Clinical trial NCT04668209
Conditions: Coronavirus
Keywords: SARS-CoV-2 COVID-19
Sponsor: University of Arizona
Start date: 2021-01-21; Completion date: 2022-10-19
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multi-center, open-label, 2 arm parallel-group, randomized, interventional prospective exploratory study in 40 patients aimed to evaluate safety and explore putative clinical benefits of Silmitasertib 1000 mg BID dose in patients with severe illness caused be SARS-COV-2. This will be a two-arm trial comparing the SOC/best supportive care alone to the SOC/best supportive care with addition of Silmitasertib (allocation ratio 1:1).

Detailed description:
This is a phase II multi-center, randomized, open-label, 2 arm parallel-group controlled interventional prospective study of CX-4945 in patients with severe COVID-19. Up to approximately 40 patients will be enrolled into this study. A screening evaluation will occur within 7 days prior to Day 1. All qualified patients will be randomized at Day 1 in a ratio of 1:1 to one of the following two treatment arms:

Arm A: SOC/ best supportive care in combination with CX-4945 1000 mg BID PO or Arm B: SOC/ best supportive care alone The standard of care (SOC) is not pre-specified, may vary among patients, and may include agents with anti-viral activity, such as remdesivir, among others. Investigator discretion is to be applied for any established SOC. Active concomitant treatment with other investigational antivirals or immunomodulators are not permitted Best supportive care is defined as intensive care therapy according to current guidelines, evidence, and best practice, including but not limited to lung protective ventilation, thrombosis prophylaxis, renal replacement therapy when indicated, and access to advanced therapies including extracorporeal membrane oxygenation.

The total duration of the treatment will be 14 days. Patients will be followed up at 28, 45 and 60 days from the start of the treatment. The total duration for each patient in the study (including the screening) will be up to 67 days.

Arms: arm 1: Standard of care / supportive care in combination with Silmitasertib (CX-4945) arm 2: Standard of care / supportive care
Interventions: intervention 1: Silmitasertib
Intervention descriptions: intervention 1: Standard of care / best supportive care in combination with CX-4945 1000 mg administered orally, two times a day.

Protocol documents:
Prot_SAP_002.pdf: 
Phase II, Randomized, Investigator Initiated Trial to Evaluate Safety and to 
Explore Clinical Benefit of Silmitasertib (CX-4945) in Patients With Severe 
Coronavirus Disease 2019 (COVID-19)   
Study Protocol and Statistical Analysis Plan 
NCT04668209   
February 10, 2021 


A Phase II, Randomized, Investigator Initiated Trial to Evaluate Safety and to 
Explore Clinical Benefit of Silmitasertib (CX-4945) in Patients with Severe 
Coronavirus Disease 2019 (COVID-19)   
Protocol Number: 
CX4945-AV02-IIT 
Version: 
3.0 
Date: 
01 February 2021 
Study Product: 
Silmitasertib (CX-4945) 
Sponsor-Investigator: 
Dr. Marilyn Glassberg Csete, MD 
University of Arizona 
475 N. 5th Street  
Phoenix, AZ 85004 
        Drug Provider: 
Senhwa Biosciences, Inc.  
10F, No.225, Sec. 3, Peihsin Rd, Hsintein Dist. 
New Taipei City 23143 
Telephone: +886-2-8911-9856 


Protocol # CX4945-AV02-IIT
                                                                                                   Version 3.0
 
 
 
Date: 01 February 2021
PROTOCOL APPROVAL PAGE
 
 
 
Protocol Number:  
CX4945-AV02-IIT 
Version: 
 
3.0
Date: 
01 Feb 2021
We, the undersigned, have reviewed this protocol and agree that it contains all relevant information 
required to meet FDA, GCP and all applicable regulatory guidelines and statutes. 
PROTOCOL APPROVAL FOR USE 
Marilyn Glassberg Csete, MD
University of Arizona College of Medicine
Chief of Pulmonary, Critical Care, and Sleep 
Medicine
Date
lyn Glassberg Csete, MD
i
f A i
C ll
f M
February 10, 2021


 
 
Protocol # CX4945-AV02-IIT 
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Date: 01 February 2021 
INVESTIGATOR’S SIGNATURE PAGE 
 
 
 
Protocol Number:  
CX4945-AV02-IIT 
 
Version: 
 
3.0 
 
Date: 
 
01 February 2021 
 
I have read the protocol specified above and agree to participate in and comply with the procedures, 
as outlined herein for the conduct of this clinical trial. I also agree to comply with US Food and 
Drug Administration (FDA) regulations and Investigational Review Board/Institutional Ethics 
(IRB/IEC) requirements for testing on human subjects. I agree to ensure that the requirements for 
obtaining informed consent are met.  
 
 
 
 
 
Principal Investigator’s Signature 
 
 
 
 
Date 
Print Name 
 
 
 
 
 
 
Site Name 
 
 
 
 
 


Protocol # CX4945-AV02-IIT
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Date: 01 February 2021
Table of Contents 
Page 
1.
PROTOCOL SUMMARY .....................................................................................................9
1.1. Synopsis .............................................................................................................................9
1.2. Schema .............................................................................................................................14
1.3. Schedule of activities (SOA) ...........................................................................................15
2.
INTRODUCTION AND BACKGROUND ........................................................................17
2.1. Study Rationale ................................................................................................................17
2.2. Background ......................................................................................................................17
2.3. Silmitasertib (CX-4945) ..................................................................................................19
2.4. Risk/Benefit assessment ..................................................................................................21
3.
OBJECTIVES AND ENDPOINTS .....................................................................................22
4.
STUDY DESIGN...................................................................................................................25
4.1. Overall Design .................................................................................................................25
4.2. Justification for dose ........................................................................................................25
4.3. End of Study Definition ...................................................................................................25
5.
STUDY POPULATION .......................................................................................................27
5.1. PATIENT ELIGIBILITY CRITERIA .............................................................................27
Inclusion Criteria ....................................................................................................27
Exclusion Criteria ...................................................................................................28
5.2. Screen failures .................................................................................................................29
6.
STUDY TREATMENT ........................................................................................................30
6.1. Study treatment administration ........................................................................................30
Investigational Drug Product Description ..............................................................30
Randomization ........................................................................................................30
Dosing and Administration of CX-4945.................................................................30
Investigational Product Compliance .......................................................................31
Silmitasertib (CX-4945) Dose Modifications .........................................................31
6.2. Investigational Product Supplies, Storage and Accountability ........................................32


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Investigational Product Supplies ............................................................................32
Formulation, Appearance and Packaging...............................................................32
Product Storage and Stability .................................................................................33
6.3. Concomitant Medication .................................................................................................33
Premedication - Antiemetic Drugs (Mandatory) ....................................................33
Anti-Diarrheal Medication (Recommended): .........................................................33
Electrolyte Abnormalities .......................................................................................34
6.4. Silmitasertib (CX-4945) Drug Interaction .......................................................................34
Effect of CX-4945 in Human Liver Microsomes...................................................34
7.
STUDY DISCONTINUATION ...........................................................................................36
7.1. Subject Completion .........................................................................................................36
7.2. Subject Withdrawal From Participation ..........................................................................36
7.3. Subject Discontinuation from study treatment ................................................................36
8.
STUDY ASSESSMENTS AND PROCEDURES ...............................................................38
8.1. Study Procedures .............................................................................................................38
Screening Period:....................................................................................................38
Treatment Period: ...................................................................................................38
Follow Up Period ....................................................................................................38
Unscheduled Visits .................................................................................................39
8.2. Assessments .....................................................................................................................39
Safety Assessment ..................................................................................................39
Pregnancy Testing ..................................................................................... 39
Adverse Events .......................................................................................... 39
Vital Signs and Physical Examination ...................................................... 40
Laboratory Safety Assessment .................................................................. 40
Electrocardiogram ..................................................................................... 41
Other Assessments..................................................................................... 41
Efficacy/Anti-viral Activity Assessment ................................................................41
Clinical Evaluation to Assess Recovery .................................................... 41
EQ-D5-5L .................................................................................................. 42
COVID-19 8-Point Clinical Progression Outcomes Scale ........................ 42


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Pulse Oxygen Saturation (SpO2): ............................................................. 42
Laboratory Assessment of Changes and Trend in Inflammatory Markers 42
RT-PCR ..................................................................................................... 43
Chest Radiograph or CT ............................................................................ 43
8.3. Adverse Events and serious adverse events .....................................................................43
Definitions of Adverse Event (AE) ........................................................................43
Definition of Serious Adverse Events ....................................................................43
Classification of an Adverse Event .........................................................................44
Severity of Event ....................................................................................... 44
Causality Assessment ................................................................................ 44
Expectedness ............................................................................................. 46
Reporting of Adverse Events ..................................................................................47
Impact on Study Treatment ....................................................................... 47
Treatment Given as a Result of the Event ................................................. 47
Outcome Assessment................................................................................. 47
Reporting of Serious Adverse Events (SAE)..........................................................47
SAE Follow-Up ......................................................................................................48
9.
STATISTICAL ANALYSIS ................................................................................................49
9.1. Treatment Groups ............................................................................................................49
9.2. Description of Study Outcomes (Endpoints) ...................................................................49
Safety Measures:.....................................................................................................49
9.3. Sample Size Determination and Rationale ......................................................................49
9.4. Randomization .................................................................................................................49
9.5. Blinding ...........................................................................................................................50
9.6. Interim Analysis ...............................................................................................................50
9.7. General Statistical Considerations ...................................................................................50
Analysis Populations ..............................................................................................50
Intent-to-Treat Population ......................................................................... 50
Per Protocol Population ............................................................................. 50
Safety Population....................................................................................... 50
Covariates ...............................................................................................................50


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Missing Data...........................................................................................................50
9.8. Analysis Methods ............................................................................................................51
Subject Disposition.................................................................................................51
Demographic and Baseline Characteristics ............................................................51
Concomitant Medications/Therapies ......................................................................51
Study Outcome Assessment ...................................................................................51
Efficacy Analysis....................................................................................... 51
Supportive Analysis................................................................................... 52
Safety Summaries ...................................................................................... 52
9.9. DMC PERIODIC SAFETY REVIEW ............................................................................53
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION .....................................54
11. QUALITY CONTROL AND QUALITY ASSURANCE ..................................................55
11.1.
Monitoring Requirements ....................................................................................55
11.2.
Modification of Protocol ......................................................................................55
11.3.
Reporting Protocol Deviations .............................................................................55
Major Protocol Deviation or Violation.................................................................55
Minor Protocol Deviation or Violation .................................................................56
12. ETHICS AND REGULATORY REQUIREMENTS ........................................................57
12.1.
Institutional Review Board/Independent Ethics Committee (IRB/IEC) ..............57
12.2.
Investigator’s Responsibilities .............................................................................57
12.3.
Subject Informed Consent Requirements ............................................................58
13. DATA HANDLING AND RECORD KEEPING ...............................................................59
13.1.
Recording and Collection of Data........................................................................59
13.2.
Archiving .............................................................................................................59
14. PUBLICATION PLAN ........................................................................................................61
15. REFERENCES......................................................................................................................62
16. APPENDIX ............................................................................................................................63
16.1.
Appendix 1:  EQ-5D-5L Questionnaire ...............................................................63
16.2.
Appendix 2: Common Terminology Criteria for Adverse Events v5.03 .............66


 
 
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List of Tables 
Page 
Table 1. Schedule of activities .......................................................................................................15 
Table 2. Method of Assignment to Treatment ...............................................................................30 
Table 3. Silmitasertib (CX-4945) Dose Modification and Management for potential toxicities 
(attributable to Silmitasertib) ...........................................................................................31 
Table 4. Safety Laboratory Tests ...................................................................................................40 
Table 5. CTCAE v5.0 General Guidelines ....................................................................................44 
 
SUMMARY OF SIGNIFICANT CHANGES IN UPDATED  
CLINICAL PROTOCOL CX4945-AV02-ITT 
 
Version 3, dated 09 February 2021  
Replacing Version 2, dated 06November 2020  
 
Section /Topic 
Changes Made in Clinical Protocol v#3 
Section 1.3 Schedule of 
Activities, Footnote #16 / Data 
collection after hospital 
discharge 
Language Added: [16] Patient follow-up should continue after 
discharge via approaches available to the site staff (e.g., telehealth 
visits, COVID-19 outpatient clinic, telephone calls, texts, and emails 
to the patient and close contacts).   
Section 5.1 Patient Eligibility 
Confirmation/ Inclusion 
Criteria 
Administrative Change: Inclusion Criteria #2 shall read that a 
positive COVID-19 test is required within 7 days of 
randomization, either original diagnosis or a confirmation test.   
Administrative Change: Patient shall meet inclusion criteria #3 
if the require ≥ 2L oxygen in order to normalize SaO2. An 
adequate SaO2 does not need to be maintained for the patient to 
qualify 
Revision: Inclusion criteria #6 was revised to read that a patient 
meets eligibility in the absence of any active or recurring 
clinically significant hepatic disease’ and with a Albumin  level 
of ≥2.5 g/dL   
Section 8.1 Study Procedures/ 
Preventing Missing Data 
Language Added: Patient follow-up should continue after discharge 
via approaches available to the site staff (e.g., telehealth visits, 
COVID-19 outpatient clinic, telephone calls, texts, and emails to the 
patient and close contacts).  These efforts should prevent missing data 
while limiting additional public health risks and unnecessary 
community exposure. 


