Clinical trial NCT04440007
Conditions: Covid-19
Sponsor: Sorrento Therapeutics, Inc.
Start date: 2020-10-09; Completion date: 2021-08-23
Enrollment: 96 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to assess the safety and efficacy of STI-5656 (Abivertinib Maleate) plus SOC versus SOC in subjects hospitalized with COVID-19

Detailed description:
This is a Phase 2, open-label, randomized 2-arm multicenter study to assess the safety and efficacy of STI-5656 (Abivertinib Maleate) administered orally plus Standard of Care (SOC) versus SOC in hospitalized subjects with RT-PCR confirmed SARS-CoV-2 infection and COVID-19 pneumonia (documented radiographically). Only hospitalized patients are eligible for this study.

Arms: arm 1: STI-5656 (abivertinib maleate) capsule administered orally 200 mg QD up to 28 days or until hospital discharge, in addition to standard of care arm 2: Standard of care treatments for COVID-19 as determined appropriate by the Investigator
Interventions: intervention 1: Abivertinib intervention 2: Standard of Care
Intervention descriptions: intervention 1: Abivertinib maleate is a third-generation EGFR tyrosine kinase inhibitor and BTK Inhibitor. The starting dose is 200 mg p.o. QD for up to 28 days. intervention 2: Standard of Care as determined by the Investigator

Protocol documents:
Prot_000.pdf: 
Sorrento Therapeutics, Inc. 
STI-5656 (Abivertinib Maleate) 
 
Protocol STI-5656-2001 
Confidential 
 
Page 1 of 49 
TITLE PAGE 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF THE SAFETY AND EFFICACY OF 
STI-5656 (ABIVERTINIB MALEATE) IN SUBJECTS 
HOSPITALIZED DUE TO COVID-19 
 
STUDY INTERVENTION: 
STI-5656 
PROTOCOL NUMBER: 
STI-5656-2001 
Version 
5.0 
DATE FINAL: 
07DEC2020 
Amendment 1; V2.0 
01JUL2020 
Amendment 2; V3.0 
08JUL2020 
Amendment 3; V4.0 
12NOV2020 
IND NUMBER: 
151327 
SPONSOR NAME / ADDRESS: 
 
Sorrento Therapeutics, Inc. 
4955 Directors Place, 
San Diego, CA 92121 USA 
 
CONFIDENTIAL 
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them. 
 
 


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STI-5656 (Abivertinib Maleate) 
 
Protocol STI-5656-2001 
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Page 2 of 49 
MEDICAL MONITOR/ EMERGENCY CONTACT 
 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 
THE SAFETY AND EFFICACY OF STI-5656 (ABIVERTINIB MALEATE) IN 
SUBJECTS HOSPITALIZED DUE TO COVID-19 
 
Role in Study 
Name 
Address and Telephone number 
Responsible Physician 
Mike A. Royal MD JD 
MBA 
mroyal@Sorrentotherapeutics.com 
+1 (858) 204 1112 
 
 
 


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STI-5656 (Abivertinib Maleate) 
 
Protocol STI-5656-2001 
Confidential 
 
Page 3 of 49 
 
SORRENTO THERAPEUTICS INC. APPROVAL 
 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 
THE SAFETY AND EFFICACY OF STI-5656 (ABIVERTINIB MALEATE) IN 
SUBJECTS HOSPITALIZED DUE TO COVID-19 
 
 
 
07DEC2020 
Signature of Responsible Officer 
 
dd mmm yyyy 
Mike A. Royal MD JD MBA 
Chief Medical Officer, Sorrento Therapeutics, Inc. 
Printed Name of Responsible Officer and Title 
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable. 
 


Sorrento Therapeutics, Inc. 
STI-5656 (Abivertinib Maleate) 
 
Protocol STI-5656-2001 
Confidential 
 
Page 4 of 49 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 
THE SAFETY AND EFFICACY OF STI-5656 (ABIVERTINIB MALEATE) IN 
SUBJECTS HOSPITALIZED DUE TO COVID-19 
 
 
 
 
 
 
Signature of Site Principal Investigator 
 
dd mmm yyyy 
 
 
Printed Name of Site Principal Investigator 
Institution Name: ______________________________________ 
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Sorrento Therapeutics Inc.  representatives, the Declaration of Helsinki, ICH Good 
Clinical Practices Guidelines, and local regulations governing the conduct of clinical 
studies. 
 
 


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Protocol STI-5656-2001 
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Page 5 of 49 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
MEDICAL MONITOR/ EMERGENCY CONTACT .....................................................................2 
1. 
PROTOCOL SYNOPSIS ...........................................................................................11 
2. 
SCHEDULE OF ASSESSMENTS (SOA) .................................................................15 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................18 
3.1. 
Objectives ...................................................................................................................18 
3.1.1. 
Primary Objective .......................................................................................................18 
3.1.2. 
Secondary Objectives .................................................................................................18 
3.2. 
Endpoints ....................................................................................................................18 
3.2.1. 
Primary Endpoint ........................................................................................................18 
3.2.2. 
Secondary Endpoints ..................................................................................................18 
3.2.3. 
Exploratory Endpoints ................................................................................................19 
4. 
INVESTIGATIONAL PLAN .....................................................................................20 
4.1. 
Overall Study Design ..................................................................................................20 
4.2. 
End of Trial Definition ...............................................................................................21 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................22 
5.1. 
Subject Inclusion Criteria ...........................................................................................22 
5.2. 
Subject Exclusion Criteria ..........................................................................................23 
5.3. 
Screen Failures ............................................................................................................23 
6. 
TREATMENT OF PARTICPANTS ..........................................................................25 
6.1. 
Description of Investigational Product .......................................................................25 
6.2. 
Investigational Product Administration ......................................................................25 
6.3. 
Stopping Rule Triggers ...............................................................................................25 
6.4. 
Dosing of Subjects Unable to Take Test Article PO ..................................................25 
6.5. 
Investigational Product Compliance ...........................................................................26 
6.6. 
Overdose .....................................................................................................................26 
6.7. 
Randomization and Blinding ......................................................................................26 
6.8. 
Emergency Unblinding ...............................................................................................26 
6.9. 
Concomitant Medications ...........................................................................................26 
6.9.1. 
Prohibited Concomitant Medications .........................................................................26 
7. 
IP MATERIALS AND MANAGEMENT .................................................................27 


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7.1. 
Investigational Product ...............................................................................................27 
7.2. 
IP Packaging and Labeling .........................................................................................27 
7.3. 
IP Storage ....................................................................................................................28 
7.4. 
IP Accountability ........................................................................................................28 
7.5. 
IP Handling and Disposal ...........................................................................................28 
8. 
STUDY PROCEDURES ............................................................................................29 
8.1. 
Description of Procedures ...........................................................................................29 
8.1.1. 
Informed Consent .......................................................................................................29 
8.1.2. 
RT-PCR assay for SARS-CoV-2 ................................................................................29 
8.1.3. 
Collection of Demographics, Medical History, Prior and Concomitant 
Medications .................................................................................................................29 
8.1.4. 
Vital Signs ..................................................................................................................29 
8.1.5. 
Physical Exam ............................................................................................................30 
8.1.6. 
12-lead Electrocardiogram (ECG) ..............................................................................30 
8.1.7. 
Clinical laboratory tests ..............................................................................................30 
8.1.7.1. 
Serum Chemistry ........................................................................................................30 
8.1.7.2. 
Hematology .................................................................................................................30 
8.1.7.3. 
Coagulation .................................................................................................................30 
8.1.7.4. 
C-reactive protein, serum ferritin, absolute lymphocyte count and cytokines ...........30 
8.1.7.5. 
Urinalysis ....................................................................................................................30 
8.1.7.6. 
Urine Pregnancy Test .................................................................................................30 
8.1.8. 
Respiratory Status .......................................................................................................31 
8.1.9. 
Clinical status using 8-category ordinal scale of patient health status .......................31 
8.1.10. 
IRT Registration, Randomization and Study Discontinuation or Completion. ..........31 
8.1.11. 
Adverse Events ...........................................................................................................31 
8.1.12. 
Follow-up contact .......................................................................................................31 
8.2. 
Procedures by Study Day ............................................................................................32 
8.2.1. 
Screening ....................................................................................................................32 
8.2.2. 
Study Day 1 ................................................................................................................32 
8.2.3. 
Daily until Hospital Discharge ...................................................................................32 
8.2.4. 
Hospital Discharge or Early Termination from Study ................................................33 
8.2.5. 
Outpatient Follow-up Day 28 .....................................................................................33 
8.2.6. 
Telephone Follow-up Day 60 .....................................................................................33 


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8.2.7. 
Telephone Follow-up Day 90 .....................................................................................33 
8.3. 
Blood Volumes collected ............................................................................................33 
9. 
STATISTICS ..............................................................................................................34 
9.1. 
Statistical Considerations ............................................................................................34 
9.2. 
Sample Size Estimation ..............................................................................................34 
9.3. 
Analysis Population ....................................................................................................34 
9.4. 
Data Analysis ..............................................................................................................34 
9.4.1. 
Subject Disposition .....................................................................................................34 
9.4.2. 
Demographics and Baseline Characteristics ...............................................................34 
9.4.3. 
Primary Endpoints ......................................................................................................35 
9.4.4. 
Secondary Endpoints (Safety) ....................................................................................35 
9.4.5. 
Secondary Endpoints (Efficacy) .................................................................................35 
9.4.6. 
Exploratory Endpoints ................................................................................................36 
9.4.7. 
Interim Analysis ..........................................................................................................36 
10. 
ADVERSE EVENT DEFINITIONS AND PROCEDURE FOR 
RECORDING, EVALUATING, FOLLOW-UP AND REPORTING .......................37 
10.1. 
Monitoring, Recording and Reporting of Adverse Events .........................................37 
10.2. 
Evaluation of Adverse Events ....................................................................................37 
10.2.1. 
Seriousness .................................................................................................................37 
10.2.2. 
Severity / Intensity ......................................................................................................38 
10.2.3. 
Causality .....................................................................................................................39 
10.2.4. 
Duration ......................................................................................................................39 
10.2.5. 
Action Taken ..............................................................................................................39 
10.2.6. 
Outcome ......................................................................................................................40 
10.3. 
Abnormal Laboratory Values .....................................................................................40 
10.4. 
Pregnancy ...................................................................................................................40 
10.4.1. 
Females of Childbearing Potential..............................................................................40 
10.4.2. 
Male Subjects ..............................................................................................................41 
10.5. 
Reporting of Serious Adverse Events .........................................................................41 
10.6. 
Expedited Reporting of Adverse Events .....................................................................41 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................43 
11.1. 
Study Monitoring ........................................................................................................43 
11.2. 
Audits and Inspections ................................................................................................43 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................45 
13. 
ETHICS ......................................................................................................................46 
13.1. 
Ethics Review .............................................................................................................46 
13.2. 
Ethical Conduct of the Study ......................................................................................46 
13.3. 
Written Informed Consent ..........................................................................................46 
14. 
APPENDICES ............................................................................................................47 
14.1. 
List of Abbreviations and Definitions of Terms .........................................................47 
14.2. 
Ordinal Scale for Clinical Improvement.....................................................................49 


