A Phase II, Randomized and Controlled Investigator Initiated Trial Evaluating Safety, Pharmacokinetics and Clinical Benefit of Silmitasertib (CX-4945) in Outpatient Adult Subjects With Moderate Coronavirus Disease 2019 (COVID-19)
Phase: PHASE2
Conditions: Covid19
Sponsor: Senhwa Biosciences, Inc.

 
A Phase II, Randomized and Controlled Investigator Initiated Trial Evaluating 
Safety, Pharmacokinetics and Clinical Benefit of Silmitasertib (CX-4945) in 
Outpatient Adult Subjects with Moderate Coronavirus Disease 2019 (COVID-
19)  
 
Protocol Number: 
CX4945-AV01-IIT 
Protocol Amendment: 
1.0 
Date: 
11-May-2021 
Study Product: 
Silmitasertib (CX-4945) 
Sponsor-Investigator: 
Dr. Chris Recknor, MD 
Center for Advanced Research & Education 
2350 Limestone Pkwy  
Gainesville, GA 30501 
 
 
 
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-AV01-IIT 
                                                                                                   Protocol Amendment 1.0 
 
 
 
Date: 11-May-2021 
CONFIDENTIAL 
 
  
 
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Document History  
 
Document 
Version 
Date 
Summary of Changes and Rationale 
Amendment 1 
11 May 2021  The primary purpose of the amendment is to add 1-2 additional 
sites to boost enrollment and  incorporate feedback received 
from the United States (US) Food and Drug Administration 
(FDA).   
In addition, clarifications, reconciliations, administrative and 
typographical modifications were made. 
1. “Single-center study” was replaced by “Multicenter 
study” throughout the protocol. 
2. As study population is outpatients with moderate 
COVID-19, a Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials will be used for grading of  
AEs associated with systemic (general) abnormalities, 
vital signs, illnesses and lab abnormalities instead of 
CTCAE v.5.0 (FDA recommendation).  Full guidelines 
may 
be 
obtained 
at 
https://www.fda.gov/media/73679/download . 
3. Section 1.1. SYNOPSIS:  
• Study Description: It was clarified that CX-4945 
neither impacts on the effectiveness of other 
antiviral drugs nor contributes to the emergence of 
viruses with reduced susceptibility to the drug, 
since CX-4945 targets the host protein kinase. 
• Study Description. Number of enrolled patients was 
changed from “20” to “approximately 20” to add 
flexibility in case any patients to be replaced due to 
protocol violation or discontinue the study prior to 
the first dose, etc. 
• Secondary 
Objectives 
and 
Endpoints: 
The 
secondary objective to evaluate time to clinical 
recovery measured by time to resolution of clinical 

Protocol # CX4945-AV01-IIT 
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CONFIDENTIAL 
 
  
 
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signs and symptoms was split to two objectives 
measured separately by duration of clinical signs 
and duration of clinical symptoms correspondingly 
(FDA recommendation). 
• Secondary 
Objectives 
and 
Endpoints: 
The 
secondary objective to evaluate CX-4945 PK was 
updated to clarify that PK samples will be collected 
from the first four patients randomized to treatment 
arm A. Further PK collection is not required, as 
enough data have been collected in two CX-4945 
studies to proceed with PK analysis. 
• Secondary Objectives and Endpoints (other clinical 
benefit of treatment with CX-4945): evaluation of 
disease progression and health improvement 
measured by the ordinal 8- Point Clinical 
Progression Outcome Scale was clarified. 
• Secondary Objectives and Endpoints (other clinical 
benefit of treatment with CX-4945): Outcome 
measure for changes of SpO2 was updated to 
number of days to normalization of oxygen 
saturation (categorized as <96% versus ≥96%). 
• Study Duration was changed from 5 months to 12 
months due to enrollment challenges. 
4. Section 1.3: SHEDULE OF ACTIVITIES 
• Assessment for the requirement of mechanical 
ventilation, ECMO, non-invasive ventilation, or 
high-flow nasal cannula oxygen delivery was 
deleted as it was the same as clinical status 
assessment using the ordinal 8- Point Clinical 
Progression Outcome Scale. 
• PK collection was removed from the Schedule of 
Activities (SOA). PK samples will not be collected 
anymore, as enough data have been collected in two 
CX-4945 studies to proceed with PK analysis. 
• Numbers of footnotes were reconciled 

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• Footnote 14: It was clarified that Follow-up visits 
(Day 28, Day 45, and Day 60) may be performed 
via phone or telehealth only for recovered patients. 
• Day 2, Day 15, Day 16 and Day 17 visits were 
deleted from the SOA as these visits are required 
only for patients participating in the PK study. PK 
collection is not required anymore, as enough data 
have been collected to proceed with PK analysis. 
5. Section 2.1: STUDY RATIONALE 
• Study Rationale was updated in accordance with the 
recent COVID-19 Treatment Guidelines of 8-Apr-
21 
(https://www.covid19treatmentguidelines.nih.gov). 
6. Section 2.4: RISK/BENEFIT ASSESSMENT 
• It was added that CX-4945 does not impact the 
effectiveness of other antiviral drugs or contribute 
to the emergence of viruses with reduced 
susceptibility to the drug, since CX-4945 is an 
inhibitor of the host protein kinase.     
7. Section 3: STUDY OBJECTIVES AND ENDPOINTS 
• The same changes were made in Section 3 as listed 
above under Item 3, bullets 4, 5, 6 and 7.  
8. Section 4.1: OVERALL DESIGN 
• Addition to SOC: Patients progressed on treatment 
with monoclonal antibodies can be enrolled, if meet 
eligibility criteria. 
9. Section 5.1.1: INCLUSION CRITERIA 
• The inclusion criterion #2: a timeframe of 7 days 
before Day 1 was specified for the positive 
screening PCR test required for eligibility 
evaluation. 
• The inclusion criterion #3: the names of the 
symptoms were aligned with those in the proposed 
patient-reported outcome (PRO) instrument (FDA 
recommendation). 

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• The inclusion criterion #9 was added: Patient must 
agree not to participate in another clinical trial for 
the treatment of COVID-19 during the study period 
until 
disease 
progression, 
hospitalization, 
withdrawal from study treatment or 28 days after 
the start of the study, whichever occurs first. 
10. Section 5.1.2: EXCLUSION CRITERIA 
• The exclusion criterion #5 of “concomitant 
treatment with another investigational drug from 
Day 1 through Day 28” was revised to “concomitant 
treatment with another investigational drug” as it 
should not be applied after treatment initiation 
(FDA recommendation). 
• The exclusion criterion #7 was added: Any active 
or recurring clinically significant hepatic disease 
(FDA recommendation). 
11. Section 6.1.5: CX-4945 DOSE MODIFICATION 
• Table 3, CX-4945 Dose Modification and 
Management for Potential Toxicities: Standardized 
toxicity grading scale (CTCAE v.5.0) was modified 
to Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive 
Vaccine 
Clinical 
Trials 
https://www.fda.gov/media/73679/download (FDA 
recommendation) 
• Reasons for dose discontinuation were listed 
12. Section 
7: 
STUDY 
COMPLETION 
OR 
DISCONTINUATION 
• This Section was revised to reconcile discrepancies 
and 
clarify 
difference 
between 
study 
discontinuation and withdrawal from treatment 
(FDA recommendation). 
13. Section 8.2.2: EFFICACY/ANTI-VIRAL ACTIVITY 
ASSESSMENT 
• COVID-19-related symptoms and signs will be 
evaluated separately for recovery assessment (FDA 

