, IEC approval letter, List of 
IEC members, CVs of Investigators, all subject CRFs, adverse event form (if any), Investigational Product 
Accountability records, Randomization list, Summary report of statistical analysis, protocol deviations, 
demographics and baseline characteristics and safety data will be submitted to sponsor with the final study 
report. 
23.0
ARCHIVING 
All data generated in connection with this study, together with the copy of this protocol and the audited final 
report will be archived according to the ICH guideline for good clinical practice and regulatory requirement and 
the TMF plan agreed with the Sponsor. Subject files, original source notes with Signed informed consent form 
and Patient Information Sheet (PIS), CRFs (If paper CRF has been used) and the Site Investigator File will be 
retained at individual study site as per applicable regulatory guidelines. 
All other data generated will be retained at Veeda as mentioned in Research Service Agreement. The sponsor 
will then arrange for the maintenance of these documents.   
24.0
INSURANCE POLICY 
The sponsor has a clinical trial insurance policy to cover the risks to subjects and/or any other eventualities 
pertaining to study. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 70 of 80
25.0
CONFIDENTIALITY OF DATA 
The data identifying each subject by name will be kept confidential and will be accessible to the study personnel 
and if necessary, to the QA auditors, IEC, Sponsor representative and Regulatory agency(ies). 
Information related to COVID-19 infection may be highly sensitive in nature with a lot of scope for 
stigmatization, discrimination, violence etc. Maintaining confidentiality of research related data and its 
publication is important to protect the privacy of individuals and avoid any discrimination against them. 
26.0
PUBLICATION POLICY 
The results of the study including all data obtained will be the property of sponsor of this study. For any 
publication pertaining to the data or results of the study, a written approval of the sponsor will be obtained prior 
to communicating for publication and the manuscript will be sent for sponsor’s approval, if the sponsor asks to 
do so. 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 71 of 80
27.0
REFERENCES 
1. CLINICAL MANAGEMENT PROTOCOL: COVID-19 released by Government of India Ministry of 
Health and Family Welfare Directorate General of Health Services (EMR Division). Version 6. Released 
on: 24.05.21
2. WHO R&D Blueprint novel Coronavirus COVID-19 Therapeutic Trial Synopsis. February 18, 2020, 
Geneva, Switzerland 
3. Declaration of Helsinki, Fortaleza, Brazil, October 2013. 
4. International Council on Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use- Good Clinical Practice (ICH-GCP) E6 (R2). 
5. Ethical Guidelines for Biomedical Research On Human Participants, Indian Council of Medical Research, 
2017.
6. Investigational Brochure Brequinar for COVID-19 Version: 5.0 Date: 23 September 2021. 
7. Prescribing Information of dipyridamole USP 25 mg, 50 mg, and 75 mg tablets.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 72 of 80
28.0
CLINICAL LABORATORY TESTS
HEMATOLOGY
Hemoglobin
Absolute WBC Counts (Neutrophils, Lymphocyte, Eosinophils, Monocyte, Basophils)
Complete Blood Counts, hematocrit, RBC count and indices
White blood cell (WBC) count, Differential Leucocyte count, Platelet count
BIOCHEMICAL PARAMETERS
SGOT (AST)
Alkaline Phosphatase
Serum Magnesium
SGPT (ALT)
Random Blood Glucose
Serum Potassium 
Total Bilirubin
Serum Cholesterol
Total Protein
Direct Bilirubin
Serum Triglyceride 
Indirect Bilirubin
Serum Creatinine
Blood urea nitrogen (BUN)
Creatinine clearance 
Pregnancy test by β-hCG Method
(for all females of child bearing 
potential)
Urea
SEROLOGY
HIV 
HbsAg (Hepatitis B surface 
antigen)
HCV antibodies
URINE ANALYSIS
Color
Glucose
WBC
Odor
Bilirubin
Epithelial Cells
Clarity
Blood
Casts
Specific gravity
Ketones
Crystals
pH
Urobilinogen
Bacteria
Protein
Nitrite
x
Any laboratory test, if required for adverse event management, may be performed at a local clinical 
laboratory at the discretion of Investigator.
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 73 of 80
29.0
LIST OF CHANGES IN THE PROTOCOL FROM VERSION 02 TO VERSION 2.1
Sr. 
No.
Section
Protocol
(Version 02 Dated 30 Sep 
2021)
Changes in Protocol
(Version 2.1 Dated 28 Dec 
2021)
Reason
1
Section 3.1 
Synopsis 
(Study 
Design)
&
Section 9.1 
Study 
Design
An expansion cohort of 
approximately 48 subjects will 
be added to the cohort with the 
highest brequinar dose that 
meets safety criteria.
All subjects will receive SOC as 
per relevant guidelines for 
treatment of patients with mild 
to moderate COVID-19 
infection.
An expansion cohort of 
approximately 48 subjects will 
be added to the cohort with the 
highest brequinar dose that 
meets safety criteria.