 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
SYNOPSIS 
Title:  
A Phase II, Randomized, Investigator-Initiated Trial to Evaluate Safety and to 
Explore Clinical Benefit of Silmitasertib (CX-4945) in Patients with Severe 
Coronavirus Disease 2019 (COVID-19) 
Study 
Description: 
COVID-19 is characterized by SARS-COV-2-induced upregulation of host protein 
kinase CK2 that catalyzes phosphorylation of many proteins, modulating their 
activities in cellular processes. SARS-COV-2 nucleocapsid directly targets CK2 and 
this viral-host protein interaction affect many vital processes in host cells 
contributing to dysregulated host immune response, viral survival, replication and 
spread to nearby cells. Silmitasertib demonstrated anti-viral and anti-inflammatory 
efficacy in COVID-19 in vitro studies and remarkable clinical benefits under 
emergency IND authorization 
This multi-center, open-label, 2 arm parallel-group, randomized, interventional 
prospective exploratory study in 40 patients aimed to evaluate safety and explore 
putative clinical benefits of Silmitasertib 1000 mg BID dose in patients with severe 
illness caused be SARS-COV-2. This will be a two-arm trial comparing the 
SOC/best supportive care alone to the SOC/best supportive care with addition of 
Silmitasertib (allocation ratio 1:1).  
Primary 
Objective 
and 
Endpoints: 
Primary Objective 
Primary Endpoint 
To assess safety and 
tolerability of CX-4945 
administered 
orally 
twice daily to patients 
with severe COVID-19 
Adverse Events experienced by the patients from 
randomization to Day 60 (including vital signs, physical 
findings, clinical laboratory, and ECG results) as 
characterized by type, frequency, severity (as graded by 
Common Terminology Criteria for Adverse Events 
(CTCAE version 5.0), timing, seriousness, and 
relationship to study therapy. 
Secondary 
Objectives 
and 
Endpoints: 
Secondary Objectives Secondary Endpoints 
To compare time to 
clinical recovery in CX-
4945 treatment group 
evaluated 
from 
 Number of days from randomization to discharge, or 
to alleviation of cough (defined as mild or absent in 
a patient reported scale of 0=absent, 1=mild, 


 
 
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randomization through 
Day 28 as compared to 
the control arm. 
2=moderate, and 3=severe). Improvement must be 
sustained for at least 48 hours.  
 Number 
of 
days 
from 
randomization 
to 
normalization of fever (defined as <36.6°C from 
axillary site, or < 37.2°C from oral site or < 37.8°C 
from rectal or tympanic site), normalization of 
respiratory rate (< 24 bpm while breathing room air), 
resolution of hypoxia (defined as SpO2 ≥ 93% in 
room air or P/F ≥ 300 mmHg). All these 
improvements must be sustained for at least 48 
hours. 
 Number of days from randomization to the first day 
on which the subject satisfies one of the following 
three categories from the ordinal NIAID 8- point 
Clinical Progression Outcomes scale collected  
daily from randomization through Day 28: 
 
Hospitalized, not requiring supplemental 
oxygen - no longer requires ongoing medical 
care;  
 
Not hospitalized, limitation on activities 
and/or requiring home oxygen;  
 
Not hospitalized, no limitations on activities. 
To compare changes in 
clinical 
status 
of 
patients enrolled to CX-
4945 treatment arm as 
compared to the control 
arm at Day 14 and Day 
28.  
 Difference in percentage of subjects with clinical 
recovery compared at Day 14 and Day 28. Clinical 
recovery is defined as:  
 Discharge from the hospital, or alleviation of 
cough (defined as mild or absent in a patient 
reported scale of 0=absent, 1=mild, 2=moderate, 
and 3=severe). Improvement must be sustained 
for at least 48 hours.  
 normalization of fever (defined as <36.6°C from 
axillary site, or < 37.2°C from oral site or < 
37.8°C 
from 
rectal 
or 
tympanic 
site), 
normalization of respiratory rate (< 24 bpm 
while breathing room air), resolution of hypoxia 
(defined as SpO2 ≥ 93% in room air or P/F ≥ 300 


 
 
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mmHg). All these improvements must be 
sustained for at least 48 hours. 
 Percentage of Participants at Each Clinical Status at 
Day 14 and Day 28 assessed by using the ordinal 
NIAID 8- point Clinical Progression Outcomes 
scale: 
1) Death;  
2) Hospitalized, on invasive mechanical ventilation 
or 
extracorporeal 
membrane 
oxygenation 
(ECMO);  
3) Hospitalized, on non-invasive ventilation or high 
flow oxygen devices;  
4) Hospitalized, requiring supplemental oxygen;  
5) Hospitalized, not requiring supplemental oxygen 
- requiring ongoing medical care (COVID-19 
related or otherwise);  
6) Hospitalized, not requiring supplemental oxygen 
- no longer requires ongoing medical care;  
7) Not hospitalized, limitation on activities and/or 
requiring home oxygen;  
8) Not hospitalized, no limitations on activities 
To evaluate preliminary 
evidence of anti-viral 
activity of CX-4945 as 
compared to the control 
arm. 
 Difference in proportions of patients with 
conversion of positive RT-PCR to negative RT-
PCR as assessed at Day 1, Day 8, Day 14 and Day 
28. 
 Changes in chest imaging from Screening  to Day 5 
or 14 (if applicable) as defined by: 
o Number of quadrants/ pulmonary lobes affected  
o Change in number and/or size of COVID-19 
pulmonary 
lesions 
(ground-glass 
opacity, 
consolidation, mix pattern) assessed by chest 
CT/X-ray 


 
 
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To evaluate the Clinical 
Benefit of Silmitasertib 
(CX-4945) relative to 
the 
control 
arm 
in 
patients with Severe 
COVID-19. 
 Days of hospitalization from randomization through 
Day 28. 
 Days of supplemental oxygen (if applicable) from 
randomization through Day 28. 
 All-cause mortality status - the number of deaths 
occurred 
in 
each 
treatment 
group 
from 
randomization through Day 60. 
 Days of non-invasive ventilation/high flow oxygen 
(if applicable) from randomization through Day 28. 
 Days of invasive mechanical ventilation/ECMO (if 
applicable) from randomization through Day 28. 
 Number of patients returned to room air after 
randomization through Day 14 or Day 28. 
 Change in pulse oxygen saturation (SpO2) from 
randomization  to Day 4, 8, 11, 14 and 28. 
 Number of documented venous thromboembolism 
(VTE), arterial thrombosis (stroke, myocardial 
infarction, other) and microthrombosis events from 
randomization through Day 28. 
 Changes in EQ-D5-5L (used as an indicator of 
symptom improvement) from randomization to Day 
8, 14 and 28. 
To evaluate changes in 
inflammatory markers  
 Changes in plasma IL-6 level from randomization  
to Day 4, 8, 11, and 14. 
 Changes in CRP, LDH, CPK, ferritin, D-dimer from 
randomization to Day 4, 8, 11, and 14. 
Study 
Population: 
This study will enroll male and non-pregnant female patients ≥ 18 years of age with 
severe Coronavirus Disease 2019 (COVID-19). Approximately 40 patients will be 
equally randomized in 2 treatment groups. 
Phase: 
II 


 
 
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Description 
of Sites 
Enrolling 
Participants: 
All patients will be enrolled at University of Arizona at Banner University Medical 
Center located in Phoenix or at University of Arizona College of Medicine in 
Tucson. 
Description 
of Study 
Intervention: 
CX-4945 will be administered twice a day for up to 14 days. The starting dose will 
be 1000 mg BID (2000 mg total daily dose). 
Study 
Duration: 
6 months (from study initiation until completion of data analyses) 
Participant 
Duration: 
The total duration of the treatment will be 14 days. Patients will be followed up at 
28, 45 and 60 days from the start of the treatment. The total duration for each patient 
in the study (including screening) will be up to 67 days. 
 
 


 
 
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1.2. 
SCHEMA 
Prior to  
Enrollment 
 
 
Day 1 
 
 
 
 
 
 
 
Day 1 
(Baseline) 
 
 
 
 
Days  4, 8, 11 
 
 
 
Day 14 
 
 
 
Follow-up 
Phase 
Days 28, 45 
 
 
 
 
60-Day Follow-up 
 
 
 
Total N = 40:   Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria; obtain history, complete screening 
Perform baseline assessments. 
- refer to Section 1.3, Schedule of Activities 
Arm A: StartCX-4945 Administration 1000 mg PO BID  
 
Follow-up assessments of study endpoints and safety 
- refer to Section 1.3, Schedule of Activities 
Perform visit procedures as specified in Section 1.3, Schedule of Activities 
Arm A: Last day of CX-4945 Administration 1000 mg PO BID 
Final Assessments 
of adverse event and survival status 
Arm B: 
 SOC/supportive care,  
N=20 
Arm A: 
SOC/ supportive care 
+CX-4945, N=20 
Perform visit procedures as specified in Section 1.3, Schedule of Activities 
Arm A: CX-4945 Administration 1000 mg PO BID on Day1-Day 14 
Randomize 


 
 
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1.3. 
SCHEDULE OF ACTIVITIES (SOA) 
Table 1. Schedule of activities 
Procedure/Assessments 
Screeni
ng Visit 
Treatment Phase [16] 
Follow-Up [17] 
Day 
SV 
Day 1 
(Baseline) 
Day   
4 
Day   
8 
Day 
11 
Day 
14  
Day 
28 
Day 
45 
Day 
60 
Window Period 
Day -7 
to 
Day -1 
within 7 
days after 
SV 
±1  
day 
±1  
day 
±1  
day 
±1    
day 
±3 
days 
±3 
days 
±3 
days 
Informed Consent [1] 
X 
 
 
 
 
 
 
 
 
Eligibility Evaluation [2] 
X 
 
 
 
 
 
 
 
 
Subject Demographics  
 
X 
 
 
 
 
 
 
 
 
Medical History [3] 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X[4] 
 
X[4] 
 
X[4] 
X[4] 
X[4] 
 
Vital Signs [5] 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of clinical recovery [6] 
 
X 
X 
X 
X 
X 
X 
X 
 
EQ-D5-5L 
 
X 
 
X 
 
X 
X 
 
 
Clinical Status - Ordinal 8-point 
Scale     Assessment [7] 
X 
X 
Daily from Day 1 through Day 28 
 
 
 
 
X 
X 
Pulse oxygen saturation (SpO2) 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
X 
 
 
 
Laboratory tests:  
 
 
 
 
 
 
 
 
 
Complete Blood Count [8] 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biochemistry [9] 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation Indices [10] 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum/Urine Pregnancy Test 
[11] 
X 
 
 
 
 
X 
 
 
 
Urinalysis [12] 
X 
X 
X 
X 
X 
X 
X 
X 
 
IL-6 levels 
 
X 
X 
X 
X 
X 
 
 
 
PT-PCR[13] 
X[13] 
X 
 
X 
 
X 
X 
 
 
Chest radiograph or CT   
X 
Day 5, Day 14 if indicated [14]  
 
 
 
Randomization [15] 
 
X 
 
 
 
 
 
 
 
IP Administration (Treatment Arm 
A only) 
 
Arm A: CX-4945 1000 mg BID PO  on 
Days 1 - 14 
 
 
 


 
 
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Mortality Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
[1] Informed consent must be obtained prior to patient participation in any protocol-related activities that are not part 
of routine care. 
[2] Initial evaluation of patient eligibility will be performed by Investigator. 
[3] Medical history and current therapies (medications and non-medications). 
[4] Symptom-directed physical examination 
[5] Vital signs will include blood pressure, heart rate, respiration rate, and temperature. 
[6] Based on hospital discharge or normalization of fever, respiratory rate, alleviation of cough, and resolution of 
hypoxia. 
[7] Clinical Assessment to be performed daily for at least 28 days, regardless of discharged or treatment discontinuation. 
Remote data collection methods, such as electronic data collection, phone, and telehealth assessments can be used from 
the day of discharge through Day 28, and at every follow-up visit (Days 28, 45 and 60). 
[8] Hemoglobin, Hematocrit (HCT), Red Blood Cells (RBC), White Blood Cells (WBC) with total and differential 
count, Absolute Neutrophil Count (ANC) and platelets. 
[9] Biochemistry (Comprehensive Metabolic Panel (CMP)) 
 
Hepatic function indicators: total bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), total protein, albumin, lactate dehydrogenase (LDH) 
 
Renal function indicators: BUN, Serum creatinine, creatinine clearance, or eGFR 
 
Electrolytes: sodium, potassium, chloride, calcium and bicarbonate 
 
Other: Creatine phosphokinase (CPK), C-reactive protein (CRP), serum ferritin, d-dimer 
[10] Prothrombin time (PT) and International Normalized Ratio (INR) 
[11] ONLY performed on women of childbearing potential. 
[12] Urine samples will be tested for color, appearance, specific gravity, pH, protein, glucose, occult blood, ketones, 
leukocyte esterase, nitrite, bilirubin, urobilinogen, and microscopic examination of urine sediment. 
[13] Positive standard RT-PCR assay or equivalent testing completed within 7 days prior to Day 1 is acceptable for 
eligibility evaluation at screening. 
[14] Chest radiograph or CT will be performed if clinically indicated by the treating physician 
[15] Randomization: Patient number and treatment arm allocation is performed on Day 1, prior to any Day 1 study 
assessments 
[16]   Patient follow-up should continue after discharge via approaches available to the site staff (e.g., telehealth visits, 
COVID-19 outpatient clinic, telephone calls, texts, and emails to the patient and close contacts).   
[17]   Follow-up visits may be performed via phone or telehealth, as appropriate 


 
 
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2. 
INTRODUCTION AND BACKGROUND 
2.1. 
STUDY RATIONALE 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human pathogen that 
emerged at the end of 2019 and rapidly spread worldwide caused a global pandemic. SARS-CoV-
2, an enveloped, positive-sense, single-stranded RNA beta-coronavirus of the family Coronaviridae 
that causes COVID-19. Patients with COVID-19 have had mild to severe respiratory illness with 
symptoms of fever, cough, and shortness of breath along with non-specific symptoms including 
myalgia and fatigue. Many infected people are asymptomatic or experience mild symptoms and 
recover without medical intervention. Some patients are more likely to develop a severe respiratory 
illness including pneumonia, severe acute respiratory syndrome, multi-organ failure, and death.  
Along with the development of new antiviral drugs, repurposing of existing drugs for COVID-19 
treatment has also accelerated. A number of clinical studies have been conducted to test the efficacy 
of FDA-approved drugs, re-purposed for COVID-19 (lopinavir, chloroquine, favipiravir, and 
remdesivir (RDV). At present, the main antiviral strategies currently employed against SARS-CoV-
2 can be divided into two types: strategies directly targeting the virus and strategies indirectly 
targeting the virus via host modulation. Despite some drugs demonstrated good efficacy, there are 
number of patients not responsive to available anti-COVID-19 therapy. There is no specific 
antiviral treatment recommended for COVID-19 by Centers for Disease Control and Prevention 
(CDC). People with COVID-19 should receive supportive care to help relieve symptoms. For 
severe cases, treatment should include care to support vital organ functions. Clinical management 
includes symptomatic and supportive care, such as supplemental oxygen, mechanical ventilation, 
and extracorporeal membrane oxygenation (ECMO) when indicated. Therefore, development of an 
effective antiviral drug for COVID-19 is a global health priority and discovery of novel cellular 
targets for SARS-Cov2 coronavirus has led to novel putative clinical strategies which merit going 
into clinical research in COVID-19. 
2.2. 
BACKGROUND 
Silmitasertib is a first-in-class small molecule drug that targets Casein Kinase 2 (CK2). Protein 
kinase CK2 phosphorylates key proteins required to trigger mechanisms vital for viral replication 
and also is involved in development of host anti-viral immune response. To counter host immune 
response and create more favorable environment for infection and viral multiplication, viruses have 
developed an arsenal of strategies. SARS-CoV-2 viral proteins interacting with many human host 
proteins affect multiple innate immune pathways. One of these key proteins dysregulated by SARS-
CoV-2 is the protein kinase CK2. Previous study showed that CK2 is involved in SARS-COV-2 
nucleocapsid (N-protein) interactome (virus-host protein interactions).  SARS-COV-2 upregulates 
CK2 to support viral replication, avoid innate immune response and spread virus to nearby cells. 