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recommendation). 
Section 
8.2.2.1 
describes 
COVID-19-related symptoms assessment. Section 
8.2.2.2. describes clinical signs assessment. Heart 
rate was added to clinical sign assessment (section 
8.2.2.2). It was added that any abnormal signs or 
symptoms not related to COVID-19 and caused by 
other conditions documented in medical history and 
started before COVID-19 will not be included to 
recovery assessment. The patient can be considered 
as recovered, when these symptoms return to the 
previous (pre-COVID-19) values. 
14. Section 8.3.3.1: SEVERETY OF AEs 
• As study population is outpatients with moderate 
COVID-19, a standardized toxicity grading scale 
was modified to reflect the study population. 
Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials will be used for grading of  
AEs 
associated 
with 
systemic 
(general) 
abnormalities, vital signs, illnesses and lab 
abnormalities instead of CTCAE v.5.0 (FDA 
recommendation).  Full guidelines may be obtained 
at https://www.fda.gov/media/73679/download . 
15. Section 
9.2: 
DESCRIPTION 
OF 
STUDY 
OUTCOMES 
• Duplicate information has been removed and 
reference to Section 1.1. and Section 3 is added. 
16. Section 9.4: RANDOMIZATION 
• WebView IWRS has been removed as it not 
applicable for this study. 
 
 
 

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TABLE OF CONTENTS  
 
 
 
Page 
1. PROTOCOL SUMMARY ....................................................................................................14 
1.1. Synopsis ........................................................................................................................14 
1.2. Schema ..........................................................................................................................20 
1.3. Schedule of Activities (SOA) ......................................................................................21 
2. INTRODUCTION AND BACKGROUND ..........................................................................23 
2.1. Study Rationale............................................................................................................23 
2.2. Background ..................................................................................................................24 
2.3. CX-4945 ........................................................................................................................25 
2.4. Risks/Benefits Assessment ..........................................................................................27 
3. STUDY OBJECTIVES AND ENDPOINTS ........................................................................28 
4. STUDY DESIGN ....................................................................................................................32 
4.1. Overall Design ..............................................................................................................32 
4.2. Justification for dose ...................................................................................................32 
4.3. End of Study Definition ..............................................................................................33 
5. STUDY POPULATION ........................................................................................................34 
5.1. Patient Eligibility Criteria ..........................................................................................34 
5.1.1.Inclusion Criteria ..................................................................................................34 
5.1.2.Exclusion Criteria .................................................................................................35 
5.2. Screen Failures ............................................................................................................36 
6. STUDY TREATMENT .........................................................................................................37 
6.1. Study Treatment Administration ...............................................................................37 
6.1.1.Investigational Drug Product Description ............................................................37 
6.1.2.Randomization ......................................................................................................37 
6.1.3.Dosing and Administration of CX-4945 ..............................................................37 
6.1.4.CX-4945 Compliance ...........................................................................................38 
6.1.5.CX-4945 Dose Modifications ..............................................................................38 
6.2. INVESTIGATIONAL PRODUCT SUPPLIES, STORAGE AND ACCOUNTABILITY ...............39 

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6.2.1.Investigational Product Supplies ......................................................................39 
6.2.2.Formulation, Appearance and Packaging ........................................................39 
6.2.3.Product Storage and Stability ...............................................................................40 
6.3. CONCOMITANT MEDICATION .......................................................................................40 
6.3.1.Premedication - Antiemetic Drugs (Mandatory) .............................................40 
6.3.2.Anti-Diarrheal Medication (Recommended): ..................................................40 
6.3.3.Electrolyte Abnormalities ..................................................................................41 
6.4. CX-4945 DRUG INTERACTION .....................................................................................41 
6.4.1.Effect of CX-4945 in Human Liver Microsomes .............................................41 
7. STUDY COMPLETION OR DISCONTINUATION .........................................................43 
7.1. Patient Completion ......................................................................................................43 
7.2. Patient Withdrawal from Participation in the Study ...............................................43 
7.3. Patient Discontinuation from Study Treatment .......................................................43 
8. STUDY ASSESSMENTS AND PROCEDURES ................................................................45 
8.1. Study Procedures .........................................................................................................45 
8.1.1.Screening Period: .................................................................................................45 
8.1.2.Treatment Period: .................................................................................................45 
8.1.3.Follow Up Period .................................................................................................45 
8.1.4.Unscheduled Visits ...............................................................................................45 
8.2. Assessments ..................................................................................................................46 
8.2.1.Safety Assessment ................................................................................................46 
8.2.2.Efficacy/Anti-viral Activity Assessment ..............................................................49 
8.3. Adverse Events (AEs) and Serious Adverse Events (SAEs) ....................................51 
8.3.1.Definitions of AE ................................................................................................51 
8.3.2.Definition of SAEs ..............................................................................................51 
8.3.3.Classification of AEs ..........................................................................................52 
8.3.4.Reporting of AEs ..................................................................................................54 
8.3.5.Reporting of SAEs ..............................................................................................54 
8.3.6.SAE Follow-Up ...................................................................................................55 
9. STATISTICAL ANALYSIS .................................................................................................56 
9.1. Treatment Arms ..........................................................................................................56 
• 
Arm B: Best supportive/standard of care .................................................................56 

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9.2. Description of Study Outcomes (Endpoints) .............................................................56 
9.2.1.Safety Measures: ..................................................................................................56 
9.3. Sample Size Determination and Rationale ................................................................56 
9.4. Randomization .............................................................................................................56 
9.5. Blinding ........................................................................................................................57 
9.6. Interim Analysis ..........................................................................................................57 
9.7. General Statistical Considerations .............................................................................57 
9.7.1.Analysis Populations ............................................................................................57 
9.7.2.Covariates .............................................................................................................58 
9.7.3.Missing Data .........................................................................................................58 
9.8. Analysis Methods .........................................................................................................58 
9.8.1.Patient Disposition ...............................................................................................58 
9.8.2.Demographic and Baseline Characteristics ..........................................................58 
9.8.3.Concomitant Medications/Therapies ....................................................................58 
9.8.4.Study Outcome Assessment .................................................................................59 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ......................................61 
11. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................62 
11.1. Monitoring Requirements ..........................................................................................62 
11.2. Modification of Protocol .............................................................................................62 
11.3. Reporting Protocol Deviations ...................................................................................62 
11.3.1.Major Protocol Deviation or Violation ..............................................................62 
11.3.2.Minor Protocol Deviation or Violation ..............................................................63 
12. ETHICS AND REGULATORY REQUIREMENTS .........................................................64 
12.1. Institutional Review Board/Independent Ethics Committee (IRB/IEC)................64 
12.2. Investigator’s Responsibilities ....................................................................................64 
12.3. Patient Informed Consent Requirements ..................................................................65 
13. DATA HANDLING AND RECORD KEEPING ................................................................66 
13.1. Recording and Collection of Data ..............................................................................66 
13.2. Archiving ......................................................................................................................66 
14. PUBLICATION PLAN .........................................................................................................68 
15. REFERENCES .......................................................................................................................69 