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Protocol STI-5656-2001 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................15 
Table 3: 
Stopping Rule Triggers ...............................................................................................25 
Table 4: 
Abbreviations ..............................................................................................................47 
 


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STI-5656 (Abivertinib Maleate) 
 
Protocol STI-5656-2001 
Confidential 
 
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LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................14 
 
 
 


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1. 
PROTOCOL SYNOPSIS 
A Phase 2, Randomized, Double-Blind, Placebo-controlled Study of the Safety and Efficacy of 
STI-5656 (Abivertinib Maleate) in Subjects Hospitalized Due to COVID-19 
Protocol Number:  STI-5656-2001, Version 4.0 
Investigator(s)/ Study Centers 
This study will be conducted at multiple study centers located in the United States.   
Phase:  2 
Objectives 
Primary Objective: 
• 
To assess the efficacy of STI-5656 in subjects with severe coronavirus disease 2019 (COVID-
19) 
Secondary Objectives: 
• 
To assess the safety and tolerability of STI-5656 in subjects with severe COVID-19 
• 
To assess the pharmacokinetic profile in the study population 
Endpoints 
Primary Endpoint: 
• 
Proportion of subject alive and free of respiratory failure at Day 28 
Respiratory failure, is defined based on resource utilization of any of the following modalities: 
o Noninvasive positive pressure ventilation or continuous positive airway pressure 
o Endotracheal intubation and mechanical ventilation 
o Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via 
reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) 
o Extracorporeal membrane oxygenation (ECMO) 
Secondary Endpoints:   
• 
Types, frequencies, and severities of adverse events (AEs) and the relationships of AEs to IP; 
includes serious adverse events (SAEs) 
• 
Proportion of subjects alive and free of respiratory failure at Day 60 
• 
Change in clinical status (on a 0-8-point ordinal scale)1 of subject at Day 7, Day 14 and Day 28 
 
1 8-category ordinal scale of patient health status ranges:  0=no clinical or virological evidence of infection; 1=no 
limitation of activities; 2=limitation of activities; 3=hospitalized, no oxygen therapy; 4=oxygen by mask or nasal 
prongs; 5=non-invasive ventilation or high-flow oxygen; 6=intubation and mechanical ventilation; 7=ventilation + 
additional organ support – pressors, rapid response team (RRT), extracorporeal membrane oxygenation (ECMO); 
8=death.   See Section 14.2 for form. 
 


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• 
Proportion of subjects alive and discharged from Intensive Care Units (ICU) at Days 14 and 28 
• 
Time from randomization to first occurrence of respiratory failure or death on study due to any 
cause up to Day 28  
• 
Percent change from baseline in CRP at Days 3, 5, 7, 10, 14, 28  
• 
Relative change from baseline in oxygenation index (PaO2/FiO2) up to Day 5 
• 
All-cause mortality at Day 60 and Day 90 
• 
Number of days alive and free of respiratory failure at Day 28 
• 
Number of days with respiratory failure up to Day 28 
• 
Number of days hospitalized up to Day 28 
• 
Number of days in ICU (length of stay) up to Day 90 
• 
Number of days alive outside of hospital up to Day 28 
• 
Number of days alive outside of hospital up to Day 90 
• 
Pharmacokinetics in the study population at 100 mg QD 
Exploratory Endpoints: 
• 
See Section 3.2.3  
Subject Population 
• 
≥18 years with reverse transcriptase polymerase chain reaction (RT-PCR) confirmed infection 
with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)  
• 
COVID-19 pneumonia (documented radiographically) requiring hospitalization; oxygen 
saturation level <94% on room air or subject requires supplemental oxygen. 
Refer to Section 5 for complete eligibility details. 
Investigational Product (IP) Description: 
Investigational Product (IP) is STI-5656 (Abivertinib maleate)  
Planned Sample Size 
Approximately 80 subjects will be enrolled in this study, 40 will be randomized to each of two 
treatment arms.   
Treatment Arms  
All subjects will receive current standard of care (SOC) treatments.   
In this setting, subjects will receive one of two treatments up to Day 14 or until hospital discharge (if 
sooner): 
Arm 1:  STI-5656 (100 mg QD starting dose)    


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Arm 2:  Placebo QD  
Duration of Study  
For subjects, the total duration of the study will be up to 94 days (up to 4 days for the screening period 
plus up to 14 days for treatment and up to 90 days from randomization for follow-up).   
The length of the study will be approximately 7 months (4 months for enrollment plus up to 90 days 
study duration). 
Study Design 
This is a Phase 2, randomized, double blind, placebo-controlled, 2-arm multicenter study to assess the 
safety and efficacy of STI-5656 (capsule administered orally) in the setting of current standard of care 
(SOC) in subjects with RT-PCR confirmed SARS-CoV-2 (COVID-19) infection and pneumonia 
(documented radiographically) requiring hospitalization.  Subjects must have oxygen saturation levels 
< 94% on room air or subject requires supplemental oxygen.  
Eighty (80) subjects meeting eligibility criteria will receive SOC treatment and will be randomized at a 
1:1 ratio to one of two treatment arms  
• 
Arm 1:  STI-5656  
• 
Arm 2:  Placebo  
The starting dose of STI-5656 is 100 mg PO QD administered up to 14 days or until hospital discharge 
whichever is sooner.  Placebo follows the same schedule. 
Subjects who discontinue at any time after randomization will not be replaced.  There is no treatment 
crossover in this study. 
Once subjects provide informed consent, they will have screening assessments performed (up to a 7-
day screening window).  Study Day 1 is the day of randomization.  Subjects randomized should receive 
their first dose of STI-5656 or placebo on the day they are randomized (Day 1).    
Subjects will be assessed daily while hospitalized.  Subjects in both arms are assessed for adverse 
events and toxicities and all adverse events should be reported regardless of treatment arm assignment 
or causality.   
PK samples will be collected from the first 20 subjects enrolled in this trial. For sampling time points 
please refer to the schedule of assessments. 
Subjects will have an outpatient visit on Day 28 (for various study procedures) and a telephonic contact 
on Day 60 to collect any additional AEs and follow-up for unresolved AEs to resolution or to 
establishment of a new baseline.  
SOC treatments will be collected in the electronic case report form (e-CRF) until hospital discharge.  
Continued outpatient treatment (concomitant medications) will be collected until Day 28. Any 
investigational medication received will be collected until Day 90.   
Note:  Investigational medicines other than STI-5656 are prohibited up to Day 28 or hospital discharge. 


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Discharged subjects will be contacted at Day 60 and Day 90 to collect survival, any experimental 
treatments and additional hospitalization information since the study hospital discharge.   
Subjects should be encouraged to remain in the study even if Study Drug is discontinued (for any 
reason).   
Statistical Design 
An evaluable sample size of 40 subjects per group (treatment arm) will provide 80% power 
(alpha=0.05, 2-sided) to detect a difference between groups in the number of subjects alive and free of 
respiratory failure at Day 28. This assumes that 95.7% of subjects who received STI-5656 plus SOC 
(group 1) and 70% of subjects who received only SOC (group 2) will be alive and free of respiratory 
failure at Day 28.  This represents a treatment effect difference of approximately 26%.   
All tests of significance will be assessed at alpha level=0.05, 2-sided. 
Figure 1: 
Study Design 
 
Schedule of Assessments (SOA) 
See Table 1 for SOA 
Data Monitoring Committee 
An independent data monitoring committee (DMC) will be established under a charter for the trial and 
tasked to evaluate data from the study to ensure the ongoing safety of the study subjects and make 
recommendations to the Sponsor concerning safety and trial conduct.  A blinded independent 
statistician will be used to facilitate DMC support.  This statistician will have no role in the statistical 
assessments conducted for the study at its conclusion.  Discussions with the independent statistician 
will be conducted during a closed session during the DMC deliberations.  Sponsor, CRO and study site 
personnel will only participate in the open session.  Unblinding of a given subject to assess an AE 
stopping rule trigger will be handled in a way to keep the Sponsor, CRO (and staff) and study site 
personnel blinded.   
A futility analysis will be performed by an independent biostatistician after the first 40 subjects are 
enrolled. 
Additional details may be found in the Statistical Analysis Plan (SAP) for this study. 
Screening
Day -7 to Day-1
Randomization
1:1
40 subjects per 
Treatment Arm
Treatment Arm 1
STI-5656 + SOC
STI-5656 up to Day 14 or 
hospital discharge if earlier
or
Treatment Arm 2
Placebo + SOC
Placebo up to Day 14 or 
hospital discharge if earlier
Follow-up 
visit Day 28 
and 
Telephonic 
contact on
Day 60 and 
Day 90


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2. 
SCHEDULE OF ASSESSMENTS (SOA) 
Table 1: 
Schedule of Assessments 
Assessments 
Screening  
(Day -4 
to -1) 
Day 1 
(Dose 1)1 
Daily until 
hospital 
discharge 
Hospital 
discharge or 
Early Term 2 
Outpatient visit:  
Day 28 
Telephone 
Follow-up 
at Day 60 
and 90 
Informed Consent 
X 
 
 
 
 
 
Assess eligibility 
X 
X 
 
 
 
 
Demographics3 
X 
 
 
 
 
 
RT-PCR assay for SARS-CoV-24 
X 
 
 
 
 
 
Medical history (including COVID-19 history) 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
 
Physical exam, including weight; height5 
X 
 
 
X 
X 
 
Vital signs6 
X 
X 
X 
X 
X 
 
12-lead ECG (performed locally)7 
X 
X 
 
 
 
 
Pregnancy test for FCBP only8 
X 
X 
 
X 
X 
 
Urinalysis9 
X 
X 
X 
 
X 
 
Blood for hematology, coagulation and 
chemistry10 
X 
X 
X 
X 
X 
 
Blood for  CRP , serum ferritin, VEGF-A and 
cytokines11 
Day 3, 5, 7, 10, 14 and 28 only 
X 
X 
X 
X 
X 
 
Respiratory Status12 
X 
X 
X 
X 
 
 
Adverse Events13 
X 
X 
X 
X 
X 
 
Assess clinical status14 
X 
X 
X 
X 
 
 
IRT entry (at screening, randomization, then 
early termination or study completion 
X 
X 
 
X 
 
X 
Study Drug administration (QD p.o.) 
 