Safety data of cohort 1 to 
cohort 4 (or highest dose 
cohort evaluated) will be 
submitted to the regulators 
and their approval will be 
obtained prior to commencing 
recruitment in the expansion 
cohort.
All subjects will receive SOC as 
per relevant guidelines for 
treatment of patients with mild 
to moderate COVID-19 
infection.
Updated for 
better 
clarification
2
Section 5.3 
Safety of 
Dipyridamole
---
Introduction:
Dipyridamole was first 
approved for use in 1961 as an 
adjunct to coumarin 
anticoagulants in the 
prevention of postoperative 
thromboembolic complications 
of cardiac valve replacement.
The primary therapeutic 
actions of dipyridamole relate 
to its activity in (1) inhibiting 
platelet function and 
aggregation and (2) 
vasodilatation.
Dipyridamole inhibits the 
uptake of adenosine into 
platelets, endothelial cells and 
Additional 
dipyridamole 
information 
added
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 74 of 80
erythrocytes in vitro and in 
vivo; the inhibition occurs in a 
dose-dependent manner at 
therapeutic concentrations 
(0.5−1.9 μg/mL). This 
inhibition results in an 
increase in local 
concentrations of adenosine 
which acts on the platelet A2-
receptor thereby stimulating 
platelet adenylate cyclase and 
increasing platelet cyclic-3',5'-
adenosine monophosphate 
(cAMP) levels. Via this 
mechanism, platelet 
aggregation is inhibited in 
response to various stimuli 
such as platelet activating 
factor (PAF), collagen and 
adenosine diphosphate (ADP).
Dipyridamole also inhibits 
phosphodiesterase (PDE) in 
various tissues. While the 
inhibition of cAMP-PDE is 
weak, therapeutic levels of 
dipyridamole inhibit cyclic-
3',5'-guanosine 
monophosphate-PDE (cGMP-
PDE), thereby augmenting the 
increase in cGMP produced by 
EDRF (endothelium-derived 
relaxing factor, now identified 
as nitric oxide).
Preclinical study data:
In addition to the effects upon 
platelet function, dipyridamole 
can cause vasodilatation.
Hemodynamics:
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 75 of 80
In dogs intraduodenal doses of 
dipyridamole of 0.5 to 4.0 
mg/kg produced dose-related 
decreases in systemic and 
coronary vascular resistance 
leading to decreases in 
systemic blood pressure and 
increases in coronary blood 
flow. Onset of action was in 
about 24 minutes and effects 
persisted for about 3 hours.
Similar effects were observed 
following intravenous 
dipyridamole in doses ranging 
from 0.025 to 2.0 mg/kg.
In man the same qualitative 
hemodynamic effects have 
been observed. However, acute 
intravenous administration of 
dipyridamole may worsen 
regional myocardial perfusion 
distal to partial occlusion of 
coronary arteries.
3
Section 5.5 
Adverse 
Reactions
---
Brequinar:
As discussed above, brequinar 
is an investigational drug that 
has been given to 71 patients 
with COVID-19. Adverse 
events related to brequinar 
were mild to moderate and 
infrequent, and no subjects 
discontinued brequinar 
treatment due to a related 
adverse event in either of the 
two COVID-19 studies.
Brequinar has also been given 
to more than 800 patients with 
various forms of cancer in 
more than 20 clinical trials 
Additional 
dipyridamole 
information 
added
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 76 of 80
and has also been tested in 
patients with psoriasis and 
those who have had a kidney 
or liver transplant. The most 
common side effects in cancer
patients when given higher 
doses of brequinar have been:
x
Thrombocytopenia, which 
may require replacement.  
Low platelet count can lead 
to bruising, nose bleeds, 
vomiting blood, bloody 
diarrhea, blood in the 
urine, bloody gums, 
coughing up blood, and 
taking longer to stop 
bleeding from cuts. 
x
Stomatitis/mucositis.
x
Other risks associated with 
brequinar include:
o
Skin rash,
o
Nausea,
o
Vomiting,
o
Diarrhea,
o
Leukopenia,
o
Anemia, 
o
Yellowing of the skin or 
whites of the eyes caused 
by high levels of the 
pigment bilirubin,
o
Abnormal liver tests,
o
Abnormal kidney 
function,
o
Cardiac complications, 
and 
o
Fatigue 
Some of these side effects were 
severe enough in patients 
treated with brequinar to 
require hospitalization or 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 77 of 80
caused death. In most cases, 
these side effects went away
within about 2 weeks after 
patients stopped taking 
brequinar. 