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16. APPENDIX .............................................................................................................................70 
16.1. Appendix 1:  EQ-5D-5L Questionnaire .....................................................................70 
16.2. Appendix 2: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials ..................................................................72 
16.3. Appendix 3: Assessment of COVID-19-related symptoms (patient diary) ............73 
 
 
 

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LIST OF TABLES 
Page 
Table 1: Schedule of Activities ......................................................................................................21 
Table 2: Method of Assignment to Treatment ...............................................................................37 
Table 3: CX-4945 Dose Modification and Management for Potential Toxicities (Attributable to 
CX-4945) .......................................................................................................................38 
Table 4. Safety Laboratory Tests ...................................................................................................47 
Table 5. PK Sample Collection Times ...........................................................................................49 
Table 6. Toxicity Grading General Guidelines ..............................................................................52 
 

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clinical signs in CX-
4945 
treatment 
arm 
versus the control arm. 
1, Day 4, Day 8, Day 11 and Day 14) and at Follow-up 
visits (Day 28 and Day 45): 
o Fever is <36.6°C from axillary site, or < 
37.2°C from oral site or < 37.8°C from 
rectal or tympanic site 
o Respiratory rate is < 20 breaths per 
minute 
o SpO2 > 96% in room air without 
shortness of breath or dyspnea caused by 
COVID-19 
o Heart rate < 90 beats per minute  
Note: If some signs listed above were 
caused by other conditions documented 
in the medical history and started before 
COVID-19, 
the 
patient 
can 
be 
considered as recovered, when these 
signs return to the previous (pre-COVID-
19) values.  
To compare duration of 
COVID-19-Related 
clinical symptoms in 
CX-4945 treatment arm 
versus the control arm. 
Number of days from randomization (Day1) to the day 
when: 
• No key COVID-19-related symptoms scored 
higher than 1 as documented using a Patient 
Reported Outcome (PRO) instrument (a Patient 
Diary for Assessment of Common COVID-19-
Related Symptoms – see Appendix 3), evaluated 
daily from Day 1 through Day 14 and at Day 28 
and Day 45.  
Note: Each symptom is scored individually using 
the following response options and scoring 
values: 
o Items 1–18: None = 0; Mild = 1; 
Moderate = 2; and Severe = 3  
o Items 19 and 20: Not at all = 0; 1–2 times 
= 1; 3–4 times = 2; 5 or more times = 3 

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o Items 21-22: The same as usual = 0, Less 
than usual = 1, NO sense of smell/taste = 
2.  
Note: If some symptoms were caused by other 
conditions documented in the medical history 
and started before COVID-19 (e.g. insomnia), 
the patient can be considered as recovered, when 
these symptoms return to the previous (pre-
COVID-19) value. 
 
To evaluate preliminary 
evidence of anti-viral 
activity of CX-4945 as 
compared to the control 
arm. 
• Change in virologic measure:  
• Proportion of patients with conversion of 
positive RT-PCR to negative RT-PCR from 
randomization (Day 1) through Day 28. 
• Time to SARS-CoV-2 viral clearance measured 
as number of days from positive RT-PCR 
collected at randomization (Day1) to negative 
RT-PCR.  
• Quantitative changes in viral load from 
randomization (Day 1) to Day 28. 
 
Note: RT-PCR/viral load tests will be performed 
at randomization (Day 1) and then on Day 8, 
Day 14 and Day 28. 
 
To evaluate the PK of 
CX-4945 when given at 
1000 
mg 
BID 
PO 
(Treatment Arm A only) 
• Plasma sample for PK assessment are collected at 
the following timepoints from the first four patients 
randomized to treatment arm A: 
o Day 1: pre-dose, 1, 2, 3, 6 and 24 hours post 
Day 1 morning dose. 
o Day 14: pre-dose, 1, 2, 3, 6, 24, 48 and 72 hours 
post Day 14 morning dose. 

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Note: The following PK parameters will be 
calculated: Cmax, Tmax, AUC0-T, AUC0-6, and 
T1/2 
To 
evaluate 
other 
Clinical 
Benefit 
of 
treatment with CX-4945 
relative to the control 
arm 
• All-cause mortality status – the number of deaths 
occurred in each treatment group from 
Randomization (Day 1) through Day 60. 
• Number of respiratory failure (i.e., need for 
mechanical ventilation, ECMO, noninvasive 
ventilation, or high-flow nasal cannula oxygen 
delivery) occurred in each treatment group from 
Randomization (Day 1) through Day 45. 
• Number of patients hospitalized in each 
treatment arm from Randomization (Day 1) to 
Day 45 
• Number  of days to normalization of oxygen 
saturation level measured by pulse oximeter at 
Randomization (Day 1), Day 4, Day 8, Day 11, 
Day 14, Day 28 and Day 45  and categorized as 
<96% versus ≥96%.Proportion of patients with 
disease progression or improvement in health 
status occurring  from Randomization (Day 1) to 
Day 28. Disease progression is defined as change 
in patient health status assessment from item 7 to 
items 1- 6 and health improvement -as change 
from item 7 to item 8, evaluated  by the ordinal 
NIAID 8-Point Clinical Progression Outcomes 
scale collected at every visit from Day 1 through 
Day 45. 
The 8-category ordinal scale of patient health 
status ranges from: 
1. Death;  
2. Hospitalized, on invasive mechanical 
ventilation or extracorporeal membrane 
oxygenation (ECMO);  

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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. 
• Changes in EQ-D5-5L (used as an indicator of 
symptom improvement) from randomization 
(Day 1) to Day 8, Day 14 and Day 28. 
To evaluate changes in 
inflammatory markers  
• Changes in plasma IL-6 level from randomization 
(Day 1) to Day 4, 8, 11, and 14. 
• Changes in CRP, LDH, CPK, ferritin, D-dimer from 
randomization (Day 1) to Day 4, 8, 11, and 14. 
Study 
Population: 
This study will enroll male and non-pregnant female patients ≥ 18 years of age with 
moderate COVID-19. Approximately 20 outpatients will be equally randomized in 
two treatment arms. 
Phase: 
II 
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: 
12 months (from study initiation until completion of data analyses) 

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Patient 
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 
(Baseline) 
 
 
 
Days 4, 8, 11 
 
 
 
 
Day 14/EOT 
 
 
 
Follow-up 
Phase 
Days 28, 45 
 
 
 
 
60-Day Follow-up 
 
 
 