 
 
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Over activation of CK2 indirectly contribute to successful viral replication and development of 
cytokine storm. 
Researchers noted that the disruption of CK2, promotes the formation of Stress Granules (SGs), 
resulting in host cell translational arrest and significant limitation of the resources in cells required 
for viral replication [1]. Besides, SARS-CoV2 uses over activated CK2 in the infected cells to 
stimulate production of filopodia, as CK2 can promote actin polymerization and regulates 
cytoskeleton organization. Filopodia with assembled viral particles can invade and transfer the 
disease in the nearby healthy cells. Induction of virus-containing filopodia are important for SARS-
CoV-2 egress and cell-to-cell spread within epithelial monolayers. CK2 is also an important protein 
for Retinoic acid-inducible gene I (RIG-I) helicase activity regulation. RIG-I is an intracellular 
RNA virus sensor that mediates a signaling pathway that triggers alpha/beta interferon (IFN-α/β) 
immune defenses.  CK2 phosphorylates a RIG-I repressor domain to inactivate RIG-I in the resting 
uninfected state. SARs-Cov-2-induced overexpression of CK2 suppresses RIG-I-mediated 
signaling, while pharmacological inhibition of CK2 enhances expression of IFN-β and suppresses 
virus proliferation. CK2 signaling appears to be an important pathway hijacked by SARS-CoV-2. 
In several pre-clinical and clinical trials in oncology and some other diseases driven by pro-
inflammatory cytokines it was demonstrated that CK2 inhibitor CX-4945 significantly reduce 
cytokine expression (especially IL-6, IL-8, IL-17) and their signaling pathways. 
Senhwa's Silmitasertib is a targeted inhibitor of Casein kinase 2 (CK2). Silmitasertib demonstrated 
strong anti-viral and anti-inflammatory efficacy in vitro in human Calu-3 and HRCE cells and in 
monkey Vero-6 cell lines infected with SARS-COV-2.  As it targets host protein kinase CK2, 
SARS-COV-2 virus mutations are unlikely to affect Silmitasertib anti-viral or anti-inflammatory 
efficacy. 
Emerging pre-clinical and clinical data and results of independent efficacy evaluation conducted 
by Utah State University [2], UCSF COVID-19 Research Group [1] and Senhwa Biosciences 
hypothesize that Silmitasertib (CX-4945) could potentially quell virus-provoked aberrant 
hyperactivation of the innate immune system by inhibition of upregulated CK2 protein kinase, 
preferentially restoring  normal host cell cytokine regulation, and attenuating viral replication in 
patients with severe COVID-19, thereby preventing disease progression and improving clinical 
outcomes. The intended target patient population for treatment with Silmitasertib (CX-4945) are 
SARS-COV-2 positive patients with severe COVID-19, since in a severe stage of the disease 
infected cells actively produce viral proteins that dysregulate signaling pathways to allow viruses 
manipulate host immune responses to create an environment more favorable for infection, that may 
not be observed in the initial or mild stage of the disease. 
CX-4945 demonstrated remarkable clinical benefits under emergency IND authorization in a 
patient with severe COVID-19 pneumonia not responsive to remdesivir, dexamethasone and 


 
 
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antibiotics and requiring supplemental oxygen. The patient recovered and was discharged from 
the hospital in five days of treatment with CX-4945. 
 
2.3. 
SILMITASERTIB (CX-4945) 
Silmitasertib (CX-4945) is a first-in-class potent and highly selective small molecule inhibitor of 
CK2 that interacts competitively with the ATP-binding site of CK2 subunit alpha, leading towards 
the inhibition of several downstream signaling pathways. CK2 is involved in regulation of signaling 
pathways (Sonic Hedgehog (SHH), IL-6/STAT3, mTOR signaling pathways) through protein 
phosphorylation and also plays a multifunctional role in signal transduction, transcriptional control, 
apoptosis and inflammation. Overexpression of CK2 was observed in diseases with high 
proliferative activities, inflammatory reaction and dysregulated immune response (viral infections, 
auto-immune inflammations, cancer). 
The biological activity of CX-4945 has been evaluated in both in vitro and in vivo studies: 
 CX-4945 demonstrated strong anti-viral efficacy in human cells infected by SARS-CoV-2 
(pre-clinical in vitro study). [2] 
(https://www.biorxiv.org/content/10.1101/2020.04.21.054387v1)  
 CX-4945 significantly reduced replication of human papillomavirus in vivo. [3] 
 In several pre-clinical and clinical trials in the diseases driven by pro-inflammatory 
cytokines CX-4945 demonstrated anability to significantly reduce plasma level of 
interleukins (IL-6, IL-8, IL-17) in vitro and in vivo (inflammatory breast cancer, 
Alzheimer’s disease, autoimmune encephalomyelitis). [4] 
 CK2 inhibitor down-regulated replication, budding and release of influenza virus in pre-
clinical studies. [5] 
 CK2 inhibitor reduced phosphorylation dependent ICP27 protein export, which is 
necessary for its ability to export herpes simplex viral RNAs. [6] 
 CX-4945 also demonstrated anti-tumor activity in a variety of primary human xenografts 
and tumor cell line xenograft models and in clinical trials. 
Silmitasertib (CX-4945) is currently under development in several oncology programs in adults and 
in children with recurrent/advanced or metastatic cancer.  CX-4945 is being used as an antitumor 
agent that inhibits the Sonic Hedgehog signaling pathway (basal cell carcinoma, medulloblastoma) 
and/or DNA repair in tumor cells damaged by chemotherapy (cholangiocarcinoma) through 
inhibition of CK2. Three phase I clinical trials of CX-4945 in cancer patients have been completed 
to date (solid tumors, multiple myeloma), and there is one ongoing phase I study (BCC) and two 
ongoing phase II studies (CCA, Medulloblastoma). 
Approximately 200 patients have been treated with CX-4945 to date.  


 
 
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All patients in the completed trials had advanced and/or relapsed or refractory cancer and had 
undergone previous cancer treatments. The median age of the patients was ≥60 years, and all were 
taking concomitant medications during the studies. 
CX-4945 was generally well-tolerated when administered following a twice-daily (bid) or four 
times-daily (QID) oral dosing schedule for 21 days followed by 7 days of rest. Most adverse events 
reported were mild to moderate in severity. The most common toxicities associated with CX-4945 
were gastrointestinal disorders, including diarrhea, nausea and vomiting. Other frequently reported 
drug-related adverse events were hypokalemia and fatigue. Severe adverse events related to CX-
4945 were diarrhea, hypokalemia, hyponatremia, hypophosphatemia and lymphopenia. 
Most toxicities related to CX-4945 were manageable with drug discontinuation, use of antidiarrheal 
medication and potassium supplementation. 
The highest planned dose, 1000 mg bid, was found to be safe and tolerable. At this dose, 1 out of 
12 patients experienced DLT, grade 4 hypokalemia. 
Generally, dose dependent peak plasma concentrations and AUC have been observed in the 
pharmacokinetic studies at steady state during both the twice daily and four-times daily 
administration of CX-4945. The observed terminal half-life at steady state is approximately 15 
hours. 
Dose-proportional (Cmax and AUC) biomarker effects have been observed in CX-4945-treated 
patients, including reduced phosphorylation of Akt and p21 in PBMCs beginning with the 300 mg 
bid dose level and 300 mg QID dose level. Reduced levels of plasma IL-6 and IL-8 have also been 
observed. 
The existing safety and pharmacokinetic data generated from prior studies, supports the planned 
dosing frequency of twice daily (BID) for up to 14 days under the expanded access use for the 
severe COVID-19 indication. 
CX-4945 was used in a patient with severe COVID-19 pneumonia under emergency IND 
authorization. The patient had been treated with multiple therapeutics within two weeks, but 
remained hypoxic and required up to 2 liters of supplemental oxygen daily. Within 24 hours of the 
first dose of CX-4945 the oxygen requirement was weaned to room air. No drug-related toxicities 
were observed. The patient was discharged from the hospital within five days.  
The purpose of this open-label, 2 arm parallel-group, randomized, controlled interventional 
prospective exploratory, Investigator-Initiated Trial (IIT) in 40 patients is to evaluate safety and 
tolerability of Silmitasertib (CX-4945) 1000 mg BID dose. Secondary objectives will be used to 
make an initial assessment of the potential for clinical benefit. The drug supplier, Senhwa 


 
 
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Biosciences, is taking steps toward a subsequent randomized, double-blind, placebo-controlled 
study in a large number of subjects (NIH-sponsored ACTIV study).  
 
2.4. 
RISK/BENEFIT ASSESSMENT 
Silmitasertib is a generally well-tolerated medication. Most adverse events reported were mild to 
moderate in severity. The most common toxicities associated with CX-4945 were gastrointestinal 
disorders, manageable with drug discontinuation or use of anti-diarrheal medication.  Based on the 
currently available data, the identified or potential risks of the product do not outweigh its identified 
or potential benefits.  
 
 


 
 
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3. 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoint 
 To assess safety and tolerability 
of CX-4945 administered orally 
twice daily to patients with 
severe COVID-19 
 Adverse Events experienced by patients from randomization to 
Day 60 (including vital signs, physical findings, clinical 
laboratory, and ECG results) as characterized by type, 
frequency, severity (as graded by Common Terminology 
Criteria for Adverse Events (CTCAE version 5.0), timing, 
seriousness, and relationship to study therapy. 
Secondary Objectives 
Secondary Endpoints 
 To compare time to clinical 
recovery 
in 
the 
CX-4945 
treatment group evaluated from 
randomization through Day 28 
as compared to the control arm. 
 Number of days from randomization to discharge, or 
alleviation of cough (defined as mild or absent in a patient 
reported scale of 0=absent, 1=mild, 2=moderate, and 
3=severe).  Improvement must be sustained for at least 48 
hours. 
 Number of days from randomization to normalization of fever 
(defined as <36.6°C from axillary site, or < 37.2°C from oral 
site or < 37.8°C from rectal or tympanic site), normalization of 
respiratory rate (< 24 bpm while breathing room air), resolution 
of hypoxia (defined as SpO2 ≥ 93% in room air or P/F ≥ 300 
mmHg). All these improvements must be sustained for at least 
48 hours. 
 Number of days from randomization to the first day on which 
the subject satisfies one of the following three categories from 
the ordinal NIAID 8-point Clinical Progression Outcomes scale 
collected  daily from  randomization through Day 28: 
o 
Hospitalized, not requiring supplemental oxygen - no 
longer requires ongoing medical care;  
o 
Not hospitalized, limitation on activities and/or requiring 
home oxygen;  
o 
Not hospitalized, no limitations on activities. 
 To compare changes in clinical 
status of patients enrolled to 
CX-4945 treatment arm as 
 Difference in percentage of subjects with clinical recovery 
compared at Day 14 and Day 28. Clinical recovery is defined 
as:  


 
 
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compared to the control arm at 
Day 14 and Day 28. 
 Discharge from the hospital, or alleviation of cough 
(defined as mild or absent in a patient reported scale of 
0=absent, 1=mild, 2=moderate, and 3=severe). 
Improvement must be sustained for at least 48 hours.  
 normalization of fever (defined as <36.6°C from axillary 
site, or < 37.2°C from oral site or < 37.8°C from rectal or 
tympanic site), normalization of respiratory rate (< 24 bpm 
while breathing room air), resolution of hypoxia (defined 
as SpO2 ≥ 93% in room air or P/F ≥ 300 mmHg). All these 
improvements must be sustained for at least 48 hours. 
 Percentage of participants at each clinical status at Day 14 and 
Day 28 assessed by using the ordinal NIAID 8- point Clinical 
Progression Outcomes scale: 
1) Death;  
2) Hospitalized, on invasive mechanical ventilation or 
extracorporeal membrane oxygenation (ECMO);  
3) Hospitalized, on non-invasive ventilation or high flow 
oxygen devices;  
4) Hospitalized, requiring supplemental oxygen;  
5) Hospitalized, not requiring supplemental oxygen - requiring 
ongoing medical care (COVID-19 related or otherwise);  
6) Hospitalized, not requiring supplemental oxygen - no longer 
requires ongoing medical care;  
7) Not hospitalized, limitation on activities and/or requiring 
home oxygen;  
8) Not hospitalized, no limitations on activities 
 To evaluate preliminary 
evidence of anti-viral activity of 
CX-4945 as compared to the 
control arm. 
 Difference in proportions of patients with conversion of 
positive RT-PCR to negative RT-PCR as assessed at Day 1, 
Day 8, Day 14 and Day 28.. 
 Changes in chest imaging from Screening (Day 0)to Day 5 or 
Day 14 (if applicable) as defined by: 
o Number of quadrants/ pulmonary lobes affected  


 
 
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o Change in number and/or size of COVID-19 pulmonary 
lesions (ground-glass opacity, consolidation, mix pattern) 
assessed by chest CT/X-ray 
 To evaluate the Clinical Benefit 
of 
Silmitasertib 
(CX-4945) 
relative to the control arm in 
patients with Severe COVID-19. 
 Days of hospitalization from randomization through Day 28.  
 Days 
of 
supplemental 
oxygen 
(if 
applicable) 
from 
randomization through Day 28. 
 All-cause mortality status: the number of deaths occurred in 
each treatment group from randomization through Day 60. 
 Days of non-invasive ventilation/high flow oxygen (if 
applicable) from randomization through Day 28. 
 Days of invasive mechanical ventilation/ECMO (if applicable) 
from randomization through Day 28. 
 Number of patients returned to room air after randomization 
through Day 14 or Day 28. 
 Change in pulse oxygen saturation (SpO2) from randomization 
to Day 4, 8, 11, 14 and 28. 
 Number of documented venous thromboembolism (VTE), 
arterial thrombosis (stroke, myocardial infarction, other) and 
microthrombosis events from randomization through Day 28. 
 Changes in EQ-D5-5L (used as an indicator of symptom 
improvement) from randomization to Day 8, 14 and 28. 
 To evaluate changes in 
inflammatory markers 
 Changes in plasma IL-6 level from randomization to Day 4, 8, 
11, and 14 
 Changes in CRP, LDH, CPK, ferritin, D-dimer from 
randomization to Day 4, 8, 11, and 14 
 
 
 


 
 
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4. 
STUDY DESIGN   
4.1. 
OVERALL DESIGN 
This is a phase II multi-center, randomized, open-label, 2 arm parallel-group controlled 
interventional prospective study of CX-4945 in patients with severe COVID-19. Up to 
approximately 40 patients will be enrolled into this study. A screening evaluation will occur within 
7 days prior to Day 1. All qualified patients will be randomized at Day 1 in a ratio of 1:1 to one of 
the following two treatment arms:  
 Arm A:  SOC*/ best supportive care** in combination with CX-4945 1000 mg BID PO or  
 Arm B: SOC*/ best supportive care** alone 
* The standard of care (SOC) is not pre-specified, may vary among patients, and may include 
agents with anti-viral activity, such as remdesivir, among others. Investigator discretion is to be 
applied for any established SOC.  Active concomitant treatment with other investigational 
antivirals or immunomodulators are not permitted 
** Best supportive care is defined as intensive care therapy according to current guidelines, 
evidence, and best practice, including but not limited to lung protective ventilation, thrombosis 
prophylaxis, renal replacement therapy when indicated, and access to advanced therapies 
including extracorporeal membrane oxygenation.  
The total duration of the treatment will be 14 days. Patients will be followed up at 28, 45 and 60 
days from the start of the treatment. The total duration for each patient in the study (including the 
screening) will be up to 67 days.  For details on randomization see Randomization in Section 6.1.2. 
4.2. 
JUSTIFICATION FOR DOSE 
CX-4945 will be administered twice a day for up to 14 days. The starting dose will be 1000 mg 
BID (2000 mg total daily dose). This starting dose is based on three completed Phase I studies 
where patients were administered CX-4945 following a twice-daily (BID) or four-times-daily 
(QID) dosing regimen for 21 days followed by 7 days of rest. A total of 12 patients were treated in 
single agent studies at the 1000 mg bid dose level. Additionally, the safety and tolerability of 28 
day continuous dosing of CX-4945 at 1000 mg BID was verified during an ongoing Basal Cell 
Carcinoma (BCC) study with 12 subjects enrolled to date. In total, approximately 115 patients have 
been treated with 1000 mg twice daily dosing of CX-4945 in several completed and ongoing 
studies. 
4.3. 
END OF STUDY DEFINITION 


 
 
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A participant is considered to have completed the study if he or she has completed the treatment 
phase and follow-up visits at Day 28, Day 45, and Day 60.  
Discontinuation from the study drug does not mean the withdrawal from the study assessments. 
Subjects who discontinued therapy should remain in the study and continue follow-up for key 
outcomes. The only reasons for study withdrawal are withdrawal of consent and loss to follow-up. 