Patients must be contact to 
study doctor/study staff if they 
experience any of the 
following:
x
Discoloration/bruising of 
the skin or a rash of 
red/purple spots on your 
skin.  These can be caused 
by bleeding in or under the 
skin,
x
Nose bleed,
x
Coughing up blood,
x
Blood in urine,
x
Bleeding gums,
x
Prolonged bleeding time 
from needle sticks, 
abrasions or lacerations,
x
Vomiting blood,
x
Rectal bleeding,
x
Blood in stool, 
x
Any other unusual 
bleeding  
Dipyridamole:
Dipyridamole will be used in 
this study as a pyrimidine 
salvage inhibitor when co-
administered with brequinar 
(see Rationale below). When 
used per the labeled 
indications of stroke 
prevention and inhibitor of 
blood clot formation, adverse 
reactions at therapeutic doses 
are usually minimal and 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 78 of 80
transient. In combination with 
warfarin, the dipyridamole 
label reports dizziness 
(13.6%), abdominal distress 
(6.1%), headache (2.3%), and 
rash (2.3%). Reactions from 
uncontrolled studies include 
diarrhea, flushing, and 
pruritus. Angina pectoris has 
been reported rarely and there 
have been rare reports of liver 
dysfunction. In post-marketing 
reporting experience, there 
have been rare reports of 
hypersensitivity reactions 
(such as rash, urticaria, severe 
bronchospasm, and 
angioedema), larynx edema, 
fatigue, malaise, myalgia, 
arthritis, nausea, dyspepsia, 
paresthesia, hepatitis, 
thrombocytopenia, alopecia, 
cholelithiasis, hypotension, 
palpitation, and tachycardia.
In the case of real or suspected 
overdose, symptoms may 
occur such as warm feeling, 
flushes, sweating, restlessness, 
and feeling of weakness and 
dizziness. There is an 
increased risk of 
thrombocytopenia when 
taking dipyridamole. There 
are no clinical data to suggest 
that dipyridamole is beneficial 
for treating COVID-19.
Co-Administration of 
Brequinar and Dipyridamole:
This combination has not 
previously been tested in the 
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 79 of 80
clinic. There is a potential for 
increased bleeding when 
taking either drug as well as
the combination, and the risk 
compared to brequinar or 
dipyridamole when 
administered alone is
unknown. To address any
potential increased risk, 
careful attention will be paid 
to laboratory reports and any 
increased signs or symptoms 
of bleeding during this study.
4
Section 5.6
Rational
(…) It has also been widely 
prescribed in combination with 
aspirin to prevent stroke.
(…)
(…) It has also been widely 
prescribed in combination with 
aspirin to prevent stroke. There 
is no clinical evidence that 
dipyridamole used alone is
effective for treating SARS-
CoV-2.
(…)
Additional 
dipyridamole 
information 
added
5
Section 3.1 
Synopsis 
(Exclusion 
Criteria)
&
Section 8.2 
Exclusion 
Criteria
(…)
13. Chronic hepatitis B 
infection, active hepatitis C 
infection, active liver disease 
and/or cirrhosis per subject 
report.
(…)
(…)
13. HIV, Chronic hepatitis B 
infection, active hepatitis C 
infection, active liver disease 
and/or cirrhosis per subject 
report.
(…)
To rectify the 
error
6
Section 27
References
(…)
---
(…)
6. Investigational Brochure 
Brequinar for COVID-19
Version: 5.0 Date: 23 
September 2021.
7. Prescribing Information of 
dipyridamole USP 25 mg, 
50 mg, and 75 mg tablets. 
Updation
	
		


Protocol for clinical study of Brequinar 
Protocol No.: 21-VIN-0372
Version No.: 2.1; Dated: 29 Dec 2021
Supersedes: 02; Date of Supersedes: 30 Sep 2021
Confidential                                                                                                                                                      Page 80 of 80
SIGNATURE(S) OF INVESTIGATOR(S) 
I, the undersigned, have read and understood this protocol, entitled 
“The CRISIS-04 Study: A phase II, randomized, assessor-blind, multicenter, multi-dose, placebo-
controlled study assessing the safety and anti-coronavirus response of brequinar combined with 
dipyridamole in patients with mild to moderate SARS-CoV-2 infection.”
and hereby agree to conduct the study in accordance with this protocol and to comply with all the requirements 
regarding the obligations of Investigators and all other pertinent requirements of the Ethical guidelines for 
biomedical research on human participants (ICMR) 2017 guidelines, New Drugs and Clinical Trial Rules (2019) 
of India, ICH (Step 5) ‘Guidance on Good Clinical Practice’ ICH Guidance E6 (R2), Declaration of Helsinki 
(Brazil, 2013) and with procedures oriented to Good Laboratory Practice and applicable regulatory guidelines. 
I agree to comply with all relevant SOPs required for the conduct of this study. I further agree to ensure that all 
associates assisting in the conduct of this study are informed regarding their obligations. 
___________________________________________           Date: ____________________
Investigator
Name:       
Address:   _________________________________________________________________
__________________________________________________________________________
__________________________________________________________________________
__________________________________________________________________________
Tel. No.:  ________________________________________
Fax: ____________________________________________
E-mail: __________________________________________
	
		