 
Total N = ~20:   Obtain informed consent. Screen potential patients by 
inclusion and exclusion criteria; obtain history, complete screening 
Randomize 
Arm A: 
SOC/ supportive care 
+CX-4945, N=10 
Arm B: 
SOC/ supportive care,  
N=10 
Final Assessments 
of adverse event and survival status 
Perform baseline assessments. 
- refer to Table 1: Schedule of Activities  
Arm A: Starting of CX-4945 Administration 1000 mg PO BID  
Perform visit procedures as specified in Table 1: Schedule of Activities 
Arm A: CX-4945 Administration 1000 mg PO BID on Day1-Day 14 
Perform Day 14/EOT visit procedures as specified in Table 1: Schedule of Activities 
Arm A: Last day of CX-4945 Administration 1000 mg PO BID 
 
Follow-up assessments of study endpoints and safety 
- refer to Table 1: Schedule of Activities 

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1.3. 
SCHEDULE OF ACTIVITIES (SOA) 
Table 1: Schedule of Activities 
Procedure/Assessments 
Screening 
Visit 
Treatment Phase 
Follow-Up [14] 
Day 
SV 
Day 1 
(Baseline) 
Day 4 
Day 8 
Day 11 
Day 14 
(EOT) 
Day 28 
Day 45 
Day 60 
Window Period 
D-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 
 
 
 
 
 
 
 
 
Patient 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 COVID-19-related Symptoms [6] 
X 
Assessed Daily from Day 1-Day 14 
X 
X 
 
EQ-D5-5L 
 
X 
 
X 
 
X 
X 
 
 
Clinical 
Status 
- 
Ordinal 
8-point 
Scale 
Assessment  
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulse Oxygen Saturation (SpO2) 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 
 
 
 
X 
 
 
 
Laboratory Tests:  
 
 
 
 
 
 
 
 
 
Hematology [7] 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry [8] 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation [9] 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum/Urine Pregnancy Test [10] 
X 
 
 
 
 
X 
 
 
 
Urinalysis [11] 
X 
X 
X 
X 
X 
X 
X 
X 
 
IL-6 levels 
 
X 
X 
X 
X 
X 
 
 
 
Nasopharyngeal Swab Sample Collection [12] 
X 
X 
 
X 
 
X 
X 
 
 
Randomization [13] 
 
X 
 
 
 
 
 
 
 

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IP Administration (Arm A only) 
 
 
Arm A: CX-4945 1000 mg BID (Day 1-Day14)  
 
 
 
SOC/Supportive care (Arm A and Arm B) 
X (as needed)  
Mortality Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
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] Common COVID-19-Related Symptoms (see Appendix 3) should be assessed by patients daily from Day 1 through Day 14/EOT and at  Day 28 and Day 45 Follow-up 
visits.. 
[7] Hematology: Hemoglobin, Hematocrit (HCT), Red Blood Cells (RBC), White Blood Cells (WBC) with total and differential count, Absolute Neutrophil 
Count (ANC) and platelets.  
[8] Blood Chemistry: 
• 
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, total calcium and bicarbonate 
• 
Other: Creatine phosphokinase (CPK), C-reactive protein (CRP), serum ferritin, d-dimer 
  
[9] Coagulation: Prothrombin time (PT) and International Normalized Ratio (INR) 
[10] ONLY performed on women of childbearing potential. 
[11] 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. 
[12] Swabs will be used for RT-PCR and quantitative virologic testing: 
• 
Positive RT-PCR collected within 7 days before Day 1 is required at screening for patient eligibility evaluation. 
• 
Nasopharyngeal swab for RT-PCR and viral load assessment should be collected at Day 1, 8, 14 and 28 visits. Samples are to be stored at -70°C and shipped to the 
Fulgent lab twice a month. 
[13]  Randomization: Patient number and treatment arm allocation can be performed on Day 1 
[14]  For recovered patients Follow-up visits may be performed via phone or telehealth, as appropriate 
 
 

 
 
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2. 
INTRODUCTION AND BACKGROUND 
2.1. 
STUDY RATIONALE 
The COVID-19 pandemic is an ongoing global pandemic caused by severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2). It was first identified in December 2019 in Wuhan, China. 
As of 2 April 2021, more than 129 million cases have been confirmed, with more than 2.82 million 
deaths attributed to COVID-19. Symptoms of COVID-19 are highly variable, ranging from none 
to life-threatening illness. The virus spreads mainly through the air from person to person. Common 
symptoms include headache, loss of smell and taste, nasal congestion and rhinorrhea, cough, muscle 
pain, sore throat, fever, diarrhea, and breathing difficulties. Most people develop mild to moderate 
symptoms. 
The COVID-19 Treatment Guidelines Panel (https://www.covid19treatmentguidelines.nih.gov) 
that includes representatives from federal agencies, health care and academic organizations, and 
professional societies, continues to review the most recent clinical data to provide up-to-date 
treatment recommendations for clinicians who are caring for patients with COVID-19. Remdesivir, 
an antiviral agent, is currently the only drug that is approved by the FDA for the treatment of 
COVID-19, but it is recommended for use only in hospitalized patients who require supplemental 
oxygen. Dexamethasone, a corticosteroid, has been found to improve survival in hospitalized 
patients who require mechanical ventilation, but it is not recommended for use in outpatients with 
moderate disease. Preliminary data suggests that outpatients may benefit from receiving anti-
SARS-CoV-2 monoclonal antibodies early in the course of infection. The Food and Drug 
Administration (FDA) has issued Emergency Use Authorizations (EUAs) for certain anti-SARS-
CoV-2 monoclonal antibodies for the treatment of outpatients with mild to moderate COVID-19. 
However, the COVID-19 Treatment Guidelines includes information on the various reported 
SARS-CoV-2 variants and the potential impact of mutations on in vitro susceptibility to different 
anti-SARS-CoV-2 monoclonal antibodies. Because of these limitations, the COVID-19 Treatment 
Guidelines Panel (the Panel) recommends using anti-SARS-CoV-2 monoclonal antibody 
combinations only to treat outpatients with mild to moderate COVID-19 who are at high risk of 
clinical progression Ongoing clinical trials will provide further evidence information about the 
safety and efficacy of these agents. 
Despite some drugs demonstrating good efficacy, there are a number of patients not responsive to 
available anti-COVID-19 therapy. There is no specific antiviral treatment recommended for 
outpatients with moderate COVID-19. Current standards of therapeutic management of outpatients 
with moderate COVID-19 includes symptomatic and supportive care, such as NSAIDs to relieve 
symptoms (fever, body aches, cough).  
Along with the development of new antiviral drugs, repurposing of existing drugs for COVID-19 
treatment has also been accelerated. At present, the main antiviral strategies currently employed 

 
 
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against SARS-CoV-2 can be divided into two types: Strategies directly targeting the virus and 
strategies indirectly targeting the virus via host modulation. Therefore, development of an effective 
antiviral drug for COVID-19 is a global health priority and discovery of novel cellular targets for 
SARS-CoV-2 has led to novel putative clinical strategies which merit going into clinical research 
in COVID-19. 
2.2. 
BACKGROUND  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Emerging pre-clinical and clinical data and results of independent efficacy evaluation conducted 
by Utah State University [2] and UCSF COVID-19 research group [1] and Senhwa Biosciences 
hypothesize that 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 moderate to 
severe COVID-19, thereby preventing disease progression and improving clinical outcomes. The 
intended target patient population for treatment with CX-4945 is SARS-CoV-2 positive patients 
with moderate to severe COVID-19, since in the moderate to 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 COVID-19 pneumonia not responsive to remdesivir, dexamethasone and antibiotics 
and requiring supplemental oxygen. The patient recovered and was discharged from the hospital 
within five days of treatment with CX-4945.  
 