X 
X15 
 
 
 


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12-Jun-2020 
Assessments 
Screening  
(Day -4 
to -1) 
Day 1 
(Dose 1)1 
Daily until 
hospital 
discharge 
Hospital 
discharge or 
Early Term 2 
Outpatient visit:  
Day 28 
Telephone 
Follow-up 
at Day 60 
and 90 
Sampling for pharmacokinetics16 
X16 
X16 
X16 
 
 
 
Survival and additional experimental meds/ 
hospitalization/ICU status 
 
 
 
 
X 
X 
Abbreviations: AEs: adverse events; ALC: Absolute lymphocyte count; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CRP: C-reactive 
protein;  BUN: blood urea nitrogen; CMP: complete metabolic panel; COVID-19: Coronavirus Disease 2019; D: day; ECG: electrocardiogram; ECMO: 
extracorporeal membrane oxygenation; ET: Early Termination; F: Fahrenheit; FCBP: female of childbearing potential; FiO2: Fraction of inspired oxygen; IRT: 
Interactive Response Technology; IL: Interleukin; IFNγ: interferon gamma; QD: once daily; PaO2: partial pressure of oxygen in arterial blood;  p.o.: by mouth; 
RBC: red blood cells; rbc/hpf: red blood cells per high power field; RRT: rapid response team; RT- PCR: Reverse transcription polymerase chain reaction; 
TNF: tumor necrosis factor alpha; WBC: white blood cells 
 
1 All assessments on Day 1 are to be performed prior to first dose of STI-5656.  Day 1 laboratory results do not need to be available prior to randomization (and 
first dose of STI-5656 if assigned to that arm) if lab results are available from the previous 24 hours 
2 If the subject wishes to discontinue from the study prior to Day 28 or hospital discharge, every effort should be made to perform an Early Termination (ET) 
Visit within 7 days after the decision to discontinue the study. 
3 Demographics includes age, sex, race, ethnicity, date of birth. 
4 SARS-CoV-24 positive RT-PCR test results received more than 7 days prior to planned randomization may be used to confirm eligibility if the site is unable to 
obtain a repeat sample and confirm results prior to planned randomization day and if the subject has progressive disease consistent with COVID-19. 
5 Height at screening only 
6 Vital signs include body temperature (F), respiratory rate, radial pulse rate, systolic and diastolic blood pressure, and oxygen saturation (pulse oximetry).  Pulse 
and blood pressure should be taken with subject in at least in a semi-recumbent position.  It is preferred to collect vital signs approximately mid-afternoon each 
day. Vital signs may be obtained at additional times as deemed necessary by the Investigator. 
7 ECG to be performed at Screening, between 2 and 4 hours after study drug dosing, and as clinically indicated. 
8 Females of childbearing potential must have a negative pregnancy test at screening and within 24 hours before randomization (Day 1) unless the previous 
negative pregnancy test was within 72 hours of Day 1.  Urine pregnancy test is acceptable.  The test should be repeated at the time of the Day 28 visit. 
9 Urinalysis performed locally. Urinalysis includes protein, glucose, and blood (microscopic) – red blood cells per high power field (rbc/hpf). 
10 Laboratory tests performed locally.   
 Hematology: Hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, platelet count (or estimate), and white blood cell count including differential. 
 Coagulation: INR, PTT. 
Chemistry:  performed locally. 14-analyte complete metabolic panel (CMP) :  Albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bicarbonate, total bilirubin (TBIL), blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, potassium, sodium, 
total protein, D-dimer, fibrinogen. 
11 Cytokines include TNF, IFNγ, IL-6, IL-1β, IL-7, IL-8, IL-10, IL-12, IL-17, IL-18, IP 10, VEGF-A  


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12-Jun-2020 
12 Record FiO2 (and PaO2) at the time of arterial blood gas sampling.  If PaO2 is not available, use SPO2. Other respiratory status data to collect includes oxygen 
supplementation status:  mechanical ventilation, face mask, nasal cannula or room air.  Radiographic findings will also be collected. 
13 AEs will be collected from the time of informed consent to Day 60.  Any ongoing AEs at Day 28 will be followed until resolution or stabilization. 
14 An 8-category ordinal scale of patient health status ranges:  0=no clinical or virological evidence of infection; 1=no limitation of activities; 2=limitation of 
activities; 3=hospitalized, no oxygen therapy; 4=oxygen by mask or nasal prongs; 5=non-invasive ventilation or high-flow oxygen; 6=intubation and 
mechanical ventilation; 7=ventilation + additional organ support – pressors, rapid response team (RRT), extracorporeal membrane oxygenation (ECMO); 
8=death.   See Section 14.2 for form. 
15 STI-5656 or placebo administration up to Day 14 or hospital discharge, whichever is sooner for subjects in Treatment Arm 1.  Study drug capsules should be 
taken orally with 200-250 mL of water following at least 2 hours of fasting.   
16Samples will be collected from the first 20 subjects enrolled. Sampling timepoints are as follows: Day 1 (predose) and at 0.5, 1, 2, 4, 8, 12, postdose on dosing 
days 1 and 8. 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary Objective 
To assess the efficacy of STI-5656 in subjects with severe COVID-19 
3.1.2. 
Secondary Objectives 
To assess the safety and tolerability of STI-5656 in subjects with severe COVID-19 
To assess pharmacokinetics in the study population. 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
• Proportion of subjects alive and free of respiratory failure at Day 28 
Respiratory failure, is defined based on resource utilization of any of the following 
modalities: 
− Noninvasive positive pressure ventilation or continuous positive airway pressure 
− Endotracheal intubation and mechanical ventilation 
− Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen 
delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of 
delivered oxygen ≥0.5) 
− Extracorporeal membrane oxygenation 
3.2.2. 
Secondary Endpoints 
• Types, frequencies, and severities of AEs and the relationships of AEs to IP; includes 
serious adverse events SAEs 
• Proportion of subjects alive and free of respiratory failure at Day 60 
• Change in clinical status (on a 0-8-point ordinal scale2) of subject at Day 7, Day 14, 
and Day 28 
• Proportion of subjects alive and discharged from ICU at Days 14 and 28 
 
2 8-category ordinal scale of patient health status ranges:  0=no clinical or virological evidence of infection; 1=no 
limitation of activities; 2=limitation of activities; 3=hospitalized, no oxygen therapy; 4=oxygen by mask or nasal 
prongs; 5=non-invasive ventilation or high-flow oxygen; 6=intubation and mechanical ventilation; 7=ventilation + 
additional organ support – pressors, rapid response team (RRT), extracorporeal membrane oxygenation (ECMO); 
8=death.  
 


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• Time from randomization to first occurrence of respiratory failure or death on study 
due to any cause up to Day 28 
• Percent change from baseline in CRP at Days 3, 5, 7, 10, 14, 28  
• Relative change from baseline in oxygenation index (PaO2/FiO2) up to Day 5 
• All-cause mortality at Day 60 and Day 90 
• Number of days alive and free of respiratory failure at Day 28 
• Number of days with respiratory failure up to Day 28 
• Number of days hospitalized up to Day 28 
• Number of days in ICU (length of stay) up to Day 90 
• Number of days alive outside of hospital up to Day 28 
• Number of days alive outside of hospital up to Day 90 
• To assess the pharmacokinetic profile in the study population 
3.2.3. 
Exploratory Endpoints 
• Change from baseline in absolute lymphocyte counts at Days 3, 5, 7, 10, 14, 28  
• Change from baseline in ferritin at Days 3, 5, 7, 10, 14, 28 
• Change from baseline in VEGF-A at Days 3, 5, 7, 10, 14, 28 
• Change from baseline for inflammatory cytokines (IL-6, TNF-, IFNγ, IL1β, IL-7, 
IL-8, IL-10, IL-12, IL-17, IL-18, IP-10) at Days 3, 5, 7, 10, and 28 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, 2-arm multicenter study to 
assess the safety and efficacy of oral STI-5656 (or placebo) in the setting of current SOC in 
subjects with RT-PCR confirmed SARS-CoV-2 infection and COVID-19 pneumonia 
(documented radiographically) requiring hospitalization.  Subjects must have oxygen saturation 
levels <94% on room air or subject requires supplemental oxygen.  
Eighty (80) subjects meeting eligibility criteria will be randomized at a 1:1 ratio to one of two 
treatment arms in addition to SOC treatments: 
• Arm 1:  STI-5656 
• Arm 2:  Placebo  
The STI-5656 dose is 100 mg p.o. QD administered up to 14 days or until hospital discharge if 
sooner.   
SOC treatments will be collected in the electronic case report form (e-CRF). 
Subjects who discontinue at any time after randomization will not be replaced.  There is no 
treatment crossover in this study. 
Once subjects provide informed consent, they will have screening assessments performed (up to 
4-day screening window).  Study Day 1 is the day of randomization.  Randomized Subjects 
should receive their first dose of Study Drug on Day 1.    
Subjects will be assessed daily while hospitalized.  Subjects in both arms are assessed for 
adverse events (AEs) and toxicities and all AEs should be reported regardless of treatment arm 
assignment or causality.  Subjects will be contacted on Day 28 to collect any additional AEs and 
follow-up for unresolved AEs,  
SOC treatments will be collected in the electronic case report form (e-CRF) until hospital 
discharge.  Continued outpatient treatment (concomitant medications) will be collected until Day 
28. Any investigational medication received will be collected until Day 90.  Note:  
Investigational medicines other than STI-5656 are prohibited up to Day 28 or hospital discharge. 
Discharged subjects will be contacted at Day 60 and 90 to ensure survival and collect any 
experimental treatments and additional hospitalization information since the study hospital 
discharge.  Subjects on Treatment Arm 1 (STI-5656) should be encouraged to remain in the 
study even if Study Drug is discontinued (for any reason).   
An independent data monitoring committee (DMC) is established to evaluate the safety data 
from the study to ensure the ongoing safety of the study subjects and make recommendations to 
the Sponsor concerning safety and trial conduct  (please refer to the DMC charter for details).  A 
blinded independent statistician will be used to facilitate DMC support.  This statistician will 
have no role in the statistical assessments conducted for the study at its conclusion.  Discussions 
with the independent statistician will be conducted during a closed session during the DMC 
deliberations.  Sponsor, CRO and study site personnel will only participate in the open session.  


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Unblinding of a given subject to assess an AE stopping rule trigger will be handled in a way to 
keep the Sponsor, CRO (and staff) and study site personnel blinded. 
The study visit schedule and assessments are detailed in Table 1 Schedule of Assessment (SOA).   
For subjects, the total duration of the study will be up to 94 days (up to 4 days for the screening 
period plus up to 14 days for treatment and up to 90 days from randomization for follow-up).   
The length of the study will be approximately 7 months (4 months for enrollment plus up to 90 
days study duration). 
4.2. 
End of Trial Definition 
The End of Trial is defined as either the date of receipt of the last data point from the last subject 
that is required for primary, secondary and/or exploratory analysis, as prespecified in the 
protocol, whichever is the later date. 