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5.
STUDY POPULATION
This study will enroll up to approximately 40 patients with severe Coronavirus Disease 2019 
(COVID-19). All study participants will be identified from the currently hospitalized patients. 
SOC/Best supportive care alone or in combination with CX-4945 will be given to study subjects. 
5.1.
PATIENT ELIGIBILITY CRITERIA 
This study can fulfill its objectives only if appropriate patients are enrolled. The following 
eligibility criteria are designed to select patients for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into consideration 
when deciding whether a particular patient is suitable for this protocol. 
Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the study:  
1. Male or non-pregnant female adult ≥ 18 years of age 
2. Diagnosed or confirmation of COVID-19 infection by standard RT-PCR assay or equivalent 
testing within 7 days prior to randomization (Day1). 
3. Hospitalized patient with severe illness caused by SARS-CoV-2 (Note: Prior or current use 
of remdesivir or dexamethasone (SOC) are allowed under the investigator’s discretion. 
Concomitant treatment with other investigational antiviral drugs or immunomodulators are 
not permitted from Day1 through Day 28) 

Symptoms of severe systemic illness/infection with COVID-19: 
o
At least 1 of the following: fever, cough, sore throat, malaise, headache, muscle pain, 
shortness of breath at rest or with exertion, confusion, or symptoms of severe lower 
respiratory infection including dyspnea at rest or respiratory distress 
AND 

Clinical signs indicative of severe systemic illness/infection with COVID-19
o
At least 1 of the following: RR ≥ 30, HR ≥ 125, SaO2 <93% on room air or requires 
≥ 2L oxygen in order to normalize SaO2. 
4.
Patient (or legally authorized representative) provides written informed consent prior to 
initiation of any study procedures. 
5. Adequate hematopoietic capacity, as defined by the following: 
a.
Hemoglobin ≥ 9.0 g/dL and not transfusion dependent
b. Platelets ≥ 100,000/mm3
c. Absolute neutrophil count ≥ 1500 cells/mm3


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6. Adequate hepatic function, as defined by the following: 
a.
AST and ALT ≤ 2.5 times upper limit of normal (ULN) 
b. Total bilirubin ≤ 1.5 x ULN  
c.
Albumin ≥ 2.5 g/dL 
7. Absence of any active or recurring clinically significant hepatic disease and adequate renal 
function, as defined by the following: 
a. Renal: calculated creatinine clearance >45 mL/min for patients with abnormal, 
increased creatinine levels (Cockcroft-Gault formula).  
8. Ability to take oral medication and be willing to adhere to drug administration and 
premedication requirements (see Section 6.3) throughout study duration.  
Exclusion Criteria
Potential subjects meeting any of the following criteria will be excluded from participation in this 
study: 
1. Patient showing signs of respiratory failure necessitating mechanical ventilation 
2. Pregnant or nursing women.  
NOTE: Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; or abstinence) prior to study 
entry and for the duration of study participation. Should a man father a child, or a woman 
become pregnant or suspect she is pregnant while participating in this study, he or she 
should inform the treating physician immediately. 
3. Active or uncontrolled infections other than COVID-19 or with serious illnesses or medical 
conditions which would not permit the patient to receive study treatment 
4. Active or planned concomitant treatment with other investigational antivirals or 
immunomodulators  
5. Chronic diarrhea (excess of 2-3 stools/day above normal frequency) 
6. Current use or anticipated need for drugs that are known strong inhibitors or inducers of 
major CYP enzymes.


 
 
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5.2. 
SCREEN FAILURES 
All subjects who fail to meet eligibility criteria are considered screen failures, and are exited from 
the study. Subject number, demographics and reason for screen failure will be recorded. 
If a subject initially fails to meet inclusion/exclusion criteria and is later reconsidered for 
participation, the subject will be re-consented and assigned a new unique identification number at 
the time of re-screening and may be enrolled if they are found to meet all inclusion and no exclusion 
criteria at the subsequent screening visit. 
 
 


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6.
STUDY TREATMENT
6.1.
STUDY TREATMENT ADMINISTRATION
Investigational Drug Product Description
For this study, the investigational product is CX-4945 that will be assigned to the subjects 
randomized to the treatment Arm A.  
Refer to Investigator Brochure or summary of product characteristics. 
All subjects enrolled in the study (Arm A and Arm B) may be treated with SOC/best supportive 
care as per the investigator’s discretion and in accordance with the site standard clinical practice. 
The patients randomized to the treatment Arm A will receive SOC/best supportive care therapy in 
combination with CX-4945. The patients randomized to the control Arm B will receive SOC/best 
supportive care alone.  
Randomization 
Randomized treatment assignments for the subjects will be done after confirmation of subject’s 
eligibility, and prior to any other Day 1 study assessments. Subjects will be allocated randomly into 
Arm A and Arm B in a 1:1 ratio. 
Table 2. Method of Assignment to Treatment 
Arm
SOC/ 
SUPPORTIVE 
CARE
Daily dose of 
CX-4945 
(mg)
Dose 
administration
b.i.d. (mg)
AM Dose
(mg)
PM Dose
(mg)
No. of 
capsules/day
A
Assigned by the 
investigator
2000
1000
1000 
1000
10
B
Assigned by the 
investigator
0
0
0
0
0
     *SOC and Supportive Care are defined in Section 4.1. 
Dosing and Administration of CX-4945
Patients enrolled to the treatment Arm A will receive 1000 mg of CX-4945 twice daily by mouth, 
beginning on Day 1, and continuously through Day 14.  
Patients will be instructed to take oral antiemetic prophylaxis at least 1 hour prior to taking the 
study drug. Other oral medications should be taken at least one hour before or 2 hours after ingesting 
the dose of CX-4945 capsules. 


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Patients will take five 200-mg CX-4945 capsules twice daily, two hours after the morning meal and 
two hours after the evening meal (dinner) with water. Patients are advised to take 1 capsule at a 
time with a pause in between each. This method may prevent a clumping effected in the stomach, 
so patient can take as much as 10 minutes to swallow each capsule. 
The study drug will be taken on an empty stomach with at least six ounces (180 mL) of water. After 
CX-4945 administration, the patient will be NPO (except for water) for 2 hours, after which, the 
patient may eat. 
Investigational Product Compliance
Site staff will dispense Investigational Product (CX-4945) to the study subjects randomized to the 
Treatment Arm A. If a patient misses a dose, he or she should be instructed not to take or make up 
that dose and to resume dosing with the next scheduled dose. Missed doses will not be made up and 
should be documented in the dosing record form. Patients will be instructed to return any unused 
capsules. The number of tablets/capsules returned by the patient will be counted, documented, and 
recorded. 
Silmitasertib (CX-4945) Dose Modifications
The most common drug related adverse events reported for CX-4945 are predominantly 
gastrointestinal disorders, including nausea, vomiting and diarrhea. The dose interruption, 
reduction, and permanent discontinuation for any toxicity are described below. Dose modification 
instructions provided bellow do not substitute for investigators’ medical judgement. Investigators 
should always manage their patients according to their medical judgement based on the particular 
clinical circumstances. 
Table 3. Silmitasertib (CX-4945) Dose Modification and Management for potential toxicities 
(attributable to Silmitasertib) 
CTCAE 5.0 Grade
(attributable to 
Silmitasertib)
Treatment Modifications
Grade 1
Treat on time. dose reduction is not required
Grade 2
Hold until< Grade 1, resume at same dose
Grade 3
Hold until< Grade 2, resume at dose reduced by 1 level (200 mg)
Grade 4
Hold until< Grade 2, resume at dose reduced by 1 level (200 mg). 
Permanent discontinuation can be considered by at the 
Investigator’s discretion

Dose Reduction: If a dose-response relationship for toxicity is observed, a reduced dose 
can be given to the subject. Dose adjustments will be allowed based on the toxicity, efficacy 
evaluation, and clinical judgment by physician.  


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
Dose Interruption: Refer to Table 3 above. Recovery to acceptable levels must occur to 
allow Silmitasertib (CX-4945) continuation. 

Dose Discontinuation: Treatment with CX-4945 can be discontinued prematurely due to 
the following reasons: 
o
Disease Progression  
o
Respiratory failure requiring invasive mechanical ventilation, 

Shock (defined by SBP < 90 mm Hg, or Diastolic BP < 60 mm Hg), or 

Multiple organ dysfunction/failure 

Intolerable toxicity most probably attributable to CX-4945. 
o
Pregnancy 
o
Significant study therapy non-compliance  
o
If any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued treatment under the protocol would 
not be in the best interest of the participant 
o
Withdrawal of consent from study treatment or participation 
Discontinuation from the study drug does not mean the withdrawal from the study 
assessments. Subjects who discontinued therapy should remain in the study and continue 
follow-up for key outcomes. The only reasons for study withdrawal are withdrawal of 
consent from study participation and loss to follow-up.
6.2.
INVESTIGATIONAL PRODUCT SUPPLIES, STORAGE AND ACCOUNTABILITY
Investigational Product Supplies
CX-4945 will be supplied by Senhwa Biosciences. Study center will receive CX-4945 prior to 
enrollment of the first patient.  The clinical site pharmacy /qualified staff member will dispense the 
supplies to the patients enrolled to the treatment Arm A in quantities appropriate for the study visit 
schedule. Any unused product or waste material should be disposed of in accordance with local 
requirements. 
Formulation, Appearance and Packaging
CX-4945-PIC has been manufactured as neat API powder in hard shell gelatin capsules (Capsugel) 
in a dose strength of 200 mg capsules (Powder in Capsule (PIC) formulation), for immediate 
release, oral administration.  There are no excipients used for PIC formulation. 
Clinical trial material supply of CX-4945-PIC for oral administration are supplied as 200 mg 
strength in size 1, opaque blue capsules, contained in 60 cc, wide mouth, white, high-density 


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polyethylene (HDPE) bottles.  Each bottle contains fifteen capsules with one (1 gram), white plastic 
PTC-0005 desiccant pod, and is induction heat sealed. 
Product Storage and Stability
CX-4945 clinical trial material should be stored in the container provided, between 15°C-30°C 
(59°F-86°F), and should be protected from moisture, freezing, and bright light. 
6.3.
CONCOMITANT MEDICATION
Premedication - Antiemetic Drugs (Mandatory)
All patients assigned to treatment with CX-4945 (Arm A)  will take an oral 5-HT3 antagonist daily, 
at least 1 hour prior to taking the CX-4945 capsules or a 5-HT3 antagonist transdermal patch at 
least 24 hours prior to taking the CX-4945 capsules every 7 days. If a patient prefers 5-HT3 
antagonist transdermal patch, the patient is expected to apply the patch approximately 24 hours 
before the day 1. If the patch is missed, the patient will be suggested to taking the oral 5-HT3 
antagonist 1 hour before taking CX-4945 on day 1 and continue taking the oral 5-HT3 antagonist 
for 7 days in order to switch to an antagonist patch. 
Medications within the 5-HT3 antagonist class are interchangeable depending on availability and 
tolerability.  Dose(s) of the antiemetic medication, either intensity or frequency can be adjusted as 
clinically indicated.  Patients should receive enough supply to cover the entire treatment.  
5-HT3 antagonist (choose one)
-
Dolasetron 100 mg PO daily
-
Granisetron 1 mg PO twice daily; the first 1 mg dose should be given up to 1 hour 
before CX-4945 (with second 1 mg dose 12 hours later) or 3.1 mg/24-h transdermal 
patch every 7 days
-
Ondansetron 8 mg PO twice daily; the first 8 mg dose should be given up to 1 hour 
before CX-4945 (repeat dose 8 hours after the initial dose)
Management of breakthrough nausea and vomiting should take place as necessary. 
Anti-Diarrheal Medication (Recommended):

All patients assigned to treatment with CX-4945 (Arm A) should be advised to obtain an 
adequate supply of loperamide (IMODIUM®) with explicit instructions for the 
management of diarrhea. 

Early diarrhea or abdominal cramps occurring within the first 24 hours is treated with 
atropine 0.3 - 1.2 mg IV or SC. Prophylactic atropine may be required for subsequent 
treatments.  


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
Late diarrhea has a median onset of 2 days post-treatment with CX-4945 and must be treated 
with loperamide (e.g., IMODIUM®). Instruct patient to have loperamide on hand and start 
treatment at the first poorly formed or loose stool, or earliest onset of more frequent stool 
than usual:  
o
4 mg start  
o
then 2 mg every 2 hours until diarrhea-free for 12 hours  
o
may take 4 mg every 4 hours at night  
Electrolyte Abnormalities
Electrolyte abnormalities are common adverse events with Silmitasertib (CX-4945) which may 
predispose subjects to arrythmias. 
a. Mandatory 5-HT3 antagonist pre-medication may compound this effect. To adequately 
monitor for this risk, a 24-hour telemetry monitoring for subjects with electrolyte 
abnormalities may be performed, if clinically indicated.  
b. Use of atropine as an anti-diarrheal medication may also compound this effect. Investigator 
should consider use of another anti-diarrheal agent for subjects who have persistent diarrhea 
despite use of loperamide. 
6.4.
SILMITASERTIB (CX-4945) DRUG INTERACTION
Effect of CX-4945 in Human Liver Microsomes 
The absorption, distribution, metabolism, and excretion (ADME) properties of CX-4945 have been 
evaluated in in vivo to support nonclinical safety evaluations and to assess the potential relevance 
to humans. CX-4945 was tested in a non-GLP in vitro ADME-TOX in human liver microsomes 
with the following seven key CYP450 isoenzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4. CX-4945 did not show significant inhibition or induction of 
any CYP isoenzymes tested in this study (for all isozymes more than 80 percent remained after 60 
minutes and it was not possible to calculate a specific half-life).  
The result suggests that CX 4945 does not inhibit or induce these seven CYP450 isozymes, and can 
therefore be safely co-administered with drugs that are metabolized via this pathway. 
Antiemetic drugs (5-HT3 antagonist) are required and anti-diarrheal drugs are recommended for 
concomitant use in the treatment group A for management of possible GI toxicities. CYP3A4 is the 
predominant enzyme pathway for ondandestron and granisteron metabolism. Loperamide is 
metabolized by the cytochrome P450 (CYP) system and is a substrate for the CYP3A4 isoenzyme. 
Approximately 200 subjects have been treated with CX-4945 in Phase I/II clinical trials to date and 
approximately 115 subjects received required and /or recommended concomitant treatment with 


 
 
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antiemetic and antidiarrheal drugs. CX-4945 was safely co-administered with concomitant 
medications with no drug-drug interaction (DDI) observed.  
 
Because complete CX-4945 metabolism information is not available at this point and treatment 
with 5-HT3 antagonist and anti-diarrheal drugs is planned for treatment arm A, current use or 
anticipated need for drugs that are known strong inhibitors or inducers of major CYP enzymes 
should be avoided from Day 1 through Day 14. If the replacement is not possible, then patients 
taking strong inhibitors or inducers of major CYP enzymes should not be enrolled to the study 
(exclusion criterion #6).   
 