2.3. 
CX-4945 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

 
 
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CX-4945 is currently under development in several oncology programs in adults and in children 
with recurrent/advanced or metastatic cancer.  CX-4945 is 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 (basal cell carcinoma) and two ongoing 
phase II studies (cholangiocarcinoma, medulloblastoma). 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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2.4. 
RISKS/BENEFITS ASSESSMENT 
CX-4945 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. As CX-4945 
is an inhibitor of the host protein kinase CK2, it does not impact the effectiveness of other antiviral 
drugs or contribute to the emergence of viruses with reduced susceptibility to the drug.   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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evaluated daily from randomization (Day 1) through Day 14 
and at Day 28 and Day 45.  
Note: Each symptom is scored individually using the 
following response options and scoring values: 
o Items 1–18: None = 0; Mild = 1; Moderate = 2; and 
Severe = 3  
o Items 19 and 20: Not at all = 0; 1–2 times = 1; 3–4 
times = 2; 5 or more times = 3 
o Items 21-22: The same as usual = 0, Less than usual 
= 1, NO sense of smell/taste = 2.  
Note: If some symptoms were caused by other conditions 
documented in the medical history and started before 
COVID-19 (e.g., insomnia), the patient can be considered 
as recovered, when these symptoms return to the previous 
(pre-COVID-19) value. 
 
To evaluate preliminary evidence of 
anti-viral activity of CX-4945 as 
compared to the control arm. 
Change in virologic measure:  
• Proportion of patients with conversion of positive RT-PCR 
to negative RT-PCR from Randomization (Day 1) through 
Day 28. 
• Time to SARS-COV-2 viral clearance measured as number 
of days from positive RT-PCR collected at randomization 
(Day 1) to negative RT-PCR.  
• Quantitative changes in viral load from Randomization 
(Day 1) to Day 28. 
 
Note: RT-PCR/viral load tests will be performed at 
Randomization (Day 1) and then on Day 8, Day 14 and Day 28. 
To evaluate the PK of CX-4945 
when given at 1000 mg BID PO 
(Treatment Arm A only) 
• Plasma sample of CX-4945 are collected at the following 
timepoints from the first four patients randomized to treatment 
arm A: 
o Day 1: pre-dose, 1, 2, 3, 6 and 24 hours post Day 1 morning 
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o Day 14: pre-dose, 1, 2, 3, 6, 24, 48 and 72 hours post Day 
14 morning dose. 
Note: The following PK parameters will be calculated: Cmax, 
Tmax, AUC0-T, AUC0-6, and T1/2. 
• To 
evaluate 
other 
Clinical 
Benefit of treatment with CX-
4945 relative to the control arm  
• All-cause mortality status – the number of deaths occurred 
in each treatment group from Randomization (Day 1) 
through Day 60. 
• Number of patients hospitalized in each treatment group 
from Randomization (Day 1) to Day 45 
• Number of days to normalization of oxygen saturation level 
measured by pulse oximeter at Randomization (Day 1), Day 
4, Day 8, Day 11, Day 14, Day 28 and Day 45 and 
categorized as <96% versus ≥96%.  
• Proportion of patients with disease progression or 
improvement 
in 
health 
status 
occurring 
 
from 
Randomization (Day 1) to Day 28. Disease progression is 
defined as change in patient health status assessment from 
item 7 to items 1- 6 and health improvement -as change from 
item 7 to item 8, evaluated by the ordinal NIAID 8- point 
Clinical Progression Outcomes scale   – collected at every 
visit. from randomization (Day 1) through Day 45. 
An 8-category 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);  

 
 
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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. 
• 
Changes in EQ-D5-5L (used as an indicator of symptom 
improvement) from Baseline (Day 1) to Day 8, 14, 28. 
• To evaluate changes in 
inflammatory markers 
• Changes in plasma IL-6 level from Randomization (Day 1) to 
Day 4, Day 8, Day 11, and Day 14. 
• Changes in CRP, LDH, CPK, ferritin, D-dimer from 
randomization (Day 1) to Day 4, Day 8, Day 11, and Day 14. 
 
 

 
 
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4. 
STUDY DESIGN   
4.1. 
OVERALL DESIGN 
This is a phase II multicenter, randomized, open-label, 2 arm parallel-group controlled 
interventional prospective study of CX-4945 in patients with COVID-19. Up to approximately 20 
patients will be enrolled into this study. A screening evaluation will occur within 7 days prior to 
Day 1. At the end of screening all qualified patients will be randomized in a ratio of 1:1 to one of 
the following two treatment arms:  
• Arm A:  the best supportive and/or standard of care in combination with CX-4945 1000 mg 
BID PO or  
• Arm B: the best supportive/standard of care   
The 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 standard of care (SOC) is not pre-specified and 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. Patients progressed on treatment with monoclonal antibodies can 
be enrolled, if meet eligibility criteria.  Active concomitant treatment with other investigational 
antivirals or immunomodulators are not permitted. 
Patients assigned to Arm B will do all the same assessments as Arm A. 
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 Section 6.1.2.  
4.2. 
JUSTIFICATION FOR DOSE 
CX-4945 will be administered BID 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 BID or 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 patients enrolled 
to date. In total, approximately 115 patients have been treated with 1000 mg BID dosing of CX-
4945 in several completed and ongoing studies. 

 
 
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4.3. 
END OF STUDY DEFINITION 
A patient is considered to have completed the study if he or she has completed the Treatment Phase 
and all Follow-up visits (Days 28, 45, and 60). 
Discontinuation from CX-4945 does not mean the withdrawal from the study assessments. Patients 
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 20 outpatients with moderate COVID-19. Best 
supportive and/or SOC alone or in combination with CX-4945 will be given to study patients. 
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. 
 