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5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Subjects who are randomized but discontinue prior to the end of the study will not be replaced.   
5.1. 
Subject Inclusion Criteria 
Subjects are eligible to be included in the study only if all the following criteria apply: 
1. Confirmed infection with SARS-CoV-2 per World Health Organization (WHO) criteria 
(including positive RT-PCR nucleic acid test of any specimen [eg, respiratory, blood, 
urine, stool, or other bodily fluid]) within 7 days of randomization.  Positive RT-PCR test 
results more than 7 days prior to randomization is allowed if the site is unable to obtain a 
repeat sample and if the subject has progressive disease consistent with COVID-19. 
2. COVID-19 pneumonia (documented radiographically) requiring hospitalization and 
oxygen saturation <94% on room air or subject requires supplemental oxygen. 
3. Age ≥18 years at the time of signing the informed consent form 
4. Subject or family member/caregiver must have provided written informed consent which 
includes signing the institutional review board approved consent form prior to 
participating in any study related activity.  However, if obtaining written informed 
consent is not possible, other procedures as provided in the March 27th, 2020 FDA 
Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic, Question 10, may be used. 
5. Able to swallow capsules 
6. Willing to follow contraception guidelines   
If a female, be sterile (surgically or biologically)* or at least one year post-menopausal**, or 
have a monogamous partner who is surgically sterile, or have a same sex partner, or if in a 
heterosexual relationship, must agree to do the following for at least 1 month after receiving 
IP: 
• Practice abstinence  
• Use at least 1 of the following medically acceptable methods of birth control: 
− Hormonal methods such as oral, implantable, injectable, vaginal ring, or 
transdermal contraceptives (must have started a minimum of 1 full cycle, based 
on the subject’s usual menstrual cycle period, before IP dose 
− 
Intrauterine device 
− Double-barrier method (condoms, sponge, or diaphragm with spermicidal jellies 
or cream). 
*Defined as having had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; 
or having a congenital or acquired condition that prevents childbearing 


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**Defined as at least 12 months with no menses without an alternative medical cause) 
[can be confirmed with follicle stimulating hormone level (FSH) in the post-
menopausal range (FSH levels ≥40 milli international units/mL (mIU/mL) at 
Screening) if the subject is not on hormonal replacement therapy] 
If a male of reproductive potential*, unless he has a same sex partner, must agree to do the 
following for at least 1 month after receiving IP 
• practice abstinence from heterosexual activity, or  
• use (or have their partner use) acceptable contraception (see criterion above) during 
heterosexual activity  
*Defined as having azoospermia, whether due to having had a vasectomy or due to an 
underlying medical condition. 
5.2. 
Subject Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
1. Known cardio-pulmonary resuscitation within 14 days of randomization 
2. Pregnant or breast feeding 
3. Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides infection 
with SARS-CoV-2) 
4. Alanine aminotransferase (ALT) ≥ 3x upper limit of normal (ULN) and total bilirubin 
> 2x ULN 
5. QTcF prolongation >480 milliseconds 
6. Uncontrolled or untreated symptomatic arrhythmias, myocardial infarction within the last 
6 weeks, or congestive heart failure (NYHA Grade 3 or 4). Exception: Subjects with 
controlled, asymptomatic atrial fibrillation during screening are allowed to enroll 
7. Treatment with a strong cytochrome P450 (CYP3A4 inhibitor (within 14 days before first 
dose of study drug) or inducer (within 7 days before first dose of study drug). 
8. Received anti-rejection or immunomodulatory drugs (eg, anti-cytokines, BTK inhibitors, 
JAK inhibitors, PI3K inhibitors) within 30 days before randomization on study 
9. Concurrent participation in another clinical trial involving therapeutic interventions 
(observational study participation is acceptable). 
10. Any condition that confounds the ability to interpret data from the study. 
11. Relevant renal impairment (eGFR <60ml/min) 
12. Any significant medical condition, laboratory abnormality or psychiatric illness that 
would interfere or prevent the subject from participating in the study. 
5.3. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 


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ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demographics, screen failure details, eligibility 
criteria, and any SAE. 
Individuals who meet all the screening criteria but were not selected for cohort may be re-
screened to participate in a subsequent cohort.  Screening laboratory tests and/or vital signs may 
be repeated once if, in the opinion of the Investigator, the out-of-range values are thought to be 
spurious and not indicative of an underlying disease or abnormality. 


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6. 
TREATMENT OF PARTICPANTS 
6.1. 
Description of Investigational Product 
Study treatment will be either STI-5656 (Investigational Product, or IP) or placebo. 
6.2. 
Investigational Product Administration 
Two STI-5656 or matching placebo capsules p.o. QD (two 50-mg capsules) administered up to 
14 days or until hospital discharge if sooner. 
Study drug capsules should be taken orally with 200-250 mL of water following at least 2 hours 
of fasting.   
If vomiting occurs within 30 minutes after a patient takes the dose and the patients can tolerate 
the medication, the vomited dose should be made up. 
If the subject is unable to swallow, the capsule contents may be flushed down a nasogastric or 
feeding tube with water. 
6.3. 
Stopping Rule Triggers 
Study drug dose should be paused per the guidelines in Table 2 (using the Common Terminology 
Criteria for Adverse Events, Version 5.0 [CTCAE] for severity grading). 
Table 2: 
Stopping Rule Triggers 
If any of the following possibly related AEs occur: 
• 
≥ Grade 3 (G3) non-hematologic toxicities 
• 
≥ G3 alanine aminotransferase (ALT) elevation  OR ≥ any ALT and 
total bilirubin elevation in combination which meet Hy’s Law 
criteria [i.e., any ≥ G3 hepatic impairment] 
• 
G3 thrombocytopenia with bleeding 
• 
G4 thrombocytopenia 
• 
G4 neutropenia  
• 
G3 neutropenia or thrombocytopenia in ˃ 3 subjects  
• 
≥ G3 renal impairment including acute kidney injury requiring 
hemodialysis 
• 
Any SUSAR (suspected unexpected serious adverse reaction) 
At the first occurrence of 
any of the stopping rule 
triggers, discontinue 
Study Drug for the 
affected subject and pause 
further enrollment until 
DMC deliberations have 
been completed and a 
DMC decision that 
enrollment may be 
restarted has been 
rendered. 
A DMC teleconference will be arranged within 5 business days of the stopping rule trigger.  This 
should provide sufficient time for the CRO to prepare a blinded summary of the AE and the 
independent statistician to arrange to be unblinded to assist the DMC in its deliberations.  
Additionally, the DMC will be provided with tabular safety summaries at 25%, 50% and 75% 
enrollment for ongoing surveillance.   
6.4. 
Dosing of Subjects Unable to Take Test Article PO 
Subjects unable to take the capsules PO, for example after intubation may receive the drug or 
placebo via feeding tube. The formulation is blended powder filled in capsule allowing for 


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opening the capsules and dosing the content as is with water to flush the feeding tube.  If this is 
not feasible, dosing should be discontinued. 
6.5. 
Investigational Product Compliance 
Subjects receive IP only while hospitalized and it is administered at the site; therefore, the site 
will monitor IP compliance.  
6.6. 
Overdose 
Any dose over the protocol-specified daily dose of STI-5656 will be considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the subject for any AE/SAE for at least 24 hours. 
• Document the quantity of the excess dose. 
6.7. 
Randomization and Blinding 
Screening, randomization to one of two treatment arms (1:1 ratio), as well as study completion or 
study discontinuation will be registered by the site using an IRT system.  
6.8. 
Emergency Unblinding 
Emergency unblinding may be requested by the Investigator at any time if needed to properly 
assess the patient.  The request should be submitted to the CRO and Sponsor’s medical monitor. 
6.9. 
Concomitant Medications 
Any medication (including over the counter or prescription medicines, vitamins, and/or herbal 
supplements), vaccine or transfusion that the subject received within 28 days prior to the 
Screening Visit and during the study up to hospital discharge must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.9.1. 
Prohibited Concomitant Medications 
The following medications are prohibited up to Day 28 or hospital discharge:  
Anti-cytokines, other BTK inhibitors or other tyrosine kinase inhibitors (e.g. JAK or PI3K 
inhibitors as well as any immunosuppressive drugs (except steroids), such as anti-IL6 or anti-
TNF therapy. 


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7. 
IP MATERIALS AND MANAGEMENT 
7.1. 
Investigational Product 
IP  
STI-5656 (Abivertinib maleate) 
Placebo 
Dose 
Formulation 
Capsule for oral administration 
Capsule for oral administration 
Unit Dose 
Strength(s) 
50 mg 
n/a 
Dose to be 
administered 
to subjects 
200 mg QD (4 capsules once daily) 
4 capsules once daily 
Route of 
Administration 
p.o. (by mouth) 
p.o. (by mouth) 
Use 
Experimental 
 
Manufacturer 
Shanghai Syn-The-All Pharmaceutical 
Co. Ltd. (“STA”), a wholly owned 
subsidiary of WuXi AppTec Co. 
Shanghai Syn-The-All Pharmaceutical 
Co. Ltd. (“STA”), a wholly owned 
subsidiary of WuXi AppTec Co. 
Sourcing 
Provided centrally by Sorrento 
Therapeutics, Inc. or a Sorrento 
representative 
Provided centrally by Sorrento 
Therapeutics, Inc. or a Sorrento 
representative 
Packaging and 
Labeling 
40 Capsules packaged inside an HDPE 
bottle and closed with a polypropylene 
cap. 
40 Capsules packaged inside an HDPE 
bottle and closed with a polypropylene 
cap. 
7.2. 
IP Packaging and Labeling 
STI-5656 will be distributed to the investigational site’s pharmacy. The site pharmacist will 
dispense STI-5656 to subjects in Treatment Arm 1. 
The labels on the study drug bottles will include the following information: 
• Protocol Number 
• Lot Number 
• Name of product and strength of each capsule  
• Storage conditions 
• Sponsor’s name and address 
• The statement: “Caution: New drug-limited by Federal Law to Investigational Use. 
Keep out of reach of children.” 


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7.3. 
IP Storage 
The shelf life of STI-5656 is at least 3 years when stored at room temperature (approximately 20º 
to 25°C [68º to 77°F]). 
7.4. 
IP Accountability 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
IP at the site. 
The IP provided by the Sponsor must be made available for inspection by the Sponsor or its 
representatives and regulatory agency inspectors upon request. 
7.5. 
IP Handling and Disposal 
The Investigator must keep an accurate accounting of the number of bottles and capsules of STI-
5656 delivered to the site, administered to subjects, and returned to the Sponsor/Sponsor 
representative or other disposition during and at the completion of the study.   
The IP must be dispensed to subjects only by an appropriately qualified person.  The IP is to be 
used in accordance with the protocol by subjects who are under the direct supervision of the 
Investigator.  Investigators should maintain records that document adequately that the subjects 
were provided the doses specified by the protocol and reconcile all IP received at the site before 
final disposition.   
All IP, including unused, partially used, and empty containers, should be disposed of in 
accordance with federal, state and local regulations and the institutional standard operating 
procedures (SOPs) or returned to the Sponsor/Sponsor representative as directed if destruction at 
the site is not possible. 