 
 
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7. 
STUDY DISCONTINUATION 
 
7.1. 
SUBJECT COMPLETION 
A participant is considered to have completed the study if he or she has completed the treatment 
phase and follow-up visits at Day 28, Day 45, and Day 60. Documentation to whether or not each 
subject completed the clinical study will be recorded. 
7.2. 
SUBJECT WITHDRAWAL FROM PARTICIPATION 
At any point during the study and without prejudice to future care, all subjects have the right to 
withdraw from participation, refusing to complete scheduled study assessments and follow-ups. 
The reason for withdrawal from participation will be recorded in the subject medical records.  
All patients who discontinued therapy but maintain consent for study participation to be followed 
for outcome information and should remain in the study through the end of assessment and follow-
up period for all important safety and anti-viral activity data collection and evaluation. The only 
reasons for withdrawal from participation should be withdrawal of consent and loss to follow-up. 
Before a subject is identified as lost-to-follow up, the site should make all reasonable efforts to 
contact the subject. These attempts must be documented and should include at a minimum one 
phone call and one certified letter.  
7.3. 
SUBJECT DISCONTINUATION FROM STUDY TREATMENT 
The Investigator can discontinue a subject from study therapy at any time if in his clinical judgment 
considers to be medically necessary. Investigators considering discontinuing study treatment should 
contact the medical monitor prior to such discontinuation. The reason(s) for discontinuation of 
study treatment should be documented in sourse records. Subjects who have study treatment 
discontinued will continue to be followed, per protocol, whenever possible. If visits to the site are 
not possible after discharge, subjects can be followed via telehealth or other approaches (telephone 
calls, e-mails, and texts) to ascertain vital status in all subjects. 
Subjects who have study treatment discontinued due to a serious adverse event will be followed 
until resolution or stabilization of the event. 
Discontinuation from the study therapy does not mean the withdrawal from participation. Every 
attempt should be made to collect follow-up information to minimize missing data in this study. 
An investigator may discontinue a participant from the study therapy for the following reasons: 
 Pregnancy 
 Significant study therapy non-compliance  
 If any clinical adverse event (AE) or serious adverse event (SAE), laboratory 
abnormality, or other medical condition or situation occurs such that continued 
treatment under the protocol would not be in the best interest of the participant 


 
 
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 Disease progression which requires discontinuation of the study therapy 
 Significant study therapy non-compliance  
 Withdrawal of consent from study treatment 
In the event that a subject is withdrawn from the study treatment at any time due to an 
adverse event or SAE, the procedures stated in Section 8.3 (Safety) must be followed.  


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8.
STUDY ASSESSMENTS AND PROCEDURES
The study will have three phases: Screening Phase/Visit, Treatment Phase, and Follow-Up Phase. 
A schedule of assessments and procedures is provided in Section 1.3.
Due to risk of infection for study staff and hospital personnel, the site may take steps to limit face-
to-face interaction (i.e. telehealth or eSignature). 
8.1.
STUDY PROCEDURES
Screening Period:
The subject will sign and date the informed consent form (ICF) and Health Insurance Portability 
Accountability Act (HIPAA) authorization (according to site policy and practices) prior to any 
study-related procedures. The study center will maintain the study-specific screening and 
enrollment logs at their site.  
For screening procedures see the Schedule of Activities in Section 1.3 and Assessments in Section 
8.2.
Treatment Period: 
For the treatment period procedures see the Schedule of Activities in Section 1.3 and Assessments 
in Section 8.2.
Subjects who meet the eligibility criteria will be randomized prior to any other Day 1 study 
procedures. The following evaluations and assessments should be performed on Day 1prior to 
treatment: review of any changes in medication history, physical examination, vital signs, clinical 
status – ordinal scale assessment, EQ-D5-5L questionnaire, pulse oxygen saturation (SpO2), PT-
PCR, laboratory sample collection for routine serum biochemical, hematologic, coagulation, and 
IL6 levels analysis.  
Patient follow-up should continue after discharge via approaches available to the site staff (e.g., 
telehealth visits, COVID-19 outpatient clinic, telephone calls, texts, and emails to the patient and 
close contacts).  These efforts should prevent missing data while limiting additional public health 
risks and unnecessary community exposure. 
During the treatment phase, subjects randomized to the treatment arm A will receive CX-4945 
(1000 mg) twice a day for up to 14 days. Details on study drug administration can be found in 
Section 6.
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For follow-up procedures see the Schedule of Activities in Section 1.3 and Assessments in Section 
8.2.
Unscheduled Visits
In the event that the subject will return to clinic at a time other than a regularly scheduled study 
visit, the visit will be regarded as an unscheduled visit. Assessments at unscheduled visits are at 
the discretion of the Investigator. All pertinent findings, including adverse events or changes in 
medications, will be noted in the subject medical records. 
8.2.
ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are completed 
as described. However, it is anticipated that from time to time there may be circumstances outside 
of the control of the Investigator that may make it unfeasible to perform the test. In these cases the 
investigator will take all steps necessary to ensure the safety and well-being of the patient. When a 
protocol-required test cannot be performed, the investigator will document the reason for this and 
any corrective and preventive actions that he or she has taken to ensure that normal processes are 
adhered to as soon as possible. The study team will be informed of these incidents in a timely 
manner. 
Safety Assessment
Safety assessments will include collection of AEs, serious adverse events (SAEs), vital signs and 
physical examination, electrocardiogram (ECG [12-lead]), laboratory assessments, including 
pregnancy tests and verification of concomitant treatments. 
Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at least 25 
mIU/mL and must be performed by a certified laboratory. For female patients of childbearing 
potential, a negative pregnancy test is required before receiving CX-4945 (1 negative pregnancy 
test at screening). Following a negative pregnancy test result at screening, appropriate contraception 
must be commenced: the study candidate should have used 2 forms of contraception. Pregnancy 
tests will also be repeated at Day 14 to confirm that the patient has not become pregnant during the 
study. Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the study and 
when potential pregnancy is otherwise suspected. In the case of a positive confirmed pregnancy, 
the patient will be withdrawn from administration of investigational product but may remain in the 
study. 
Adverse Events


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Assessment of adverse events will include the type, incidence, severity (graded by the CTCAE 
version 5.0) timing, seriousness, and relatedness. For AE assessment details, see Section 8.3.3.
Investigator will follow-up for any AEs/SAEs and mortality status at Day 28, Day 45 and Day 60. 
Vital Signs and Physical Examination
Patients will have a full physical examination to include an examination of all major body systems, 
height (at screening only), weight, blood pressure and pulse rate, which may be performed by a 
physician, registered nurse or other qualified health care provider, as acceptable according to local 
regulation. A symptom-directed physical examination should be limited to systems of primary 
relevance (i.e., cardiovascular, respiratory, and systems associated with symptoms). Changes from 
baseline abnormalities should be recorded at each subsequent physical examination. New or 
worsened abnormalities should be recorded as an adverse event. 
Pulse oximetry should be collected prior to collection of the blood pressure, pulse rate, and 
temperature. Oxygen levels should be evaluated on the finger in accordance with the site standard 
procedures. All abnormalities will be evaluated by the study physician.  
Blood pressure, heart rate, respiration rate, and temperature should be recorded after approximately 
5 minutes rest. An abbreviated physical exam is an assessment for emergent toxicities or changes 
from prior visits and a symptom directed exam conducted by a physician, trained physician’s 
assistant or nurse practitioner, as acceptable according to local regulation.  
Laboratory Safety Assessment
Hematology and blood chemistry will be drawn at the time points described in the Schedule of 
Activities (see Section 1.3) and analyzed at local laboratories. Unscheduled clinical labs may be 
obtained at any time during the study to assess any perceived safety concerns. Samples for 
hematology, blood chemistry, coagulation, pregnancy and urinalysis will be analyzed by the site’s 
local laboratory. 
Table 4. Safety Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy Test
Hemoglobin
ALT
PT or INR
color, appearance, 
specific gravity, 
pH, protein, 
glucose, occult 
blood, ketones, 
leukocyte esterase, 
nitrite, bilirubin, 
urobilinogen
For female
patients of
childbearing
potential, serum
or urine
Hematocrit
AST
RBC
Alk Phos
Platelets
LDH
WBC
Total Protein
Absolute Neutrophils
Sodium


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Hematology
Chemistry
Coagulation
Urinalysis
Pregnancy Test
Absolute Lymphocytes
Potassium
microscopic 
examination of 
urine sediment
Absolute Monocytes
Ferritin
Absolute Eosinophils
Chloride
Absolute Basophils
Calcium
Bicarbonate
Total bilirubin
d-dimer
Creatine (serum)
BUN
Albumin
C-reactive Protein
(CRP)
Creatinine Clearance
IL-6
Creatine 
Phosphokinase (CPK)
eGFR
Electrocardiogram
Electrocardiogram (ECG): ECG will be done at Screening and at Day 14. It is preferable that the 
machine used has a capacity to calculate the standard intervals automatically, including QT and 
QTc interval. At each time point (see the Schedule of Activities), if the significant abnormalities 
(>Grade 2) in ECG intervals are revealed, then the ECGs should be re-evaluated by a qualified 
person at the site for confirmation as soon as the finding is made, including verification that the 
machine reading is accurate.  
Other Assessments
To adequately monitor for the risk of 5-HT3 antagonist pre-medication which may predispose 
subjects to arrythmias, a 24-hour telemetry monitoring for subjects with electrolyte abnormalities 
may be performed, if clinically indicated. 
Efficacy/Anti-viral Activity Assessment
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Assessment of recovery at the time points described in the Schedule of Activities (see Section 1.3) 
is based on hospital discharge or normalization of fever, respiratory rate, alleviation of cough, and 
resolution of hypoxia.  Normalization of fever (defined as <36.6°C from axillary site, or < 37.2°C 
from oral site or < 37.8°C from rectal or tympanic site), respiratory rate (< 24 bpm while breathing 
room air), alleviation of cough (defined as mild or absent in a patient reported scale of 0=absent, 
1=mild, 2=moderate, and 3=severe) and resolution of hypoxia (defined as SpO2 ≥ 93% in room air 
or P/F ≥ 300 mmHg) must be sustained for at least 48 hours. 
EQ-D5-5L 
Administration of questionnaires for patient-reported outcomes at the time points described in the 
Schedule of Activities. The 5-level EQ-5D version (EQ-5D-5L) will be used to assess five 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 
COVID-19 8-Point Clinical Progression Outcomes Scale 
Progression is assessed on COVID-19 8-point ordinal scale collected  daily from randomization 
through Day 28, regardless of discharge or treatment discontinuation status, to adequately capture 
relevant COVID19 outcomes. Remote data collection methods, such as electronic data collection, 
phone, and telehealth assessments can be used after patient discharge from the hospital through Day 
28 (see Section 1.3).  The ordinal scale of patient health status ranges from: 1) Death; 2) 
Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) 
Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen 
- requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring 
supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on 
activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. 
Pulse Oxygen Saturation (SpO2): 
Measuring the amount of oxygen-carrying hemoglobin in the blood relative to the amount of 
hemoglobin not carrying oxygen will be done at the time points described in the Schedule of 
Activities (see Section 1.3).
Laboratory Assessment of Changes and Trend in Inflammatory Markers
Laboratory tests for IL-6 CRP, LDH, CPK, ferritin and D-dimer levels will be done at the time 
points described in the Schedule of Activities (see Section 1.3) to evaluate early markers of 
inflammation response.  Laboratory tests will be performed locally, at CLIA certified local 
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
Ferritin levels may be useful early markers of disease progression or dysregulated 
immune response. 

D-dimer level is associated with pro-inflammatory cytokine cascade and development 
of cytokine storm. 

CRP produced by the liver in response to IL-6 is a marker of inflammation and rapid 
increase of CRP level is a marker of increased risk of cytokine storm development. 
RT-PCR
RT-PCR will be done at the time points described in the Schedule of Activities (see Section 1.3). 
At screening positive RT-PCR result (presence of SARS-COV-2 RNA) is required for inclusion 
criterion evaluation. Local, fully validated, RT-PCR tests shall be performed in a CLIA-certified 
and CAP-accredited laboratory.  
Chest Radiograph or CT
Chest X-ray or chest CT will be done and evaluated locally according to the standard site practice 
at the time points described in the Schedule of Activities (see Section 1.3). Responses to CX-4945 
administration will be followed on radiograph or CT scans using the Response Evaluation in 
COVID-19 patients with pneumonia. The chest-CT analysis will be performed considering number 
of pulmonary lesions, lesion’s extend, number of pulmonary lobes affected, and common COVID-
19 typical abnormalities like consolidation, glass-round opacity and mix pattern.  
8.3.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The Investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE, as provided in this protocol. During the study when there is a safety 
evaluation, the Investigator or site staff will be responsible for detecting, documenting and reporting 
AEs and SAEs as detailed in this Section of the protocol. 
Definitions of Adverse Event (AE)
An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, or disease that 
occurs or is reported by the patient to have occurred, or a worsening of a pre-existing condition. An 
adverse event may or may not be related to the study treatment.  
AEs will be elicited through direct questioning and subject reports. Any abnormality in physical 
examination findings or laboratory results that the investigator believes is clinically significant (CS) 
to the research subject and that occurred after initiation of the first study treatment will be reported 
as AEs. Abnormal findings that are NOT clinically significant should not be recorded as an AE. 
Definition of Serious Adverse Events


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A SAE is defined as any AE that: 

Results in death 

Is life threatening (the subject is at immediate risk of dying from the adverse experience) 

Requires subject hospitalization or prolongs existing hospitalization 

Results in persistent or significant disability/incapacity 

Is a congenital anomaly/birth defect 

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse effect when, based upon appropriate 
medical judgment, they may jeopardize the subject or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Classification of an Adverse Event
Severity of Event
The guidelines outlined in CTCAE v5.0 will be used for assessing the intensity of the event. The 
general guidelines for assessing the AE grade appear below. Full guidelines may be obtained at 
http://evs.nci.nih.gov/ftp1/CTCAE. 
Table 5. CTCAE v5.0 General Guidelines 
Grade
Description
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 activities of daily living (ADL)*.
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL†.
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
*Instrumental 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.
-Common Terminology Criteria for Adverse Events (CTCAE), v5.0: November 27, 2017
Causality Assessment


 
 
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AEs will be assigned a relationship (causality) to the study treatment. The Investigator will be 
responsible for determining the relationship between an AE and the study treatment. The type of 
event, organ system affected, and timing of onset of the event will be factors in assessing the 
likelihood that an AE is related to the study treatment. Relationship of AEs to study treatment will 
be classified as follows: 
1. Definitely related: This category applies to those AEs that the Investigator feels are 
incontrovertibly related to the study treatment. An AE may be assigned an attribution of 
definitely related if or when it meets all of the following criteria: (1) it follows a reasonable 
temporal sequence from administration of the study treatment; (2) it could not be reasonably 
explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it follows a known response 
pattern to treatment with the study treatment. 
2. Probably related: This category applies to those AEs which, after careful medical 
consideration at the time they are evaluated, are felt with a high degree of certainty to be related 
to the study treatment. An AE may be considered probable if or when (must have three): (1) it 
follows a reasonable temporal sequence from administration of the study treatment. (2) It could 
not readily have been produced by subject’s clinical state, environmental or toxic factors, or 
other therapies administered to the subject. (3) Disappears or is decreased upon discontinuation 
of the study treatment. (4) It follows a known response pattern to treatment with the study 
treatment.  
3. Possibly related: This category applies to those AEs which, after careful medical consideration 
at the time they are evaluated, are judged unlikely but cannot be ruled out with certainty to the 
study treatment. An AE may be considered possible if or when (must have two): (1) it follows 
a reasonable temporal sequence from administration of the study treatment. (2) It could not 
readily have been produced by subject’s clinical state, environmental or toxic factors, or other 
therapies administered to the subject. (3) Disappears or is decreased upon discontinuation of 
the study treatment. (4) It follows a known response pattern to treatment with the study 
treatment.  
4. Remotely related: In general, this category can be considered applicable to those AEs which, 
after careful medical consideration at the time they are evaluated, are judged likely to be 
unrelated to the study treatment. An AE may be considered unlikely if or when (must have two): 
(1) it does not follow a reasonable temporal sequence from administration of the study 
treatment. (2) It could not readily have been produced by subject’s clinical state, environmental 
or toxic factors, or other therapies administered to the subject. (3) Disappears or is decreased 
upon discontinuation of the study treatment. (4) It does not follow a known response pattern to 
treatment with the study treatment.  
5. Unrelated: This category applies to those AEs which, after careful consideration at the time 
they are evaluated, are clearly and incontrovertibly due to extraneous causes (disease, 


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environment, etc.) and determined with certainty to have no relationship to the study treatment.  
Expectedness
Medical Monitor will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event 
is not consistent with the information described in the Investigator Brochure.  
Refer to the Investigator Brochure for the expected/anticipated events. 