5.1.1. 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 with COVID-19 by standard RT-PCR assay within 7 days prior to randomization 
(Day 1) 
3. Outpatients with moderate illness caused by SARS-CoV-2 infection as defined below,  
• Symptoms of moderate systemic illness/infection with COVID-19: 
o At least two of the key COVID-19-related symptoms with score 2 or higher: cough, 
sore throat, stuffy or runny nose, shortness of breath, feeling of tightness of chest, 
feeling of fast heartbeat, low energy or tiredness, muscle cramps, joint pain, chills 
or shivering, feeling hot or feverish, difficulty in concentration (brain fog), sleep 
disturbances, headache, dizziness, anxiety, feeling of tingling,nausea (scoring 
values: None = 0; Mild = 1; Moderate = 2; and Severe = 3), vomiting,  diarrhea 
(scoring values:  Not at all = 0; 1–2 times = 1; 3–4 times = 2; 5 or more times = 3), 
loss of taste or smell (scoring values: The same as usual = 0,  Less than usual = 1,  
NO sense of smell/taste = 2 )   
AND 
• Clinical signs indicative of moderate systemic illness/infection with COVID-19 
o At least one of the following: 
o  Respiratory rate ≥ 20 breaths per minute 
o Heart rate ≥ 90 beats per minute 
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• No clinical signs indicative of severe or critical illness severity required hospitalization 
(see exclusion criterion #1) 
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 
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 ≥ 3.0 g/dL 
7. 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 the study duration. 
9.  Patient must agree not to participate in another clinical trial for the treatment of COVID-
19 during the study period until disease progression, hospitalization, withdrawal from study 
treatment or 28 days after the start of the study, whichever occurs first. 
5.1.2. Exclusion Criteria 
Potential patients meeting any of the following criteria will be excluded from participation in this 
study: 
1. Any signs indicative of severe or critical illness severity required hospitalization as defined 
below: 
• Severe COVID-19: Shortness of breath at rest, or respiratory distress, 
respiratory rate (RR) > 30 per minute, heart rate (HR) > 125 bpm, 
SpO2<93% on room air at sea level or PaO2/FiO2<300 
• Critical COVID-19: Respiratory failure required mechanical ventilation, 
oxygen delivered by high-flow nasal cannula, ESMO; shock or multi-organ 
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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. Chronic diarrhea (excess of 2-3 stools/day above normal frequency) 
5. Concomitant treatment with another investigational drug  
6. Current use or anticipated need for drugs that are known strong inhibitors or inducers of 
major CYP enzymes. 
7. Any active or recurring clinically significant hepatic disease. 
5.2. 
SCREEN FAILURES 
All patients who fail to meet eligibility criteria are considered screen failures, and are exited from 
the study. Patient number, demographics and reason for screen failure will be recorded. 
If a patient initially fails to meet inclusion/exclusion criteria and is later reconsidered for 
participation, the patient 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 
6.1.1. Investigational Drug Product Description 
For this study, the investigational product is CX-4945 that will be assigned to the subjects 
randomized to treatment Arm A.  
Refer to the Investigator’s Brochure for more information. 
All patients 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 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.  
6.1.2. Randomization  
Randomized treatment assignments for the patients will be done after confirmation of patient’s 
eligibility. Patients will be allocated randomly into Arm A and Arm B in a 1:1 ratio. 
Table 2: Method of Assignment to Treatment 
Arm 
Supportive 
Care/SOC 
Daily Dose of 
CX-4945 
(mg) 
Dose 
administration 
BID (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. 
6.1.3. Dosing and Administration of CX-4945 
Patients enrolled to the treatment Arm A will receive 1000 mg of CX-4945 BID 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 CX-
4945. Other oral medications should be taken at least one hour before or 2 hours after ingesting the 
dose of CX-4945 capsules. 
Patients will take five 200-mg CX-4945 capsules BID, 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 

 
 
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• Dose Reduction: If a dose-response relationship for toxicity is observed, then a reduced 
dose can be given to the patient. Dose adjustments will be allowed based on the toxicity, 
efficacy evaluation, and clinical judgment by a physician.  
• Dose Interruption: Refer to Table 3 above. Recovery to acceptable levels must occur to 
allow 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 Withdrawal from the study treatment or participation 
o Pregnancy  
o Significant study therapy non-compliance  
o If any clinical adverse event, laboratory abnormality, or other medical condition or 
situation occurs that continued treatment under the protocol would not be in the best 
interest of the patient. 
Discontinuation from CX-4945 does not mean the withdrawal from the study assessments. 
Patients 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 
6.2.1. Investigational Product Supplies 
CX-4945 will be supplied by Senhwa Biosciences. Study sites 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 according to the 
study visit schedule. Any unused product or waste material should be disposed of in accordance 
with local requirements. 
 
 
 
 

 
 
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6.3. 
CONCOMITANT MEDICATION 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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7. 
STUDY COMPLETION OR DISCONTINUATION 
7.1. 
PATIENT COMPLETION 
A patient 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 CX-4945 does not mean the withdrawal from the study assessments. Patients 
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 further participation in the 
study and loss to follow-up.  
7.2. 
PATIENT WITHDRAWAL FROM PARTICIPATION IN THE STUDY 
At any point during the study all patients have the right to withdraw consent from further 
participation in the study refusing to complete scheduled study assessments and follow-ups without 
prejudice to future care. If the patient refuses further visits, the patient should continue to be 
followed unless the patient withdraws consent for disclosure of future information or for further 
contact. In this case, no further study-specific evaluations should be performed and no additional 
data should be collected. The sponsor/investigator may retain and continue to use any data collected 
before such withdrawal of consent. 
Another reason for withdrawal from study is 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. 
The reason for withdrawal from the study will be recorded in the subject medical records. 
7.3. 
 PATIENT DISCONTINUATION FROM STUDY TREATMENT 
Patients may withdraw from treatment at any time at their own request, or they may be withdrawn 
at any time at the discretion of the investigator/sponsor for safety or behavioral reasons, or the 
inability of the patient to comply with the protocol-required schedule of study visits or procedures 
at a given investigator site.  
All patients who discontinued from study treatment but maintain consent, should remain in the study 
through the end of the study period for all important safety and anti-viral activity assessments. 
Investigators considering patient withdrawal from study treatment should contact the medical 
monitor prior to such discontinuation. Patients who have study treatment discontinued will 
continue to be followed, per protocol, whenever possible. If visits to the site are not possible, 

 
 
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subjects can be followed via telehealth or other approaches (telephone calls, e-mails, and texts to 
ascertain vital status in all patients.  
Patients who have study treatment discontinued due to a serious adverse event will be followed 
until study completion, resolution or stabilization of the event (whichever occurs later). 
Reasons for withdrawal of study treatment may include: 
• Patient refused further treatment 
• Pregnancy 
• Unacceptable toxicity 
• Significant study therapy non-compliance  
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition 
or situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• Disease progression which requires discontinuation of the study intervention 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 

 
 
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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 the 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 
8.1.1. Screening Period:  
The patient 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.  
8.1.2. Treatment Period:  
For the treatment period procedures see the Schedule of Activities in Section 1.3 and Assessments 
in Section 8.2. 
Patients who meet the eligibility criteria and are randomized will have completed the following 
evaluations and assessments on Day 1 prior to treatment: review of any changes in medication 
history, physical examination, vital signs, clinical status – ordinal scale assessment and COVID-
19-related symptoms scale assessment, EQ-D5-5L questionnaire, pulse oxygen saturation (SpO2), 
Nasopharyngeal Swab Sample Collection (for quantitative virologic testing viaRT-PCR), 
laboratory sample collection for routine serum biochemical, hematologic, coagulation, IL-6 levels 
and CRP, LDH, CPK, ferritin, D-dimer analysis.  
During the treatment phase, patients randomized to the treatment arm A will receive CX-4945 
(1000 mg) twice a day for up to 14 days. Details on CX-4945 administration can be found in Section 
6. 
8.1.3. Follow Up Period  
For follow-up procedures see the Schedule of Activities in Section 1.3 Assessments in Section 8.2. 
8.1.4. Unscheduled Visits 

 
 
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In the event that the patient 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 patient 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. 
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation of 
the study. 
8.2.1. Safety Assessment 
Safety assessments will include collection of adverse events (AEs), serious adverse events (SAEs), 
vital signs and physical examination, electrocardiogram (ECG [12-lead]), laboratory assessments, 
including pregnancy tests and verification of concomitant treatments. 
8.2.1.1. 
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 patient should have used 2 forms of contraception. Pregnancy tests will 
also be repeated at Day 14/EOT 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. 
8.2.1.2. 
Adverse Events (AEs) 

 
 
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Assessment of AEs will include the type, incidence, severity (as graded by a Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(https://www.fda.gov/media/73679/download)) 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. 
8.2.1.3. 
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. 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 AE. 
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’s 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.  
 