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8. 
STUDY PROCEDURES 
Study procedures will be performed as described in the Schedule of Assessment Table 1.  
Additional unscheduled visit/assessments may be performed at any time if clinically indicated 
and will be captured in the eCRFs if performed. 
Protocol waivers or exemptions are not allowed, with the exception of immediate safety 
concerns. Such concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the subject should continue or discontinue the IP (subjects in 
Treatment Arm 1). Adherence to the study design requirements, including those specified in the 
Schedule of Assessments, is essential and required for study conduct.  
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.  
A subject may be re-screened once for the study if the defined screening period has been 
exceeded and the subject has not been randomized in the study. 
8.1. 
Description of Procedures 
8.1.1. 
Informed Consent 
All subjects will review and sign an IRB-approved Informed Consent Form prior to performing 
any procedures specifically for this study. 
8.1.2. 
RT-PCR assay for SARS-CoV-2 
If RT-PCR confirmation of SARS-CoV-2 is not within 7 days prior to planned randomization, 
then positive RT-PCR test results more than 7 days prior to randomization is allowed to confirm 
eligibility if the site is unable to obtain a repeat sample and if the subject has progressive disease 
consistent with COVID-19. 
8.1.3. 
Collection of Demographics, Medical History, Prior and Concomitant 
Medications 
Demographics include age, sex, race, ethnicity, date of birth. 
Current (active) medical conditions and relevant (non-active) medical history.  Details of 
COVID-19 history should include COVID-19-related symptoms, time of onset of symptoms, 
date of first positive COVID-19 test result  
Concomitant medications and prior medications taken within 28 days of informed consent 
8.1.4. 
Vital Signs 
Vital signs include body temperature (F), respiratory rate, radial pulse rate, systolic and diastolic 
blood pressure, and oxygen saturation (pulse oximetry).  Pulse and blood pressure should be 
taken with subject in at least in a semi-recumbent position.   
It is preferred to collect vital signs at approximately mid-afternoon each day. Vital signs may be 
obtained at additional times as deemed necessary by the Investigator. 


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8.1.5. 
Physical Exam 
A physical exam should be performed at Screening and at hospital discharge or Early 
Termination Visit, whichever is later.  Height (at screening) and weight (screening and 
discharge) should be recorded also. 
8.1.6. 
12-lead Electrocardiogram (ECG) 
A 12-lead ECG is to be performed during Screening, between 2 and 4 hours after study drug 
dosing and at any time a subject complains of anything suggestive of a cardiac abnormality.   
8.1.7. 
Clinical laboratory tests 
Serum chemistry, hematology, coagulation, urinalysis and urine pregnancy tests are to be 
performed locally. 
8.1.7.1. 
Serum Chemistry 
Albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bicarbonate, total bilirubin (TBIL), blood urea nitrogen (BUN), 
calcium, chloride, creatinine, glucose, potassium, sodium, total protein, D-dimer, fibrinogen. 
8.1.7.2. 
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, platelet count (or estimate), and white 
blood cell count including differential.  
8.1.7.3. 
Coagulation 
International normalized ratio (INR), PTT. 
8.1.7.4. 
C-reactive protein, serum ferritin, absolute lymphocyte count and cytokines 
Blood should be collected for measuring C-reactive protein (CRP), serum ferritin, VEGF-A, and 
cytokines (IL-6, TNF-, IFNγ, IL1β, IL-7,IL-8,  IL-10, IL-12, IL-17, IL-18, IP10) should be 
measured on Days 3, 5, 7, 10, 14 and 28.  
8.1.7.5. 
Urinalysis 
Urinalysis to be performed locally. Urinalysis includes protein, glucose, and blood (microscopic) 
– red blood cells per high power field (rbc/hpf). 
8.1.7.6. 
Urine Pregnancy Test 
Urine pregnancy tests (B-HCG) will be performed (locally) for women of childbearing potential.  
FSH tests may be performed to confirm a woman is of non-childbearing potential if the subject is 
not on hormonal replacement therapy or not surgically sterile (refer to eligibility criteria for 
details). 


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8.1.8. 
Respiratory Status 
Record FiO2 (and PaO2) at the time of arterial blood gas sampling.  If PaO2 is not available, use 
SPO2. Other respiratory status data to collect includes oxygen supplementation status:  
mechanical ventilation, face mask, nasal cannula or room air.  Radiographic findings will also be 
collected. 
8.1.9. 
Clinical status using 8-category ordinal scale of patient health status 
An 8-category ordinal scale of patient health status ranges will be used to collect subject clinical 
status where  
0 = no clinical or virological evidence of infection;  
1 = no limitation of activities;  
2 = limitation of activities;  
3 = hospitalized, no oxygen therapy;  
4 = oxygen by mask or nasal prongs;  
5 = non-invasive ventilation or high-flow oxygen;  
6 = intubation and mechanical ventilation;  
7 = ventilation + additional organ support – pressors, rapid response team (RRT), 
extracorporeal membrane oxygenation (ECMO);  
8 = death.  
See Section 14.2 for form. 
8.1.10. 
IRT Registration, Randomization and Study Discontinuation or Completion.   
Subjects will be registered in IRT after signing informed consent and will be randomized using 
the IRT on Day 1 to either Treatment Arm 1 (STI-5656 plus SOC) or Treatment Arm 2 (placebo 
plus SOC) using central integrated response technology (IRT).  Subject study discontinuation or 
study completion should also be registered in the IRT. 
8.1.11. 
Adverse Events 
Adverse events will be collected from the time of signing the ICF through Day 60. 
8.1.12. 
Follow-up contact 
The subject will be seen on Day 28 to collect laboratory samples, report on any additional AEs 
and on the status of unresolved AEs.  The subject will also be contacted at Day 60 and 90 to 
document survival (or collect date of death from family or subject’s physician).  In addition, any 
experimental medication, duration of any additional hospital or ICU admissions after the first 
“post-randomization” discharge will also be collected.  


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8.2. 
Procedures by Study Day 
8.2.1. 
Screening 
• Informed Consent 
• Registration of screening in IRT 
• RT-PCR assay for SARS-CoV-2 (if needed, see details in Section 8.1.2) 
• Collection of Demographics, Medical History, Prior and Concomitant Medications 
• Vital Signs 
• Physical Exam 
• 12-lead ECG 
• Clinical laboratory tests per Section 8.1.7 
• Respiratory Status 
• Clinical status using 8-category ordinal scale of patient health status 
• Assess eligibility 
8.2.2. 
Study Day 1 
• Vital Signs 
• Clinical laboratory tests per Section 8.1.7 
• Respiratory Status 
• Collect adverse events since screening 
• Collect con meds 
• Clinical status using 8-category ordinal scale of patient health status 
• Randomization in IRT 
• Dispense STI-5656 or placebo capsules to subjects which should be taken orally with 
200-250 mL of water following at least 2 hours of fasting.   
• 12-lead ECG to be performed between 2 and 4 hours post study drug dosing 
8.2.3. 
Daily until Hospital Discharge 
• Vital Signs 
• Clinical laboratory tests per Section 8.1.7.  Note that the urine pregnancy test is 
performed only at Screening, prior to randomization on Day 1 and at hospital 
discharge. 
• Respiratory Status 
• Collect adverse events  


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• Collect con meds 
• Clinical status using 8-category ordinal scale of patient health status 
• Dispense Study Drug to subjects which should be taken orally with 200-250 mL of 
water following at least 2 hours of fasting.   
8.2.4. 
Hospital Discharge or Early Termination from Study 
• Physical Exam 
• Vital Signs 
• Clinical laboratory tests per Section 8.1.7 
• Respiratory Status 
• Collect adverse events  
• Collect con meds 
• Clinical status using 8-category ordinal scale of patient health status 
• If early termination, register in IRT 
8.2.5. 
Outpatient Follow-up Day 28  
• Collect AEs, and update status on previously unresolved AE status 
• Clinical laboratory tests per Section 8.1.7 
• Collect survival, experimental medications since hospital discharge, any new 
hospitalizations/ ICU stays 
8.2.6. 
Telephone Follow-up Day 60  
• Update status on previously unresolved AEs 
• Collect survival, experimental medications since hospital discharge, any new 
hospitalizations/ ICU stays 
8.2.7. 
Telephone Follow-up Day 90  
• Update status on previously unresolved AEs 
• Collect survival, experimental medications since hospital discharge, any new 
hospitalizations/ ICU stays 
8.3. 
Blood Volumes collected 
Blood for hematology, coagulation and chemistry should be standard of care along with the 
addition of D-dimer and fibrinogen to the chemistry assessments.  Blood collected for measuring 
CRP, serum ferritin and cytokines (IL-6, TNF-, IFNγ, IL1β, IL-7, IL-10, IL-12, IL-17, IL-18 is 
approximately 6.5 mL per time point.  Time points are Day 1 (baseline), Day 3, 7, 10, 14 and 28 
(or at hospital discharge).  The total blood volume collected for these measurements is 
approximately 60 mL per subject. 


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9. 
STATISTICS 
9.1. 
Statistical Considerations 
All tests of significance will be assessed at alpha level=0.05, 2-sided. All analyses and data 
presentations will be generated using SAS version 9.4, or higher (Cary, NC). 
Subjects who are randomized to the study and discontinue before the end of the study will not be 
replaced.  Missing values will not be imputed. For success/failure endpoints, subjects who 
discontinue prior to the specified time point will be included in the analysis as treatment failures 
and censored at the last day of follow-up for the time-to-event analysis. For all other endpoints, 
the mixed effect model repeat measurement (MMRM) analysis will be employed. The MMRM 
analysis only includes the available data. It has been demonstrated that the MMRM approach 
leads to estimators with comparatively small bias, and controls Type I error rates at a nominal 
level in the presence of missing completely at random (MCAR) or missing at random (MAR) 
and some possibility of missing not at random (MNAR) data (see 
https://pubmed.ncbi.nlm.nih.gov/19212876/). 
9.2. 
Sample Size Estimation 
An evaluable sample size of 40 subjects per group will provide 80% power (alpha=0.05, 2-sided) 
to detect a difference between groups in the number of subjects alive and free of respiratory 
failure at Day 28. This assumes that 95.7% of subjects who received STI-5656 plus SOC and 
70% of subjects who received placebo plus SOC only will be alive and free of respiratory failure 
at Day 28. This represents a treatment effect difference of approximately 26%.   
9.3. 
Analysis Population 
The following analysis populations are planned: 
• Safety population: All randomized subjects 
• Full Analysis (FA) population: All randomized subjects 
• Per-protocol (PP) population: Subset of the Full Analysis Set and excludes subjects 
with major protocol violations, entry criteria violations or missing visits. The results 
of the Full Analysis Set will be considered primary. 
9.4. 
Data Analysis 
9.4.1. 
Subject Disposition 
The number and percentage of subjects included in each population, who completed the study, 
who discontinued study and reason for discontinuation will be presented for each cohort and 
treatment. 
9.4.2. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be presented for each population by Treatment 
arm. 