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Reporting of Adverse Events
Report initiation for all AEs and SAEs will begin at the time of randomization and continue until 
the end of final study visit.  All events will be followed to resolution or until the subject completes 
the study. A final assessment of outcome will be made at that time.  
All AEs must be recorded in the subject’s study records. AEs will be reported using customary 
medical terminology along with the following information: the onset and end dates,  whether the 
event is considered to be a SAE (see Section 8.3.2), the impact the event had on study treatment 
(see Section 8.3.4.1), the Common Terminology Criteria for Adverse Events (CTCAE) grade 
(intensity) of the event (see Section 8.3.3.1), the causality of the event (see Section 8.3.3.2), 
whether treatment was given as a result of the event (see Section 8.3.4.2), and the outcome of the 
event. (see Section 8.3.4.3) 
Impact on Study Treatment
The impact the event had on the study treatment will be assessed as either: dose increased, dose not 
changed, dose rate reduced, dose reduced, drug interrupted, drug withdrawn, not applicable, or 
unknown. The “not applicable” assessment will be used only when the subject is no longer in the 
Treatment Phase of the protocol.
Treatment Given as a Result of the Event
The event impact in terms of treatment provided will be as either: none, medication administered, 
non-drug therapy administered, surgery performed, hospitalization, or other (with a specification). 
Outcome Assessment
The outcome of the event will be assessed as either: fatal, not recovered/not resolved, 
recovered/resolved, recovered/resolved with sequelae, recovering/resolving, or unknown. Only one 
AE per subject is allowed to have an outcome assessment as “death.” If there are multiple causes 
of death for a given subject, only the primary cause of death will have an outcome of death.  
Reporting of Serious Adverse Events (SAE) 
The Investigator is required to report all SAEs that occur during the time period specified in Section 
8.3.4. The sponsor or its designated representative shall be notified within 24 hours of the 
Investigator awareness of the event. In particular, if the SAE is fatal or life-threatening, notification 
to the sponsor must be made immediately, irrespective of the extent of available AE information. 
This time frame also applies to additional new information (follow-up) on previously forwarded 
SAE reports.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
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is to report the event within 24 hours after learning of it and document the time of his or her first 
awareness of the AE.  
For all SAEs, the investigator is obligated to pursue and provide information to the sponsor in 
accordance with the time frames for reporting specified above. In addition, an investigator may be 
requested to obtain specific additional follow-up information in an expedited fashion. This 
information collected for SAEs is more detailed than that captured on the AE CRF. In general, this 
will include a description of the AE in sufficient detail to allow for a complete medical assessment 
of the case and independent determination of possible causality. Information on other possible 
causes of the event, such as concomitant medications, vaccines, and/or illnesses, must be provided. 
In the case of a patient death, a summary of available autopsy findings must be submitted as soon 
as possible to the sponsor or its designated representative.  
The Investigator is also responsible for reporting all SAEs to the appropriate Institutional Review 
Board (IRB) in accordance with local laws and regulations. The Investigator is responsible for 
maintaining documentation in the study file that indicates the IRB has been properly notified.  
SAE Follow-Up
All subjects experiencing an SAE, including the discontinued subjects, must be closely followed 
until sufficient information is obtained to indicate a return to normal status or until the event 
stabilizes at a level acceptable to the investigator (i.e., recovery, return to baseline status, no further 
improvement expected, or death). 
For each SAE indicated as an unresolved event on the initial report, regardless of whether the 
subject completed the study or withdrew, the site should submit a follow-up report with updated 
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9.
STATISTICAL ANALYSIS 
This section presents general information about statistical considerations and concepts and a brief 
discussion on analysis methodology, as well as some data conventions. Detailed descriptions of the 
statistical analysis methods and data conventions that will be used in this study will be in a separate 
document; i.e., the Statistical Analysis Plan (SAP). 
9.1.
TREATMENT GROUPS
There will be two treatment groups in the study:  

Arm A:  Best supportive and/or standard of care in combination with CX-4945 1000 mg 
BID PO or  

Arm B: Best supportive/standard of care   
9.2.
DESCRIPTION OF STUDY OUTCOMES (ENDPOINTS) 
For description of study outcomes see the Objectives and endpoints in Section 3
Safety Measures:

Incidence and severity of adverse events (AEs) 

Incidence of serious adverse events (SAEs) 

Incidence of AEs and SAEs leading to discontinuation of study medication.  

Changes in blood chemistry (including electrolyte abnormalities), hematology and 
coagulation parameter results 

Changes in vital signs including temperature, pulse, respiratory rate, systolic and diastolic 
blood pressure 

Changes in physical examination results 

Changes in electrocardiogram (ECG) results 
9.3.
SAMPLE SIZE DETERMINATION AND RATIONALE
A total of 40 subjects will be randomized 1:1 in this study. The sample size is based on clinical 
judgment. No statistical power calculation will be used to establish the sample size for this proof-
of-concept study. 
9.4.
RANDOMIZATION 
The randomization will use block size of 2 or 4 with a 1:1 ratio of CX-4945 in addition to 
SoC/supportive care group and SoC/supportive care alone group to ensure balanced distribution of 
subjects. An individual (pharmacy staff), independent of the clinical trial team, will develop the 
randomization schedules. Subjects who have provided written informed consent and have met all 
Detailed descriptions of the
statistical analysis methods and data conventions that will be used in this study will be in a separate 
document; i.e., the Statistical Analysis Plan (SAP). 


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the inclusion criteria and none of the exclusion criteria will be randomized to one of the treatment 
groups. 
9.5.
BLINDING
This is an open label study. 
9.6.
INTERIM ANALYSIS
No Interim Analysis (IA) is planned for this study.
9.7.
GENERAL STATISTICAL CONSIDERATIONS
All collected study data will be presented in subject data listings. Descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum) will be presented by treatment group for 
continuous variables. Frequencies and percentages will be presented by treatment group for 
categorical variables. 
Analysis Populations
Intent-to-Treat Population
The Intent-to-Treat (ITT) population is defined as all randomized subjects. This population will be 
used as the primary analysis population for analysis of the primary and secondary efficacy 
endpoints. 
Per Protocol Population
The Per Protocol (PP) population is defined as the set of subjects who meet the ITT Population 
requirements and are not associated with any major protocol violations. This population will be 
identified before the database lock.  This population will be used as the supportive analysis 
population for analysis of the primary and secondary efficacy endpoints. 
Safety Population
The Safety population is defined as any subject receiving at least one dose of CX-4945 or standard 
of care treatment after randomization. This population will be used for the analysis of safety 
parameters. 
Covariates
For efficacy analyses important prognostic factors that need adjustment will be specified in the 
Statistical Analysis Plan (SAP) for the study 
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The method for handling missing data will be included in the statistical analysis plan. Every effort 
will be made to obtain required data at each scheduled evaluation from all subjects who have been 
randomized in the study to minimize missing data. However, in the event when there is missing 
data the following imputation methods will be used. 
For activity/efficacy evaluations, multiple imputation methods will be used to handle missing data 
and will be detailed in the Statistical analysis Plan (SAP). This imputation method is a robust 
method to impute potential missing measurements.  
9.8.
ANALYSIS METHODS
A statistical analysis plan (SAP) will be developed and approved before the database is locked. The 
SAP will present the detailed statistical methodology to be used in analyzing the data from this trial. 
Subject Disposition
The disposition of all subjects who signed an ICF will be provided. The number of subjects 
screened, screen failed, received at least one treatment, completed, and discontinued during the 
study, as well as the reasons for all discontinuations will be summarized by treatment group. 
Disposition and reason for study discontinuation will also be provided as a by-subject listing. 
Demographic and Baseline Characteristics
Demographics and baseline characteristics including medical history, prior and concomitant 
medications/therapies will be summarized by treatment group using appropriate descriptive 
statistics. 
Concomitant Medications/Therapies
Concomitant medications/therapies will be summarized separately for the Safety population. It will 
be coded to matching Anatomic Therapeutic Classification codes using the most recent version of 
the WHO Drug Dictionary. Descriptive summaries by treatment group will be prepared using the 
coded term. 
Study Outcome Assessment
For continuous variables data will be summarized by treatment using n, mean, SD, minimum and 
maximum values. For categorical variables data will be summarized by treatment using frequency 
and percentage. No inferential statistics are planned. The Safety Population will be used for the 
analysis of safety outcomes.  
Efficacy Analysis 
Analysis of the efficacy endpoints will be summarized according to the variable type and will be 
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Continuous data:  
o
If the normality assumption is met, Analysis of Covariance (ANCOVA) would be 
used.  
o
If the normality assumption is not met, a non-parametric method or a rank –
ANCOVA analysis i.e., an ANCOVA analysis on rank-transformed data will be 
used.  
Categorical data summaries will be based on logistic regression or proportional odds model 
will be used. 
Time-dependent data: Cox proportional hazards model will be used to analyze time 
dependent data and Kaplan-Meier methods will be used to depict the time to event data.  
Supportive Analysis 
To assess the consistency of the Primary Analysis results, supportive analysis will be conducted 
using the Intent to Treat (ITT) and Per Protocol (PP) populations. Statistical methodology for the 
supportive analyses will be the same as that of the primary analysis, with the exception of the 
analysis population used.  
Safety Summaries 
Adverse Events 
Adverse events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). Treatment Emergent AE’s (TEAE) are defined as events with an onset on 
or after the first treatment. TEAEs will be summarized by treatment group, System Organ Class, 
and preferred term. The following TEAE summaries will be provided: 

Overall (i.e., regardless of severity or relationship to treatment); 

By intensity (mild, moderate, severe, life threatening or death); 

By causality (definitely, probably, possibly, remotely or unrelated); 

By impact on study treatment (dose increased, dose not changed, dose rate reduced, dose 
reduced, drug interrupted, drug withdrawn, not applicable, or unknown). 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 
Clinical Laboratory Data 
All laboratory values will be listed. Laboratory measurements will also be summarized and 
presented by treatment group and time point. 


 
 
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ECG 
All ECG values will be listed. ECG measurements will also be summarized and presented by 
treatment group and time point. 
Vital Signs 
All vital sign findings will be listed and/or summarized. 
Physical Examination 
All physical examination findings will be listed and/or summarized. 
9.9. 
DMC PERIODIC SAFETY REVIEW 
An independent Data Monitoring Committee (DMC) established by the site will be used during the 
study to ensure subject safety and trial integriry and also to provide support in assessment of any 
new possible safety risks imposed by the COVID-19 public health emergency on patient safety and 
its possible impact of protocol implementation. 
The DMC will review the listings of adverse events, protocol deviations, and an enrollment 
summary. The first formal safety review will occur after the first 3 patients randomized to the 
CX4945 treatment (Arm A) complete their treatment course. The study accrual will not be 
interrupted for  the scheduled safety reviews, if no specific study-related safety concerns are raised 
by the Sponsor-Investigator of DMC members. Subsequent periodic safety review will be 
scheduled as prespecified in the DMC charter. The DMC or Sponsor-Investigator may request an 
ad hoc meeting for any reason, including a significant unexpected safety event, follow-up of 
observations during a planned DMC meeting, high enrollemnt rate, or a report external to the study, 
such as publication of study results from a competing product.  The DMC will communicate major 
safety concerns and recommendations regarding study modification or termination to Sponsor-
Investigator. Recommendations are not legally binding but require consideration and a formal 
written response from the Sponsor-Investigator. Further details are provided in the DMC charter. 
 


 
 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Subjects will be identified on study records by a unique subject identification number and on source 
documents by name and date of birth. No personal identifier will be used in any publication or 
communication used to support this research study. The subject identification number will be used 
if it becomes necessary to identify data specific to a single subject.  
The local IRB, FDA, the monitors, auditors and personnel authorized by the Investigator/Sponsor 
are eligible to review the medical and research records related to this study as part of their 
responsibility to protect human subjects in clinical research. They will be given direct access to 
source data and documentation (e.g., medical charts/records, printouts etc.) for source data 
verification, provided that subject confidentiality is maintained in accordance with local 
requirements. Access to electronic medical records may be governed by institution policy. The 
Investigator will be required to ensure access while remaining compliant with institutional 
requirements. 
 


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11.
QUALITY CONTROL AND QUALITY ASSURANCE
11.1.
MONITORING REQUIREMENTS
The Investigator/Sponsor should be aware that the study site and subject records may be inspected 
by the FDA or other regional regulatory authority. 
11.2.
MODIFICATION OF PROTOCOL
The Investigator/Sponsor will not modify or alter this protocol without first obtaining the 
concurrence of the Sponsor. Approval by the Investigator/Sponsor’s IRB must also be obtained 
prior to implementation of the change, with two exceptions: 
1. When necessary to eliminate apparent immediate hazard to the subject; or 
2. When the modification does not involve the subject’s participation in the trial. 
An amendment may also require modification of the informed consent form.  
11.3.
REPORTING PROTOCOL DEVIATIONS
The Investigator/Sponsor is obligated to follow the protocol without departure from the 
requirements written in the protocol. The Investigator/Sponsor also has the right to discontinue the 
subject for protocol violations. The IRB may also have to be contacted if safety to the subject or if 
the scientific soundness of the study is involved.  
Major Protocol Deviation or Violation
A major protocol deviation or violation is a deviation from the IRB approved protocol that may 
affect the subject's rights, safety, or wellbeing and/or the completeness, accuracy and reliability of 
the study data. Examples of this include: 

Failure to obtain informed consent prior to initiation of study-related procedures  

A research subject does not meet the protocol's eligibility criteria but was enrolled 

A research subject received the wrong treatment or incorrect dose. 

A research subject met withdrawal criteria during the study but was not withdrawn. 

A research subject received a prohibited concomitant medication. 

Failure to treat research subjects per protocol procedures that specifically relate to primary 
outcome measures. 

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
Multiple minor violations of the same nature after multiple warnings. 
Minor Protocol Deviation or Violation
A minor protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that has not been approved by the IRB and which DOES NOT 
have a major impact on the subject's rights, safety or well-being, or the completeness, accuracy and 
reliability of the study data.  Examples of this include: 

Follow-up visits that occurred outside the protocol required time frame because of the 
participant’s schedule. 

Blood samples obtained at times close to but not precisely at the time points specified in the 
protocol. 