8.2.1.4. 
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, 
For female 
patients of 
childbearing 
potential, serum 
or urine 
Hematocrit 
AST 
 
RBC 
Alk Phos 
 
Platelets 
LDH 
 

 
 
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Hematology 
Chemistry 
Coagulation 
Urinalysis 
Pregnancy Test 
WBC 
Total Protein 
 
nitrite, bilirubin, 
urobilinogen 
Absolute Neutrophils 
Sodium 
 
microscopic 
examination of 
urine sediment 
  
Absolute Lymphocytes 
Potassium 
 
  
Absolute Monocytes 
Ferritin 
 
  
Absolute Eosinophils 
Chloride 
 
 
  
Absolute Basophils 
Calcium 
 
 
  
  
Bicarbonate 
 
 
  
  
Total bilirubin 
 
 
  
  
d-dimer 
 
 
  
  
Creatine (serum) 
 
 
  
  
BUN 
 
 
  
  
Albumin 
 
 
  
  
C-reactive Protein 
(CRP) 
 
 
  
  
Creatinine Clearance 
 
 
  
  
Creatine 
Phosphokinase (CPK) 
  
  
  
 
eGFR 
 
 
 
 
IL-6 
 
 
 
8.2.1.5. 
Electrocardiogram (ECG) 
An ECG will be done at Screening and at Day 14/EOT. 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.  
8.2.1.6. 
Other Assessments 
To adequately monitor for the risk of 5-HT3 antagonist pre-medication which may predispose 
patients to arrhythmias, 24-hour telemetry monitoring for patients with electrolyte abnormalities 
may be performed, if clinically indicated. 
8.2.1.7. 
Pharmacokinetics Assessments 

 
 
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The PK of CX-4945 will be assessed using the data collected in two CX-4945 studies.  
Note: PK samples have been collected from the first four patients by the time of release of Protocol 
Amendment 1. PK collection is not applicable for other patients.  
Table 5. PK Sample Collection Times 
Day 
Time 
 
 
Day 1 
Pre-dose* 
30 minutes post morning dose ± 5 min. 
1 hour post morning dose ± 5 min 
2 hours post morning dose ± 5 min 
3 hours post morning dose ± 10 min 
6 hours post morning dose ± 10 min 
Day 2 
24 hours post Day 1 morning dose ± 60 min* 
 
 
Day 14 
Pre-dose* 
30 minutes post morning dose ± 5 min. 
1 hour post morning dose ± 5 min 
2 hours post morning dose ± 5 min 
3 hours post morning dose ± 10 min 
6 hours post morning dose ± 10 min 
Day 15 
24 hours post Day 14 morning dose ± 60 min 
Day 16 
48 hours post Day 14 morning dose ± 60 min 
Day 17 
72 hours post Day 14 morning dose ± 60 min 
 
 
 
*On pre-dose sampling days, the CX-4945 morning dose must be administered in the clinic. 
The following PK parameters will be calculated: Cmax, Tmax, AUC0-T, AUC0-6, and T1/2. 
8.2.2. Efficacy/Anti-viral Activity Assessment 
8.2.2.1. 
COVID-19-Related Symptom Score Assessment 
Clinical Symptom Score Assessment should be completed using a Patient Reported Outcome 
(PRO) instrument (a Patient Diary for Assessment of Common COVID-19-Related Symptoms – 
see Appendix 3). Each symptom is graded from 0 to 3, sense of taste/ smell is graded from 0 to 2 
(see section 1.1 and section 3 for score values).  Clinical Improvement will be assessed daily during 
the treatment phase from Day 1 through Day 14/EOT and on Day 28 and Day 45 of the Follow-up 
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If some abnormal symptoms are not related to COVID-19 and were caused by other conditions 
documented in medical history and started before COVID-19, the patient can be considered as 
recovered, when these symptoms return to the previous (pre-COVID-19) values. 
8.2.2.2. 
Clinical Signs Evaluation to Assess Recovery 
Assessment of recovery based on clinical signs includes normalization of fever, respiratory rate, 
heart rate 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 < 20 bpm while breathing room air with no shortness of breath 
• SpO2 ≥ 96% in room air 
• Heart rate <90 bpm 
If some abnormal signs were caused by other conditions documented in the medical history and 
started before COVID-19, the patient can be considered as recovered, when these signs return 
to the previous (pre-COVID-19) values. 
8.2.2.3. 
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. 
8.2.2.4. 
COVID-19 8-Point Clinical Progression Outcomes Scale  
Progression is assessed on COVID-19 8-point outcomes scale at the time points described in the 
Schedule of Activities (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. 
8.2.2.5. 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).  

 
 
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8.2.2.6. 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 
laboratory following site’s best practices. 
• 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 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. 
8.2.2.7. RT-PCR 
RT-PCR (nasopharyngeal swab) will be done at the time points described in the Schedule of 
Activities (see Section 1.3). A positive RT-PCR test (presence of SARS-CoV-2 RNA) collected 
within 7 days prior to Day 1 is required at screening for patient eligibility evaluation. Local, fully 
validated, RT-PCR tests shall be performed at screening in a CLIA-certified and CAP-accredited 
laboratory.  
8.3. 
ADVERSE EVENTS (AES) AND SERIOUS ADVERSE EVENTS (SAES) 
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. 
8.3.1. Definitions of AE 
An 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 AE may or 
may not be related to the study treatment.  
AEs will be elicited through direct questioning and patient reports. Any abnormality in physical 
examination findings or laboratory results that the investigator believes is clinically significant (CS) 
to the research patient 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. 
8.3.2. Definition of SAEs 

 
 
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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 patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient; (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 patient’s clinical state, 
environmental or toxic factors, or other therapies administered to the patient. (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 patient’s clinical state, 
environmental or toxic factors, or other therapies administered to the patient. (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. Unlikely 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 patient’s clinical state, 
environmental or toxic factors, or other therapies administered to the patient. (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, 
environment, etc.) and determined with certainty to have no relationship to the study 
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8.3.3.3. Expectedness 
The Medical Monitor will be responsible for determining whether an 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’s Brochure.  
Refer to the Investigator’s Brochure for the expected/anticipated events. 
8.3.4. Reporting of AEs 
Report initiation for all AEs and SAEs will begin at the time of the first treatment visit and continue 
until the end of final study visit.  All events will be followed to resolution or until the patient 
completes the study. A final assessment of outcome will be made at that time.  
All AEs must be recorded in the patient’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  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). 
8.3.4.1. 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 patient is no longer in the 
Treatment Phase of the protocol. 
8.3.4.2. 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, hospitalization, or other (with a specification). 
8.3.4.3. 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 patient is allowed to have an outcome assessment as “death.” If there are multiple causes of 
death for a given patient, only the primary cause of death will have an outcome of death.  
8.3.5. Reporting of SAEs  

 
 
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The Investigator is required to report all SAEs that occur during the time period specified in Section 
8.3.4. Once the Investigator becomes aware of an SAE, he/she must report the SAE to Medical 
Monitor within 24 hours. 
 