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9.4.3. 
Primary Endpoints 
For the primary endpoint, the proportion of subjects alive and free of respiratory failure at Day 
28, the number and percentage of subjects will be presented by group. Possible differences 
between groups will be assessed using a generalized linear mixed model, assuming a binomial 
distribution and a logit link. The model will include group as a fixed effect. Subjects who 
discontinue the study prior to Day 28 will be considered treatment failures. 
9.4.4. 
Secondary Endpoints (Safety) 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will 
be summarized by System Organ Class (SOC) and Preferred Term for each group. The first 
occurrence will be tabulated for an event that occurred more than once for a subject. 
Additionally, AEs will be tabulated by maximum severity and nearest relationship to IP. SAEs 
will be summarized similarly to AEs. 
For continuous safety endpoints, descriptive statistics (number of subjects, mean, standard 
deviation, minimum, median and maximum values) will be presented by group and study day. 
The changes from Day 1 to each subsequent day will be calculated for each subject and 
descriptive statistics will be presented. Possible differences between groups will be assessed 
using a mixed effect model repeat measurement (MMRM) analysis of covariance. The model 
will include the Day 1 value as a covariate, fixed effects of group, study day and group-by-study 
day interaction with subject as a random effect. 
Categorical safety endpoints will be summarized as the number and percentage of subjects per 
category for each group. 
Treatment-emergent adverse events (TEAE) will be defined as any AE occurring post first 
administration. Adverse events will be presented for each cohort and treatment by System Organ 
Class (SOC) and Preferred Term (PT): 
• Treatment-emergent adverse events (TEAE): defined as any AE occurring postdose 
administration through 28 days following IP administration. 
• IP related TEAEs 
• SAEs  
• IP related SAEs  
• TEAEs (by grade and relationship to IP)  
• Laboratory abnormalities by toxicity grade 
9.4.5. 
Secondary Endpoints (Efficacy) 
The proportion of subjects alive and discharged from the ICU at Day 14 and Day 28 and the 
proportion alive and free of respiratory failure at Day 60 and will be presented and analyzed as 
described for the primary efficacy endpoint. Subjects who discontinue from the study prior to 
each study day will be considered treatment failures. 
Clinical Status will be assessed using a generalized linear mixed model, assuming a multinomial 
distribution. The model will include the Day 1 value as a covariate with fixed effects of group, 


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study day and group-by-study day interaction and subject as a random effect. If the group-by-
study day interaction is found to be statistically significant then comparisons between groups at 
Day 7, Day 14 and Day 28 will be obtained from this model. Additionally, stacked bar charts 
will be presented for the proportion of subjects in each category by group and study day. 
For the time from randomization to first occurrence of respiratory failure or death on study due 
to any cause, the Kaplan-Meier method will be applied. Subjects will be censored at the time of 
last follow-up. For each group, the 25th percentile, median and 75th percentile will be presented, 
if possible. Possible differences between groups will be assessed by the log-rank test. 
The total number of deaths per group will be presented for All-cause mortality at Day 90. 
9.4.6. 
Exploratory Endpoints 
For all other efficacy endpoints, descriptive statistics (number of subjects, mean, standard 
deviation, minimum, median and maximum values) will be presented by group and study day. 
The changes or percent changes from Day 1 to each subsequent day will be calculated for each 
subject and descriptive statistics will be presented. Possible differences between groups will be 
assessed using a MMRM analysis of variance\covariance. The model will include fixed effects of 
group, study day and group-by-study day interaction with subject as a random effect. The Day 1 
value will be included when appropriate. 
9.4.7. 
Interim Analysis 
An interim futility analysis will be performed after 40 subjects have been enrolled. The analysis 
will be performed by an independent biostatistician who will have no contact with the study 
team. 


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10. 
ADVERSE EVENT DEFINITIONS AND PROCEDURE FOR 
RECORDING, EVALUATING, FOLLOW-UP AND REPORTING 
10.1. 
Monitoring, Recording and Reporting of Adverse Events 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study.  It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values (as specified by the criteria below), regardless of etiology.  Any 
worsening (i.e., any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an AE.  If 
an overdose is associated with an AE, the overdose and AE should be reported as separate terms.  
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures. 
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after hospital discharge.  AEs that lead to study discontinuation should be followed 
until resolution or stabilization.  
Serious Adverse Events (SAEs), regardless of relationship to investigational product, that occur 
from the time the subject signs informed consent until the last study visit and those made known 
to the Investigator at any time thereafter must be reported to Drug Safety within 24 hours of the 
Investigator’s knowledge of the event. 
10.2. 
Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to:  
10.2.1. 
Seriousness  
A serious adverse event (SAE) is any AE occurring at any dose that: 
• Results in death; 
• Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE); 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
• Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions); 
• Is a congenital anomaly/birth defect; 


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• Constitutes an important medical event. 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
Events not considered to be SAEs are hospitalizations for: 
• A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE. 
• A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE. 
• Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• A procedure that is planned (ie, planned prior to starting of treatment on study); must 
be documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE. 
• An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication. 
• Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed. 
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to investigational product, action taken regarding investigational product, and 
outcome. 
10.2.2. 
Severity / Intensity 
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event. 
The severity of AEs will be graded based upon the subject’s symptoms according to CTCAE 
version 5.0 with unique clinical descriptions of severity for each AE based on this general 
guideline: 


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• Grade 1 = Mild –asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2 = Moderate – minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
• Grade 3 = Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL 
• Grade 4 = Life-threatening consequences; urgent intervention indicated.  
• Grade 5 = Death related to AE. 
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
10.2.3. 
Causality  
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related or Probably Related).  The 
Investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational product.  If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.”  If there is 
any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship 
between the investigational product and the occurrence of the AE, then the AE should be 
considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
10.2.4. 
Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event. 
10.2.5. 
Action Taken 
The Investigator will report the action taken with investigational product as a result of an AE or 
SAE, as applicable (e.g., discontinuation, interruption, or reduction of study treatment, as 
appropriate) and report if concomitant and/or additional treatments were given for the event.  


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10.2.6. 
Outcome 
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered or death (due to the 
SAE).  
10.3. 
Abnormal Laboratory Values 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• results in discontinuation from the study; or 
• requires treatment, modification/ interruption of study treatment dose, or any other 
therapeutic intervention; or 
• is judged to be of significant clinical importance 
Regardless of severity grade (per CTCAE version 5.0), only laboratory abnormalities that fulfill 
a seriousness criterion need to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE.  
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets). 
Adverse Laboratory values that also meet the definition of SERIOUS, will be reported as SAEs. 
10.4. 
Pregnancy 
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events. 
10.4.1. 
Females of Childbearing Potential 
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female of childbearing potential regardless of disease state) occurring while the subject is on 
investigational product, or within 1 month after last dose of investigational product, are 
considered immediately reportable events.  Investigational product is to be discontinued 
immediately.  The pregnancy, suspected pregnancy, or positive pregnancy test must be reported 
Drug Safety immediately.   
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.  The Investigator will 
follow the female subject until completion of the pregnancy and must notify Drug Safety 
immediately about the outcome of the pregnancy (either normal or abnormal outcome). 
If the outcome of the pregnancy was abnormal (e.g., spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Drug Safety by facsimile, or other appropriate method, 
within 24 hours of the Investigator’s knowledge of the event using the SAE Report Form or 
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All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in-utero exposure to the investigational product should also be reported to Drug 
Safety within 24 hours of the Investigator’s knowledge of the event. 
10.4.2. 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant at any time 
up to one month after the male subject’s last dose of IP, the male subject taking investigational 
product should notify the Investigator, and the pregnant female partner should be advised to call 
their healthcare provider immediately. 
10.5. 
Reporting of Serious Adverse Events 
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to the 
Sponsor or the Sponsor’s representative within 24 hours of the Investigator’s knowledge of the 
event by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form.  This instruction pertains to initial SAE reports as well as any follow-up reports. 
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to investigational product) that 
occur from the time the subject signs informed consent until the last study visit and those made 
known to the Investigator at anytime thereafter that are suspected of being related to 
investigational product.  ALL SAEs occurring prior to treatment (after signing the ICF) will be 
captured. 
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to the Sponsor or the 
Sponsor’s representative as soon as these become available.  Any follow-up data should be 
detailed in a subsequent SAE Report Form, or approved equivalent form, and sent to the Sponsor 
or the Sponsor’s representative. 
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board (IRB)/Ethics Committee (EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event.  The Investigator must keep copies of all SAE 
information on file including correspondence with the Sponsor or the Sponsor’s representative 
and the IRB/EC. 
10.6. 
Expedited Reporting of Adverse Events 
For the purpose of regulatory reporting, the Sponsor will determine the expectedness of events 
suspected of being related to STI-5656 based on the Investigator Brochure and determine 
regulatory reporting according to local Health Authority requirements and according to the 
Safety Management Plan for the protocol. 
Events of e.g. disease progression for the disease under study (including deaths due to disease 
progression for indications that are considered to be fatal) will be assessed but will not be usually 


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reported as expedited safety reports to regulatory authorities unless they otherwise meet the 
requirements for expedited reporting. 
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of new 
serious and unexpected AE(s) or significant risks to subjects communicated by the Sponsor. 
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Drug Safety and the IRB/EC. 
Sponsor or Sponsor’s representative Contact Information for SAE reporting: 
Please refer to the Serious Adverse Event Report Form. 


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11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of the Sponsor 
will pre-qualify the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the Sponsor or its representatives.  This 
will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator. 
As this study will be taking place during the COVID-19 pandemic, it is anticipated that most/all 
monitoring visits performed will be done remotely.  This study will rely on the use of 
technology, either video or still camera pictures, to confirm facility requirements.  The video or 
photo files will be stored in the Trial Master File.  
During the study, a monitor from the Sponsor or its representative will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that IP accountability checks are being 
performed 
• Perform source data verification.  This includes a comparison of the data in the case 
report forms with the subject’s source records.  This will require electronic access to all 
source records for each subject. 
• Record and report any protocol deviations not previously sent to the Sponsor or it’s 
representative. 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to the Sponsor or it’s representative and those SAEs that met 
criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
11.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification.  The purpose of audit or inspection by the Sponsor or its 
representative is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 


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analyzed, and accurately reported according to the protocol, Good Clinical Practice guidelines of 
the International Conference on Harmonization, and any applicable regulatory requirements.  
The Investigator should contact the Sponsor immediately if contacted by a regulatory agency 
about an inspection. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
the Sponsor or its representative may conduct a quality assurance audit.  Please see Section 11.2 
for more details regarding the audit process. 