 
 
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12. 
ETHICS AND REGULATORY REQUIREMENTS 
This study is to be conducted in accordance with the specifications of this protocol and in 
accordance with principles consistent with Declaration of Helsinki, GCP, 21 CFR, ICH E6, HIPAA 
regulations in 45 CFR Part 164 (US only), and the Belmont Principles of respect for persons, 
beneficence, and justice. No protocol changes will be implemented without the prior review and 
approval of the IRB, except when the modification does not involve the subject’s participation in 
the trial or where it may be necessary to eliminate an immediate hazard to a research subject. In the 
latter case, the change will be reported to the IRB as soon as possible, according to IRB regulations.  
Additionally, the study product used in this study is manufactured, handled and stored in accordance 
with applicable GMP. The study product provided for this study will be used only in accordance 
with this protocol. 
12.1. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
The Investigator/Sponsor will provide the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) with all appropriate materials as required by their IRB/IEC, including but 
not limited to the clinical study protocol, informed consent form, and any advertising materials. 
The study will not be initiated until the IRB/IEC provides written approval of the aforementioned 
document. The Investigator will not participate in the decision. If the Investigator is an IRB or IEC 
member, documentation must be provided indicating recusal from the approval process. 
Appropriate reports on the progress of this study by the Investigator will be made to the IRB/IEC 
as required by local and applicable government regulations. The Investigator is required to maintain 
an accurate and complete record of all written correspondence to and received from the IRB/IEC. 
No changes from the final approved protocol will be initiated without the IRB/IEC’s prior written 
approval or favorable opinion of a written amendment, except when necessary to eliminate 
immediate hazards to the subjects or when the modification does not involve the subject’s 
participation in the trial.  
12.2. INVESTIGATOR’S RESPONSIBILITIES 
The Investigators are responsible for performing the study in full accordance with the protocol and 
the current revision of the Declaration of Helsinki, the Good Clinical Practice: Consolidated 
Guideline, approved by the ICH, and any applicable national and local laws and regulations. 
Information regarding the study sites participating in this study that cannot comply with these 
standards will be documented. 
 
 


 
 
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12.3. SUBJECT INFORMED CONSENT REQUIREMENTS 
All subjects participating in this study will be given written and oral information about the study 
by the Investigator and/or designee, in a language understandable by the subject. Written informed 
consent will be obtained from each subject prior any procedures or assessments that would not 
otherwise be required for the care of the subject are done. After the objectives, methods, anticipated 
benefits, potential hazards, and insurance arrangements in force are explained and the subject has 
been given sufficient time to ask questions and consider participation in the study. It will also be 
explained to the subjects that they are free to refuse entry into the study and free to withdraw from 
the study at any time without prejudice to future treatment. It is permissible for a third person (e.g., 
a family member) to be present during the explanation of the study. 
The written Informed Consent Form (ICF) will be in compliance with CFR 21 Part 50.27 and GCP 
guidelines. A copy of the ICF to be used will be submitted by the Investigator/Sponsor to the 
IRB/IEC for review and approval prior to the start of the study. The original signed ICF is retained 
in the subject's study records, and a copy is provided to the subject. A second copy may be filed in 
the subject’s medical record, if allowed by institutional policy.  
 
 


 
 
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13. 
DATA HANDLING AND RECORD KEEPING 
13.1. RECORDING AND COLLECTION OF DATA 
The primary source document for this study will be the subject's medical record. If separate research 
records are maintained by the Investigator(s), the medical record and the research records will be 
considered the source documents for the purposes of auditing the study.  
The Investigator will maintain a confidential list of study subjects that will include each subject’s 
study number, name, date of birth, and unique hospital identification number if applicable. A 
notation will be made in the subject’s case history/medical chart that he/she is participating in a 
clinical study and has provided a signed and dated ICF as well as a release for protected health 
information as required by local policies. The Investigator must also maintain a separate screening 
log of all the subjects screened for participation in the study; it should include gender, age, 
eligibility status, reason for ineligibility, if applicable; and study allocated subject number, if 
applicable.  
13.2. ARCHIVING 
All study documentation at the Investigator site will be archived in accordance with ICH GCP E6 
and the Investigator/Sponsor’s quality standards and SOPs. 
The Investigator will maintain all research records, reports, and case history reports for a period of 
two (2) years after regulatory approval of the investigational product. If no application is filed or if 
the application is not approved, records must be maintained for two (2) years after all investigations 
have been completed, terminated or discontinued and the FDA has been notified.  
These documents should be retained for a longer period however, if required by the applicable 
regulatory requirements (as per GCP 5.5.11). 
Study records are subject to inspection by applicable health and regulatory agencies at any time. 
Records to be retained by the Investigator include, but are not restricted to: 
 Source data and the primary records upon which they are based (e.g., subject’s progress 
notes, adverse event data, test results, and any other diagnostic procedures required to 
evaluate the progress of the study) 
 Signed protocols and protocol amendments 
 Laboratory results, ranges, and certifications 
 IP and accountability records 
 Study personnel signature log 


 
 
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 Monitoring logs 
 Investigator and sub-investigator CVs 
 Signed informed consent and protected health information consent forms 
 Subject screening  
 SAE reports 
 IRB approval and re-approval letters 
 Completed quality of life questionnaire 
 Other documents pertaining to the conduct of the study 
These documents must be maintained and kept on file by the Investigator so that the conduct of the 
study can be fully documented and monitored. 
Study records are subject to inspection by applicable health and regulatory agencies at any time.  


 
 
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14. 
PUBLICATION PLAN 
All information supplied by the Investigator/Sponsor and Senhwa in connection with this study 
and not previously published, is considered confidential information. This information includes, 
but is not limited to, the Investigator’s Brochure, clinical protocol, case report forms and other 
scientific data. Any data collected during the study are also considered confidential. This 
confidential information shall remain the sole property of the Investigator/Sponsor and Senhwa, 
shall not be disclosed to others without the written consent of the Investigator/Sponsor and 
Senhwa, and shall not be used except in the performance of this study. 
It is understood by the Investigator that the Sponsor will use the information collected in this clinical 
trial in connection with the development of the Investigator/Sponsor and Senhwa. Therefore, this 
information may be disclosed as required to other Investigators or appropriate regulatory 
authorities. 


 
 
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15. 
REFERENCES 
1. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O’Meara MJ, et al. (2020) A 
SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential 
Drug-Repurposing. bioRxiv. 2020 Mar 27;2020.03.22.002386 
2. Katie Heiser, Peter F. McLean, Chadwick T. Davis, Ben Fogelson, Hannah B. Gordon, 
Pamela Jacobson, Brett Hurst, Ben Miller, Ronald W. Alfa, Berton A. Earnshaw, Mason L. 
Victors, Yolanda T. Chong, Imran S. Haque, Adeline S. Low, Christopher C. Gibson. 
Identification of potential treatments for COVID-19 through artificial intelligence-enabled 
phenomic analysis of human cells infected with SARS-CoV-2, bioRxiv 2020.04.21.054387; 
doi: https://doi.org/10.1101/2020.04.21.054387 
3. Piirsoo A, Piirsoo M, Kala M, Sankovski E, Lototskaja E, Levin V, et al. (2019) Activity of 
CK2α protein kinase is required for efficient replication of some HPV types. PLoS Pathog 
15(5): e1007788. https://doi.org/10.1371/journal.ppat.1007788 
4. Rosenberger, A.F.N., Morrema, T.H.J., Gerritsen, W.H. et al. Increased occurrence of 
protein kinase CK2 in astrocytes in Alzheimer’s disease pathology. J Neuroinflammation 
13, 4 (2016). https://doi.org/10.1186/s12974-015-0470-x 
5. Eric Ka-Wai Hui, Debi P. Nayak (2002). Role of G protein and protein kinase signalling in 
influenza virus budding in MDCK cells.  JOURNAL OF GENERAL VIROLOGY, Volume 
83, Issue 12 https://doi.org/10.1099/0022-1317-83-12-3055 
6. Koffa MD, Kean J, Zachos G, Rice SA, Clements JB. CK2 protein kinase is stimulated and 
redistributed by functional herpes simplex virus ICP27 protein. J Virol. 2003;77(7):4315‐
4325. doi:10.1128/jvi.77.7.4315-4325.2003 
 


 
 
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16. 
APPENDIX 
16.1. APPENDIX 1:  EQ-5D-5L QUESTIONNAIRE 


 
 
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16.2. APPENDIX 2: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V5.03 
 
For complete detailed information please refer to the link below: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Re
ference_5x7.pdf 
 

ICF_003.pdf: 
Phase II, Randomized, Investigator Initiated Trial to Evaluate Safety and to 
Explore Clinical Benefit of Silmitasertib (CX-4945) in Patients With Severe 
Coronavirus Disease 2019 (COVID-19)   
Informed Consent Form 
NCT04668209    
December 14, 2021 


Date Approved: 12/14/2021
Consent Version: 02/23/2021
Page 1 of 13
HSPP Use Only:
Consent form Medical v2020-10-12
Consent to Participate in Research
Study Title:  
A Phase II, Randomized, Investigator Initiated Trial to 
Evaluate Safety and to Explore Clinical Benefit of 
Silmitasertib (CX-4945) in Patients with Severe Coronavirus 
Disease 2019 (COVID-19)
Sponsor/Principal Investigator: 
Marilyn Glassberg, MD and Esa Rayyan, DO
Banner University Medical Center Phoenix
Lung Institute
755 East McDowell Road, Third Floor
Phoenix, AZ 85006
602-521-3400 24-hour
Sachin Chaudhary, MD
University of Arizona
1515 N. Campbell Ave.
Tucson, AZ 85724
520-626-8000 Daytime
520-694-6000 24-hour
Drug Provider:  
Senhwa Biosciences, Inc.
10F, No.225, Sec. 3, Peihsin Rd, Hsintein Dist.
New Taipei City 23143
Telephone: +886-2-8911-9856
Summary of the research:
This is a consent form for participation in a research study. Your participation in this research 
study is voluntary.  This consent form contains important information about this study and 
what to expect if you decide to participate.  Please consider the information carefully. Feel free 
to ask questions before making your decision whether or not to participate.
Coronavirus Disease 2019 (COVID-19) is a respiratory illness that can spread from person to 
person. The infectious agent that causes COVID-19 is a novel coronavirus (named SARS-CoV-2). 
It was first identified during a recent outbreak in December 2019 in Wuhan, China. Patients 
with COVID-19 have had mild to severe respiratory illness with symptoms of fever, cough, and 
shortness of breath along with non-specific symptoms including myalgia (muscle pain) and 
fatigue. Some patients were more likely to develop a severe respiratory illness similar to severe 
acute respiratory syndrome (SARS) or even die from the disease.


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The current standard of care treatment includes oxygen therapy. There is no specific antiviral 
treatment recommended for COVID-19 by the Centers for Disease Control and Prevention 
(CDC). Patients with COVID-19 should receive supportive care to help relieve symptoms. For 
severe cases, treatment should include support for vital organ functions.
Silmitasertib is a first-in-class small molecule drug that targets a protein, Casein Kinase 2 (CK2). 
Researchers have identified CK2 as a possible target for the treatment of COVID-19. 
Dysregulation (hyperstimulation) of CK2 can indirectly contribute to successful viral replication 
and development of a cytokine storm. A cytokine storm is an over-activation of white blood 
cells, which releases too many cytokines (inflammation-stimulating molecules) into the blood 
and is often associated with a surge of activated immune cells into the lungs. This can lead to 
acute respiratory distress syndrome (ARDS).
In ARDS, fluid builds up in the alveoli (tiny, elastic air sacs in your lungs). The fluid keeps your 
lungs from filling with enough air which means less oxygen reaches your bloodstream. This 
deprives your organs of the oxygen they need to function. ARDS is known to be one of the main 
reasons for death in patients with COVID-19. Researchers noted that by inhibiting CK2, COVID-
19's cellular environment could potentially shift into a more antiviral state.
The University receives compensation from the sponsor of this study for the conduct of this 
study.  If you have any questions, please discuss this with your study doctor.  Senhwa 
Biosciences, Inc. will be providing Silmitasertib for this research study. 
Why is this study being done?
You are being asked to participate in this research study because you have contracted severe 
COVID-19. This is a research study to test a new investigational drug, Silmitasertib. An 
investigational drug is one that has not been approved by the United States Food and Drug 
Administration (FDA). 
The purpose of this research study is to test the safety and effectiveness of Silmitasertib in 
severe COVID-19 patients. 
What will happen if I take part in this study? 
Screening Visit:
After signing this consent document, the study will begin with a screening visit.  The purpose of 
the screening visit is to find out if you meet all of the requirements to take part in this research 
study.  The procedures and assessments that will be completed during screening are listed in 
the table below.
These assessments must take place within 7 days before you receive your first dose.  It is 
possible that after the screening tests are reviewed, you will not be able to take part in this 
study. If you do not meet the requirements, the study doctor will explain why and will discuss 
with you other treatment options, if available.


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Treatment Phase: 
If you pass the screening tests, you will be randomly assigned to one of two groups  to receive 
Silmitasertib (CX-4945) plus standard treatments for COVID-19 and your symptoms, or  to 
receive standard treatments alone. You have an equal chance (50/50) of being assigned to one 
of the groups.   
If assigned, you will take Silmitasertib pills twice a day, by mouth and with only water.  The 
treatment phase can last up to 14 days.  
You will take five 200-mg pills twice daily, two hours after the morning meal and two hours 
after the evening meal (dinner).  Patients are advised to take 1 capsule at a time with a glass of 
water.  You may pause in between swallowing each pill and can take up to 10 minutes to 
swallow all 5 pills.
You will be instructed to take another medication by mouth 1 hour prior to taking the pills. This 
medication may help prevent you from feeling sick (nauseous) after taking Silmitasertib.
If you recover while on Silmitasertib to the point of discharge, it is at the treating physician’s 
discretion to take you off the study drug or have you continue the study drug at home.  In the 
case that the treating physician decides to keep you on Silmitasertib after discharge, you will be 
provided with written instructions and a diary to keep track of when to take it.  
If you are discharged from the hospital prior to day 14, you may be required to return to the 
clinic for an in-person visit at Days: 8, 11, and 14. The visit will include procedures listed below 
in the table.  
Follow Phase:
Once your treatment is stopped, three follow-up visits will occur on Days 28, 45, and Day 60.  
Follow-up visits may be completed via phone or telehealth, if your doctor thinks it is safe.
Your study coordinator will call you every day through at least Day 28 to ask you questions 
about your health status and check your medical records for new information. These calls will 
take about 5 minutes or less and will occur even if you are discharged or the study treatment is 
discontinued.
The procedures and assessments that will be required during the study are listed in the table 
below.   In addition to the visits listed, your research study doctor may ask you to come in for 
an extra visit, if necessary, to protect your well-being.  
Please let your study coordinator the best method to contact you to collect follow up 
information (telehealth visits, outpatient clinic, telephone calls, texts, and email).  They will do 
the best they can to reach you during the follow up period.


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Procedure/Assessments
Screeni
ng Visit
Treatment Phase
Follow-Up*** 
Day
SV
Day 1 
(Baseline)
Day   
4
Day   
8
Day 
11
Day 14/ 
EOT
Day 
28
Day 
45
Day 
60
Informed Consent
X
Medical History & Demographics
X
Physical Examination
X
X
X
X
X
X
Measuring vital signs
X
X
X
X
X
X
X
X
Patient Questionnaire (EQ-D5-5L)
X
X
X
X
Assessment of your clinical status/ 
recovery**
X
X
X
X
X
X
X
X
X
12-lead electrocardiogram (ECG)
X
X
Blood sample for safety tests 
X
X
X
X
X
X
X
X
Pregnancy Test (females who can 
have children)
X
X
Urine sample
X
X
X
X
X
X
X
X
Blood sample to check your 
response to treatment
X
X
X
X
X
Nasal swab to check for virus*
X
X
X
X
X
Chest scan to measure disease in 
your lungs*
X
Day 5,
Day 14 if recommended by your doctor
Treatment Assignment
X
Silmitasertib (CX-4945) treatment 
and necessary co-medicines
CX-4945 (1000mg/ 5 pills), by mouth, 
twice a day, on Days 1 - 14
Ask about medications you are 
taking
X
X
X
X
X
X
X
Ask about how you are feeling
X
X
X
X
X
X
X
X
*Nasal Swab and Chest scans will be performed if clinically indicated by treating physician.
**phone call daily for at least 28 days, regardless of discharge or treatment discontinuation.
***Follow-up continues after discharge via approaches available to the site staff (e.g., telehealth visits, COVID-19 
outpatient clinic, telephone calls, texts, and emails).
How long will I be in this study?
The total duration of the treatment will be 14 days. Patients will be followed up at 28, 45, and 
60 days from the start of the treatment. The total duration for each patient in the study 
(including screening) will be up to 67 days.
How many people will take part in this study?
About 40 patients will participate in this study. 