 
 
 
 
 
 
The Medical Monitor may request additional supporting documentation as it becomes available, 
such as lab reports, electrocardiogram [ECG] reports, discharge summary, hospital notes, etc., if 
applicable. Additional follow-up information as it becomes available must be reported to the 
Medical Monitor. 
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.  
8.3.6. SAE Follow-Up 
All patients experiencing an SAE, including the discontinued patients, 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 
patients 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 ARMS 
There will be two treatment arms 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 1.1 and Section 3. 
 
9.2.1. Safety Measures: 
• Incidence and severity of AEs 
• Incidence of 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 ECG results 
9.3. 
SAMPLE SIZE DETERMINATION AND RATIONALE 
A total of approximately 20 subjects will be randomized 1:1 in this study. The sample size is based 
on clinical judgment. No statistical power calculation is 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 
group and SOC alone group to ensure balanced distribution of subjects. An individual, independent 

 
 
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of the clinical trial team, will develop the randomization schedules. Subjects who have provided 
written informed consent and have met all 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 patient data listings. Statistical analyses will be 
performed using SAS® for Windows, version 9.4 or later. 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. 
9.7.1. Analysis Populations 
9.7.1.1. 
Intent-to-Treat (ITT)Population 
The ITT population is defined as all randomized patients. This population will be used as the 
primary analysis population for analysis of the primary and secondary efficacy endpoints. 
9.7.1.2. 
Per Protocol (PP) Population 
The PP population is defined as the set of patients 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. 
9.7.1.3. 
Safety Population 
The Safety population is defined as any patient 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. 
9.7.1.4. 
PK Population 

 
 
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The PK population includes all patients receiving at least one dose of CX-4945 and have adequate 
blood samples provided for PK evaluation and calculation of the PK parameters.  PK data collected 
in two CX-4945 studies will be used for PK analysis. 
9.7.2. Covariates 
For efficacy analyses important prognostic factors that need adjustment will be specified in the SAP 
for the study 
9.7.3. Missing Data 
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 patients who have been 
randomized in the study to minimize missing data. However, in the event when there are missing 
data the following imputation methods will be used. 
For efficacy evaluations, multiple imputation methods will be used to handle missing data and will 
be detailed in the SAP. This imputation method is a robust method to impute potential missing 
measurements. The imputation will be carried out in SAS version 9.4 or later using PROC MI. 
9.8. 
ANALYSIS METHODS 
An 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. 
9.8.1. Patient Disposition 
The disposition of all patients 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-patient listing. 
9.8.2. 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. 
9.8.3. Concomitant Medications/Therapies 
Concomitant medications/therapies will be summarized separately for the Safety population. All 
prior and concomitant medications recorded in the case report form 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. All 
concomitant medications/therapies recorded in the case report form will be listed. 

 
 
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9.8.4. 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.  
9.8.4.1. 
Efficacy Analysis  
Analysis of the efficacy endpoints will be summarized according to the variable type and will be 
detailed in the SAP.  
 
9.8.4.2. 
Supportive Analysis  
To assess the consistency of the primary analysis results, supportive analysis will be conducted 
using the ITT and 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.  
9.8.4.3. 
Safety Summaries  
Adverse Events 
AEs 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 SAEs, and AEs 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. 
ECG 

 
 
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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. 
 

 
 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Patients will be identified on study records by a unique Patient 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 patient this research study. The subject identification number will be used 
if it becomes necessary to identify data specific to a single patient.  
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 patients 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 patient 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 patient 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 patient; or 
2. When the modification does not involve the patient’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 
patient for protocol violations. The IRB may also have to be contacted if safety to the patient or if 
the scientific soundness of the study is involved.  
11.3.1. Major Protocol Deviation or Violation 
A major protocol deviation or violation is a deviation from the IRB approved protocol that may 
affect the patient's rights, safety, or well-being 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 patient does not meet the protocol's eligibility criteria but was enrolled 
• A research patient received the wrong treatment or incorrect dose. 
• A research patient met withdrawal criteria during the study but was not withdrawn. 
• A research patient received a prohibited concomitant medication. 
• Failure to treat research patients per protocol procedures that specifically relate to primary 
outcome measures. 

 
 
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• Changing the protocol without prior IRB approval. 
• Multiple minor violations of the same nature after multiple warnings. 
11.3.2.  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 patient'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 patient’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 patient’s participation in 
the trial or where it may be necessary to eliminate an immediate hazard to a research patient. 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 patients or when the modification does not involve the patient’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 to the study center participating in this study that cannot comply with these 
standards will be documented. 

 
 
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12.3. PATIENT INFORMED CONSENT REQUIREMENTS 
All patients participating in this study will be given to by the Investigator and/or designee, written 
and oral information about the study in a language understandable by the patient. Written informed 
consent will be obtained from each patient prior any procedures or assessments that would not 
otherwise be required for the care of the patient are done and after the aims, methods, anticipated 
benefits, potential hazards, and insurance arrangements in force are explained and the patient has 
been given sufficient time to ask questions and consider participation in the study. It will also be 
explained to the patients 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 patient's study records, and a copy is provided to the patient. A second copy may be filed in 
the patient’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 patient'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 patients that will include each patient’s 
study number, name, date of birth, and unique hospital identification number if applicable. A 
notation will be made in the patient’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 patients screened for participation in the study; it should include gender, age, eligibility 
status, reason for ineligibility, if applicable; and study allocated patient 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., patient’s progress 
notes, AE 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 
• Patient 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 Investigator/Sponsor and Senwha 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 Investigator/Sponsor and Senwha, 
shall not be disclosed to others without the written consent of Investigator/Sponsor and Senwha, 
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 Investigator/Sponsor and Senwha. 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: TOXICITY GRADING SCALE FOR HEALTHY ADULT AND ADOLESCENT 
VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE CLINICAL TRIALS 
For complete detailed information please refer to the link below: 
https://www.fda.gov/media/73679/download  
 

 
 
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16.3. APPENDIX 3: ASSESSMENT OF COVID-19-RELATED SYMPTOMS (PATIENT DIARY)