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13. 
ETHICS 
13.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form (ICF), must 
be approved or given a favorable opinion in writing by an IRB or IEC as appropriate.  The 
Investigator must submit written approval to the Sponsor or its representative before he or she 
can enroll any subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients/subjects for the study.  The protocol must be re-approved by 
the IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the IP.  The 
Sponsor or its representative will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
13.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the Sponsor’s policy on Bioethics. 
13.3. 
Written Informed Consent 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject. 


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14. 
APPENDICES 
14.1. 
List of Abbreviations and Definitions of Terms 
The following abbreviations and specialist terms are used in this study protocol. 
Table 3: 
Abbreviations 
Abbreviation  
Explanation 
ADL 
Activities of daily living 
AE 
Adverse Events 
ALC 
Absolute lymphocyte count 
ALT 
Alanine aminotransferase 
AST 
aspartate aminotransferase 
Β-hCG 
Beta human chorionic gonadotropin 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus 2019 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events, Version 5.0 
DMC 
Data monitoring committee 
EC 
Ethics Committee 
ECG  
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
e-CRF 
Electronic case report form 
ET 
Early Termination 
F 
Fahrenheit 
FA 
Full analysis 
FDA 
Food and Drug Administration 
FCBP 
Female of child-bearing potential 
FiO2 
Fraction of inspired oxygen 
FSH 
Follicle stimulating hormone 
G 
Grade 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive Care Unit 
IRT 
Interactive Response Technology 


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Abbreviation  
Explanation 
JAK 
Janus kinase 
L/min 
Liters per minute 
MedDRA 
Medical Dictionary for Regulatory Activities 
mIU 
Milli international units 
mL 
Milliliters 
PaO2 
Partial pressure of oxygen in arterial blood 
PI3K 
Phosphoinositide 3 kinase 
p.o. 
By mouth 
PP 
Per protocol 
PT 
Preferred term 
QD 
Once daily 
RBC 
Red blood cells 
Rbc/hpf 
Red blood cells per high power field 
RRT 
Rapid response team 
RT-PCR 
Reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2  
SAS 
Statistical Analysis System 
SOA 
Schedule of Assessments 
SOC 
Standard of Care 
SOC 
System organ class 
SOP 
Standard operating procedures 
TEAE 
Treatment-emergent adverse events 
ULN 
upper limit of normal 
VEGF 
Vascular endothelial growth factor 
WBC  
White blood cells 
WHO 
World Health Organization 
 
 
 


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14.2. 
Ordinal Scale for Clinical Improvement 
 
Source:  https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf 
 

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STATISTICAL ANALYSIS PLAN 
 
 
Sponsor:  
 
 
 
 
 
Sorrento Therapeutics, Inc. 
 
Protocol Number:  
 
 
STI-5656-2001 
 
Protocol Version/Date:  
5.0/07DEC2020 
 
Study Title: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY OF THE SAFETY AND EFFICACY OF STI-5656 (ABIVERTINIB MALEATE) IN 
SUBJECTS HOSPITALIZED DUE TO COVID-19 
 
Version and Date:  
 
 
V1.0 04Jan2020 
 
 


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Confidentiality: This document contains confidential and proprietary information that 
belongs exclusively to Sorrento Therapeutics, Inc. and/or CPAN Inc.   By accepting or 
reviewing these materials, you agree to hold such information in confidence and not to 
disclose it to others or to use it for unauthorized purposes 
 
 
 
 
 
 
Approval
 
Signature 
Date 
 
Eric Yan 
Sr. Statistical Consultant
CPAN, Inc. 
 
Sponsor Representative 
Mike A. Royal MD JD MBA 
Chief Medical Officer 
Sorrento Therapeutics, Inc. 
 
 
 
 
01/05/2021


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ABBREVIATIONS 
 
AE 
adverse event 
BMI 
body mass index 
cm 
centimeter 
COVID-19 
Coronavirus 2019 
CRP 
C-reactive protein 
DMC 
data monitoring committee 
e-CRF 
electronic case report form 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
FiO2 
fraction of inspired oxygen 
ICU 
intensive care unit 
IP 
investigational product 
kg 
kilogram 
kg/m2 
kilogram per meter squared 
L 
liter 
MAR 
missing at random 
max 
maximum 
MCAR 
missing completely at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minimum 
MMRM 
Mixed-effects Model for Repeat Measures 


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MNAR 
missing not at random 
p.o. 
By mouth 
PaO2 
partial pressure of arterial oxygen 
PK 
pharmacokinetics 
PP 
per protocol 
QD 
once daily 
RRT 
rapid response team 
RT-PCR 
reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2  
SD 
standard deviation 
SOC 
standard of care 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
VEGF-A 
Vascular endothelial growth factor 
 
 
 


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TABLE OF CONTENTS 
1.0 INTRODUCTION OF THE STATISTICAL ANALYSIS PLAN ..............................7 
2.0 INTRODUCTION TO THE STUDY ............................................................................7 
2.1 Study Objectives ..........................................................................................................7 
2.1.1 Primary Objective ........................................................................................................7 
2.1.2 Secondary Objectives ..................................................................................................7 
2.2 Study Endpoints ...........................................................................................................7 
2.2.1 Primary Endpoint .........................................................................................................7 
2.2.2 Secondary Endpoints ...................................................................................................7 
2.2.3 Exploratory Endpoints .................................................................................................8 
3.0 STUDY DESIGN .............................................................................................................8 
4.0 RANDOMIZATION AND BLINDING ........................................................................8 
5.0 SAMPLE SIZE CONSIDERATIONS ...........................................................................9 
6.0 ANALYSIS POPULATIONS .........................................................................................9 
6.1 Full Analysis Set (FAS) ...............................................................................................9 
6.2 Safety Population .........................................................................................................9 
6.3 Per Protocol (PP) Population .......................................................................................9 
7.0 GENERAL STATISTICAL CONSIDERATION AND DEFINITIONS ...................9 
7.1 Baseline and Visit Windows .......................................................................................9 
7.2 Summary Statistics ......................................................................................................9 
7.3 Missing or Incomplete Data ......................................................................................10 
7.4 Interim Analysis ........................................................................................................10 
8.0 STATISTICAL ANALYSES ........................................................................................11 
8.1 Subject Disposition ....................................................................................................11 
8.2 Demographic and Baseline Characteristics ...............................................................11 
8.3 Medical History .........................................................................................................11 
8.4 Prior and Concomitant Medications ..........................................................................11 
8.5 Protocol Deviations ...................................................................................................12 
8.6 Study Drug Administration .......................................................................................12 
9.0 EFFICACY EVALUATION ........................................................................................12 
9.1 Primary Endpoint .......................................................................................................12 
9.2 Secondary Endpoints .................................................................................................13 
9.2.1 Proportions ................................................................................................................13 


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9.2.2 Clinical Status ............................................................................................................13 
9.2.3 Continuous Endpoints ...............................................................................................13 
9.2.4 Time-to-Event Endpoint ............................................................................................14 
9.3 Exploratory Endpoints ...............................................................................................14 
10.0 SAFETY EVALUATION .............................................................................................14 
10.1 Adverse Events ..........................................................................................................14 
10.2 Laboratory Results .....................................................................................................15 
10.3 Respiratory Status ......................................................................................................15 
10.4 Vital Signs Measurements .........................................................................................15 
10.5 Electrocardiogram (ECG) Results .............................................................................15 
10.6 Physical Examination ................................................................................................15 
10.7 Pregnancy Test for FCBP ..........................................................................................15 
11.0 CHANGES TO THE PLANNED ANALYSES ..........................................................15 
12.0 APPENDICES ................................................................................................................16 
12.1 Appendix 1: Schedule of Assessments ......................................................................16 
 
 
 


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1.0 
INTRODUCTION OF THE STATISTICAL ANALYSIS PLAN 
The statistical analysis plan (SAP) is based on protocol STI-5656-2001 ‘A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled Study of The Safety and Efficacy of Sti-5656 (Abivertinib 
Maleate) In Subjects Hospitalized Due to Covid-19’, V5.0 dated 07Dec2020. It details the 
methodology to be used in analyzing the data and outlines the specifications in the Tables, 
Figures and Listings (TFLs) for data to be included for executing the final statistical analyses for 
this study. 
PK analysis is not included in this plan.  
The analyses specified in this document supersede any high-level analysis plan described in the 
protocol. 
2.0 
INTRODUCTION TO THE STUDY 
2.1 
Study Objectives 
2.1.1 Primary Objective 
• To assess the efficacy of STI-5656 in subjects with severe COVID-19 
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
• To assess the safety and tolerability of STI-5656 in subjects with severe COVID-19 
• To assess pharmacokinetics (PK) in the study population. 
2.2 
Study Endpoints 
2.2.1 Primary Endpoint 
The primary endpoint for the study is the: 
• Proportion of subjects alive and free of respiratory failure at Day 28   
2.2.2 Secondary Endpoints 
•  Types, frequencies, and severities of AEs and the relationships of AEs to IP; includes 
serious adverse events SAEs 
• Proportion of subjects alive and free of respiratory failure at Day 60 
• Change in clinical status (on a 0-8-point ordinal scale) of subject at Day 7, Day 14, and 
Day 28 
• Proportion of subjects alive and discharged from ICU at Days 14 and 28 
• Time from randomization to first occurrence of respiratory failure or death on study due 
to any cause up to Day 28 
• Percent change from baseline in CRP at Days 3, 5, 7, 10, 14, 28 
• Relative change from baseline in oxygenation index (PaO2/FiO2) up to Day 5 


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• All-cause mortality at Day 60 and Day 90 
• Number of days alive and free of respiratory failure at Day 28 
• Number of days with respiratory failure up to Day 28 
• Number of days hospitalized up to Day 28 
• Number of days in ICU (length of stay) up to Day 90 
• Number of days alive outside of hospital up to Day 28 
• Number of days alive outside of hospital up to Day 90 
• To assess the pharmacokinetic profile in the study population 
2.2.3 Exploratory Endpoints 
• Change from baseline in absolute lymphocyte counts at Days 3, 5, 7, 10, 14, 28 
• Change from baseline in ferritin at Days 3, 5, 7, 10, 14, 28 
• Change from baseline in VEGF-A at Days 3, 5, 7, 10, 14, 28 
• Change from baseline for inflammatory cytokines (IL-6, TNF-α, IFNγ, IL1β, IL-7, IL-8, 
IL-10, IL-12, IL-17, IL-18, IP-10) at Days 3, 5, 7, 10, and 28 
3.0 
STUDY DESIGN 
This is a Phase 2, randomized, double-blind, placebo-controlled, 2-arm multicenter study to 
assess the safety and efficacy of oral STI-5656 (or placebo) in the setting of current SOC in 
subjects with RT-PCR confirmed SARS-CoV-2 infection and COVID-19 pneumonia 
(documented radiographically) requiring hospitalization. Subjects must have oxygen saturation 
levels <94% on room air or subject requires supplemental oxygen. 
Eighty (80) subjects meeting eligibility criteria will be randomized at a 1:1 ratio to one of two 
treatment arms in addition to SOC treatments: 
• Arm 1: STI-5656 
• Arm 2: Placebo 
The STI-5656 dose is 100 mg p.o. QD administered up to 14 days or until hospital discharge if 
sooner. 
Details of the study conduct, visit schedule and assessments are described in the protocol. The 
Schedule of Assessments is referenced in Appendix 1. 
An independent data monitoring committee (DMC) is established to evaluate the safety data 
from the study to ensure the ongoing safety of the study subjects and make recommendations to 
the Sponsor concerning safety and trial conduct (please refer to the DMC charter for details). An 
unblinded independent statistician will be used to facilitate DMC support. 
4.0 
RANDOMIZATION AND BLINDING 
This is a randomized and double-blinded study. 