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What benefits can I expect from being in this study?
You may or may not benefit as a result of your participation in this study. There is, however, no 
guarantee that you will benefit from your participation in this study. Information learned from 
the study may help other people in the future.
What risks, side effects or discomforts can I expect from being in the study?
Taking part in this study involves some risks and possible discomforts. As with any clinical trial, 
adverse side effects, complications, and/or injury, both expected and unexpected, are possible.  
While on the study, you are at risk for these effects.  There may be risks or side effects with the 
investigational study drug, Silmitasertib, which are currently unknown. These may be serious, 
permanent, or even life-threatening. Your condition could worsen while receiving this 
treatment.  You should discuss this with the study doctor.
Approximately 75 patients with solid tumors have already been treated with Silmitasertib 
capsules as a single agent in an earlier cancer clinical trial, receiving the medication either 
twice-daily or four times daily. In general, more drug-related adverse reactions were reported 
when patients took Silmitasertib four times daily, and that is why this study will only dose 
patients twice daily.
The most frequently reported drug-related reactions when Silmitasertib was used as a single 
agent were gastrointestinal disorders (75%) such as diarrhea, nausea, and vomiting, etc. The 
metabolism and nutrition disorders were 35.3% such as hypokalemia (low potassium), and the 
general disorders were 26.9% such as fatigue. Nervous system disorders were 11.9% such as 
dizziness and headache.
You may experience some temporary changes in the laboratory result that measure the 
function of your liver (the organ that aids in digestion and the removal of waste products). In a 
study of Silmitasertib in combination with gemcitabine and cisplatin in cholangiocarcinoma (bile 
duct cancer) patients, there have been two deaths of patients while on the study or within 30 
days after the last dose that were possibly related to Silmitasertib. 
You may also experience some temporary changes in laboratory tests that measure the 
function of your kidneys (the organs that excrete waste products and maintain the balance of 
body fluids) or blood electrolytes imbalance (the salts that usually circulate in your blood), and 
tiredness. Some of the reports of diarrhea and blood electrolyte imbalance have been severe so 
you must take medicines as prescribed by your study doctor to prevent and treat nausea, 
vomiting, and diarrhea. Throughout your participation in this study, your blood will be tested 
regularly during your clinic visits to follow the effects Silmitasertib may have on the function of 
these organs.
You should discuss your concerns with your study doctor. Let your study doctor know about the 
side effects that you are experiencing.  Your study doctor may be able to give you other drugs 
to treat and make side effects less severe or less uncomfortable. Many side effects go away 


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after the Silmitasertib regimen has been stopped, but in some cases these side effects may be 
serious and/or long lasting. In rare cases, side effects could be fatal.
We do not know how well Silmitasertib capsules combine with alcohol or with other drugs. You 
should always discuss the use of alcohol or any other drugs (including over-the-counter, 
prescription, illegal, or herbal) with the study doctor while you are participating in this study.
RISKS OF STUDY PROCEDURES

Electrocardiogram (ECG, a measure of the heart’s rhythms): Skin irritation is rare but 
could occur during an ECG from the electrodes or gel that is used.

Questionnaires: The questionnaires used in this study may be upsetting. You do not 
need to answer any questions that you are not comfortable with.
UNFORESEEN RISKS
Since Silmitasertib is investigational, there may be other unknown risks. Additionally, there may 
be unknown risks to a pregnancy, embryo, or fetus if you or your female partner becomes 
pregnant.
BIRTH CONTROL RESTRICTIONS
Taking Silmitasertib may involve risks to a pregnant woman, an embryo, fetus (unborn baby), or 
nursing infant. Therefore, if you are pregnant, planning to become pregnant, planning to father 
a child, or are breastfeeding a child, you cannot participate in this study.
Females
To reduce the risk of pregnancy, you should use an effective method of birth control while you 
are participating in this study, and for six months after your last dose of Silmitasertib. During 
the study, the study doctor must confirm the use of two acceptable contraceptive methods, the 
patient’s understanding of the risk of Silmitasertib to an unborn fetus, and documentation of a 
negative pregnancy test before dispensing Silmitasertib to a woman of childbearing potential. 
Not all methods of contraception are acceptable. You will have to discuss this in detail with 
your study doctor or study staff.
If you become pregnant while you are participating in this study or within six months after you 
have stopped taking Silmitasertib, tell your study doctor or study staff immediately. 
Silmitasertib will be stopped, and your participation in this study will be ended.
Males 
To reduce the risk of pregnancy, you should use an effective method of birth control while you 
are participating in this study, and for six months after your last dose of Silmitasertib. 
Acceptable methods of birth control for use in this study will be discussed with the study doctor 
or study staff.
If your female partner becomes pregnant while you are participating in this study or within six 
months after you have stopped taking Silmitasertib, tell your study doctor or study staff 
immediately.


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What other choices do I have if I do not take part in this study?
If you decide to take part in the study, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you and you will not lose any of your usual 
benefits.  Your decision will not affect your future relationship with The University of Arizona.  If 
you are a student or employee at the University of Arizona, your decision will not affect your 
grades or employment status. 
You do not have to be in this study to receive treatment for severe COVID-19. Your options may 
include: 

Remdesivir

Dexamethasone

Taking part in another study

Getting other therapy (either experimental or not experimental)
Please talk to the study doctor about your options before you decide whether or not you will 
take part in this study.
When may participation in the study be stopped?
Your decision to participate in this study is voluntary. You may choose to not participate or you 
may withdraw from the study for any reason without penalty or loss of benefits to which you 
are otherwise entitled and without any effect on your future medical care. However, please 
note that the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study. 
If you decide to withdraw from the study, the data that was collected before you withdrew will 
continue to be part of the study. Once you withdraw from the study, no additional data will be 
collected about you for the study unless you agree otherwise to have further tests and 
examination. You can still be in the study if you are taken off the study medication early. This 
may happen if your doctor thinks it is necessary for your safety. In this case, the same study 
information will be collected from you and your medical records. 
The study doctor can stop your participation at any time without your consent for the following 
reasons:

If it appears to be medically harmful to you;

If you fail to follow directions for participating in the study;

If it is discovered that you do not meet the study requirements;

If the study is canceled; or


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
For administrative reasons.
If you leave the study for any reason, you will be asked to complete an end of study visit which 
may include but not limited to physical exam, vital signs, quality of life questionnaire, lab tests, 
questions about your medications and how you are feeling, and a medical records review. 
These tests are done as a safety follow up before you exit the study.
What happens if I am injured because I took part in this study?
Side effects (injury) can happen in any research study. These effects may not be your fault or 
the fault of the researcher involved. Known side effects have been described in this consent 
form. However, side effects that are not currently known may happen and require care. If you 
experience an injury or adverse event, please call Dr. Glassberg at (602)521-3400 immediately. 
If the investigator determines that the injury or adverse event is due to your participation in 
this research, you will be treated in the hospital with standard of care procedures.
If your condition becomes worse, other sickness develops,  or you are injured while you are in 
the study, get the medical care that you need right away. You should inform the healthcare 
professional treating you that you are participating in this study. If you tell the study staff that 
you think you have been injured, then they will help you get the care you need. 
If you are injured as a result of taking Silmitasertib, or from procedures done for this study, you 
will be treated by your doctor according to standard of care. 
If you are injured, have an adverse reaction or illness as a direct result of a defect in the 
manufacture or shipment of the study drug Silmitasertib, Senhwa will pay for the cost of 
diagnosis and treatment expenses. Senhwa will not pay for any injury, adverse reaction, or 
illness caused by the study team’s failure to correctly perform any procedures.  By signing and 
dating this document, you will not lose any of your legal rights or release anyone involved in the 
research from responsibility for mistakes. 
To pay medical expenses, the study doctor will need to know some information about you like 
your name, date of birth, and Medicare Beneficiary Identifier (MBI). This is because the study 
doctor has to check to see if you receive Medicare and if you do, report the payment it makes 
to Medicare.
You will be provided with any new information that develops during the course of the research 
that may affect your decision whether or not to continue participation in the study. 
The University of Arizona and Banner-University Medical Center have no funds set aside for the 
payment of treatment expenses for this study.
What are the costs of taking part in this study? 
Silmitasertib and required 5HT-3 antagonist (anti-nausea medication) will be provided at no 
charge to you or your insurance company.  There will be no charge to you for procedures 


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performed for research purposes only while you are participating in this study. Routine medical 
care performed while participating in study will be billed to you and/or your insurance 
company. This will include (but is not limited to) physical exam, nasal swabs, laboratory tests, 
administration of medications (to include Silmitasertib), and the treatment of side effects. 
Not all insurance companies are willing to pay for services performed in a clinical trial. You will 
be responsible for any charges that your insurance does not cover including regular co-
payments and deductibles. Please speak with your insurance company to find out what you 
may be financially liable for.
Will I be paid for taking part in this study?
You will not receive any payment for taking part in this study. 
Will my data or specimens be stored for future research?             
Your private information or biospecimens collected during this study will not be used or 
distributed for future research studies not described here, even if identifiers are removed. 
However, study data may be used for future research not described here (no private 
information will be included).
Will my specimens be sold for commercial profits?         
The information collected as part of this study may be shared with other organizations. You will 
not share in any commercial value or other compensation from products developed using the 
information. No private information will be included with any information shared.
Will I hear back on any results that directly impact me?            
Research results that are clinically relevant, including individual research results, will not be 
disclosed to you.
Will Whole Genome Sequencing be done with my specimen?          
No, whole genome sequencing will not be done with your specimen.
Will my study-related information be shared, disclosed, and kept confidential?
It is anticipated that there will be circumstances where your study related information and 
Protected Health Information (PHI) will be released to persons and organizations described in 
this form. If you sign this form, you give permission to the research team to use and/or disclose 
your PHI for this study. Your information may be shared or disclosed with others to conduct the 
study, for regulatory purposes, and to help ensure that the study has been done correctly.
These other groups may include:

Office for Human Research Protections, Food and Drug Administration, or other federal, 
state, or international regulatory agencies

Banner University Medical Group and Banner Health

The University of Arizona (UA) and the UA Institutional Review Board 


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
The funder supporting the study, Senhwa Biosciences, Inc, their agents or study 
monitors

Your primary care physician or a specialist taking care of your health.
If you agree to take part in this study a copy of this signed informed consent form will be saved 
into your electronic medical record (EMR) at Banner Health. As a result, healthcare providers 
and staff who are not working on this study, but who may provide you medical treatment in the 
future, will know that you are taking part or took part in this study.  
Your PHI may no longer be protected under the HIPAA privacy rule once it is disclosed by the 
research team. While every effort will be made to protect the privacy of your information, 
absolute confidentiality cannot be guaranteed. This does not limit the duty of the researchers 
and others to protect your privacy.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
What study-related information and PHI will be obtained, used or disclosed from my 
medical record at Banner?
Information related to this research study that identifies you and your PHI will be collected 
from your past, present, and future hospital and/or other health care provider medical records. 
The PHI you are authorizing to be used and/or disclosed in connection with this research study 
is:

Name, address, phone number, email address, medical record number

Demographics, elements of dates

Medical history

Clinical status
Demographic information to be disclosed may include, but is not limited to, your name, 
address, phone number, or social security number. If you receive compensation for 
participating in this research study, information identifying you may be used or disclosed as 
necessary to provide that compensation.
Your existing health records may include information related to the diagnosis or treatment of 
sexually transmitted disease (STD), acquired immunodeficiency syndrome (AIDS), human 
immunodeficiency virus (HIV), other communicable diseases, genetic information (e.g., genetic 
testing), and/or alcohol and/or drug abuse. The study staff and study sponsor’s monitor may 
see this information while reviewing your regular health records for this study, but they WILL 
NOT create, collect, or disclose this type of information for the purposes of this research study.


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When will my authorization expire?
There is no expiration date or event for your authorization. Therefore, unless you cancel this 
authorization (as instructed below) this authorization will continue to be effective.
Do I have to sign this authorization form?
You do not have to sign this authorization. However, if you decide not to sign, you will not be 
able to participate in this research study; and it will not affect any non-study Banner Health 
medical treatment or health care, payment, enrollment in any health plans, or benefits.
Also, by signing this form you are authorizing and permitting uses and/or disclosures of your 
PHI for future research purposes (e.g., future studies) as described in this document. 
What do I need to know if I decide to cancel my authorization?
After signing the authorization, you may decide to cancel your previous authorization for the 
research team to use your PHI. If you cancel the authorization, you will no longer be able to 
stay in the research study. Please note that any PHI collected before you cancel the 
authorization may still be used. You may revoke the authorization by contacting the Principal 
Investigator in writing. Contact information is under “Who can answer my questions about the 
study” at the end of this document. 
Will access be limited to my research study record during this study?
You may not have access to the research information developed as part of this study until it is 
completed.
Who can answer my questions about this study?
If at any time you feel you have had a research-related injury, or for questions, concerns, or 
complaints about the study you may contact:
Dr. Glassberg and research team at (602)521-3400
Dr. Chaudhary and research team at (520)626-8000
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact 
the Human Subjects Protection Program Director at 520-626-8630 or online at 
http://rgw.arizona.edu/compliance/human-subjects-protection-program.
If you are injured as a result of participating in this study or for questions about a study-related 
injury, you may contact:
Dr. Glassberg and research team at (602)521-3400
Dr. Chaudhary and research team at (520)626-8000
If you have questions, concerns, or complaints about the use or sharing of your health 
information or would like a copy of the Banner Notice of Privacy Practices, you may contact the 


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Banner Research HIPAA Liaison at 602-839-4583 or 
BHResearchCompliance@bannerhealth.com. 
To cancel your authorization for access to PHI you must notify the Principal Investigator and/or 
Research Team in writing at the following address:
Marilyn K. Glassberg, MD and Research 
Team
Banner University Medical Center Phoenix 
Lung Institute
755 East McDowell Road, Third Floor
Phoenix, AZ 85006
Sachin Chaudhary, MD and Research Team
University of Arizona
1515 N. Campbell Avenue
Tucson, AZ 85724


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Signing the consent form
I have read (or someone has read to me) this form, and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study and I authorize the 
use and/or disclosure of my PHI. I am not giving up any legal rights by signing this form.  I will be 
given a signed copy of this form.
Printed name of subject
Signature of subject
Date
Printed name of person authorized to 
consent for subject (when applicable)
Signature of person authorized to consent for subject 
(when applicable)
Date
Relationship to the subject
Investigator/Research Staff (not applicable if completed electronically)
I have explained the research to the participant or the participant’s representative before 
requesting the signature(s) above.  There are no blanks in this document.  A signed copy of this 
form has been given to the participant or to the participant’s representative.
Printed name of person obtaining consent
Signature of person obtaining consent
Date