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Subjects will be randomized using the IRT on Day 1 to either Treatment Arm 1 (STI-5656 plus 
SOC) or Treatment Arm 2 (placebo plus SOC) (1:1 ratio) using central integrated response 
technology (IRT). Subject study discontinuation or study completion should also be registered in 
the IRT. Sponsor, investigator and the CRO will be blinded throughout the study. The 
independent statistician who supports the DMC is unblinded. 
Emergency unblinding may be requested by the Investigator at any time if needed to properly 
assess the safety of a patient. The request should be submitted to the CRO and Sponsor’s medical 
monitor. 
5.0 
SAMPLE SIZE CONSIDERATIONS 
An evaluable sample size of 40 subjects per group will provide 80% power (alpha=0.05, 2-sided) 
to detect a difference between groups in the number of subjects alive and free of respiratory 
failure at Day 28. This assumes that 95.7% of subjects who received STI-5656 plus SOC and 
70% of subjects who received placebo plus SOC only will be alive and free of respiratory failure 
at Day 28. This represents a treatment effect difference of approximately 26%. 
6.0 
ANALYSIS POPULATIONS 
6.1 
Full Analysis Set (FAS)  
The full analysis set (FAS) includes all randomized patients. This is the intention to treat 
population. The FAS is based on the treatment allocated (as randomized). All efficacy endpoints 
will be analyzed using the FAS. 
6.2 
Safety Population 
The safety population includes all randomized patients who received any study drug. This set is 
based on the treatment received (as treated). Treatment compliance/administration and all 
clinical safety variables will be analyzed using the safety population. 
6.3 
Per Protocol (PP) Population 
The PP population is a subset of the FAS and excludes subjects with major protocol violations, 
entry criteria violations or missing visits. The PP population will be determined prior to the 
database lock and unblinding of the study. The PP population will be used for sensitivity 
analysis.  
7.0 
GENERAL STATISTICAL CONSIDERATION AND DEFINITIONS 
7.1 
Baseline and Visit Windows 
Unless otherwise specified, baseline, which is defined as the last non missing assessment prior to 
the first dose of the study treatment, will be used in baseline and change from baseline analyses.   
Analyses will be performed according to the scheduled visits. 
7.2 
Summary Statistics 
Analysis will be summarized by treatment group of STI-5656 plus SOC or Placebo plus SOC, 
unless specified otherwise.  


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• Continuous endpoints will be summarized using descriptive statistics (number of 
participants, mean, standard deviation [SD], median, and maximum values) for each 
cohort. The summary statistic n will be the number of subjects with non-missing values. 
All means and medians will be reported to one more significant digit than the values 
being analyzed. Standard errors and standard deviations will be reported to two more 
significant digits than the values being analyzed. The minimum and maximum will be 
reported to the same number of significant digits as the values being analyzed. 
• Categorical endpoints will be summarized as the number and percentage of participants 
per category for each cohort. Percentages will be out of the number of subjects in the 
population being reported, unless otherwise noted. All percentages will be rounded to one 
decimal point. The number and percentage of subjects will always be presented in the 
form XX (XX.X%) where the percentage is in parentheses. To ensure completeness, all 
summaries for categorical and discrete variables will include all categories, even if none 
of the subjects had a response in a particular category. Denominators for each analysis 
will be based on the population of interest (e.g., safety population; subjects with non-
missing data). 
• Subject listings of data will be presented for all enrolled subjects unless specified 
otherwise. 
7.3 
Missing or Incomplete Data 
Subjects who are randomized to the study and discontinue before the end of the study will not be 
replaced. Missing values will not be imputed unless otherwise specified.  
For success/failure endpoints, subjects who discontinue prior to the specified time point will be 
included in the analysis as treatment failures and censored at the last day of follow-up for the 
time-to-event analysis.  
For all other endpoints, the mixed effect model repeat measurement (MMRM) analysis will be 
employed. The MMRM analysis only includes the available data. It has been demonstrated that 
the MMRM approach leads to estimators with comparatively small bias, and controls Type I 
error rates at a nominal level in the presence of missing completely at random (MCAR) or 
missing at random (MAR) and some possibility of missing not at random (MNAR) data (see 
https://pubmed.ncbi.nlm.nih.gov/19212876/). 
7.4 
Interim Analysis 
A non-binding interim futility analysis will be performed after 40 subjects have reached the 
study primary endpoint. The analysis will be performed by an independent biostatistician who 
will have no contact with the study team.   
This interim analysis will use non-binding futility boundaries.  At 50% planned subjects (40 
subjects out of 80 subjects total), futility interim will be performed.  O’Brien-Fleming beta 
spending function will be used.  Futility bound on Z scale is 0.537.  The futility bound is crossed 
if an observed Z statistic is less than 0.537.   Nominal beta is 0.296 with cumulative beta being 
0.065 at the interim and 0.192 at the final analysis.  The above interim planning was performed 
under 1-sided test setting using nQuery Version 8.6.1.0.  Using 1-sided alpha of 0.025, with 


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continuity correction, sample size of 40 per group (80 total) have 80.8% power (beta 0.192) to 
detect the difference of 95.7% in active arm vs 70% in control arm. 
8.0 
STATISTICAL ANALYSES 
8.1 
Subject Disposition 
The number of percentage of subjects in screened, randomized, FAS population, Safety 
Population, PP Population, completed the study and discontinued from the study will be 
reported, along with the reason for discontinuation.  
Percentages will be out of the number of safety population. Counts only will be reported for 
screened subjects.   
8.2 
Demographic and Baseline Characteristics 
Demographic/baseline characteristics will be summarized descriptively by treatment group in 
Safety Population.  
The following variables will be included: 
• Age (years) 
• Sex (male, female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Height, Weight and Body Mass Index (BMI) (Screening) 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
• SARS-CoV-2 quantitative RT-PCR result (Screening) 
8.3 
Medical History 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary. Medical history will be summarized by system organ class (SOC) term 
and preferred term for each cohort by treatment group. For subjects with the same SOC and 
preferred term occurring more than once, the first occurrence will be tabulated. 
Conditions will be listed, including the verbatim investigator description of the relevant medical 
condition, the coded terms (SOC, preferred term), start date, end date, and whether or not the 
condition is ongoing. 
8.4 
 Prior and Concomitant Medications 
Prior medications are defined as all medications recorded in the CRF initiated prior to the start of 
the study treatment.  Prior medications will be coded with the World Health Organization Drug 


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Dictionary (WHO-DD), and summarized by drug class (Anatomical Therapeutic Chemical 
[ATC] Level 3) and preferred term; a subject will be counted only once for each medication.   
All medication will be listed with the prior medications flagged. 
8.5 
Protocol Deviations 
Protocol deviations recorded will be reviewed and major deviations will be identified prior to 
database lock and unblinding of the study. The PP population will be determined and subjects 
with major protocol violations, entry criteria violations or missing visits will be excluded.  
8.6 
Study Drug Administration 
Two STI-5656 or matching placebo capsules p.o. QD (two 50-mg capsules) are administered 
orally up to 14 days or until hospital discharge if sooner. If vomiting occurs within 30 minutes 
after a patient takes the dose and the patients can tolerate the medication, the vomited dose 
should be made up. 
If the subject is unable to swallow, the capsule contents may be flushed down a nasogastric or 
feeding tube with water. 
For study drug administration, descriptive statistics of the following parameters will be 
presented. 
•  Number of days on study treatment 
• Total dose planned 
• Total dose administered 
• Total dose missed 
• Compliance rate, defined as the total dose administered/total dose planned, expressed as a 
percentage. 
 Subject listing of study drug administration will be presented. 
9.0 
EFFICACY EVALUATION 
9.1 
Primary Endpoint 
The primary efficacy endpoint is the proportion of subjects alive and free of respiratory failure at 
Day 28, where respiratory failure, is defined based on resource utilization of any of the following 
modalities: 
• Noninvasive positive pressure ventilation or continuous positive airway pressure 
• Endotracheal intubation and mechanical ventilation 
• Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via 
reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) 
• Extracorporeal membrane oxygenation 
The number and percentage of subjects will be presented by treatment group using FAS 
population.  Primary analysis to evaluate the differences between groups will utilize a 


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generalized linear mixed model, assuming a binomial distribution and a logit link. The model 
will include group as a fixed effect. Subjects who discontinue the study prior to Day 28 will be 
considered treatment failures. 
Sensitivity analyses may be performed using PP population. 
After 40 subjects have been enrolled and completed Day 28, an interim futility analysis will be 
performed to examine the proportion of subjects alive and free of respiratory failure at Day 28.  The 
interim analysis is a non-binding analysis.  See Section 7.4 for details.  
9.2 
Secondary Endpoints 
9.2.1 Proportions  
The same method used in the primary endpoint will be repeated for the following secondary 
efficacy endpoints:  
• Proportion of subjects alive and free of respiratory failure at Day 60 
• Proportion of subjects alive and discharged from ICU at Days 14 and 28 
• All-cause mortality at Day 60 and Day 90 
Subjects who discontinue the study prior to the study day end will be considered treatment 
failures. 
9.2.2 Clinical Status 
The 8-point ordinal scale will be summarized descriptively by treatment group and study day. 
The last known clinical status will be used for days with missing clinical status. All post-baseline 
days with missing ordinal scale score will use the previous last known clinical status. 
Additionally, stacked bar charts will be presented for the proportion of subjects in each category 
by group and study day. 
9.2.3 Continuous Endpoints 
For the following continuous endpoints, descriptive statistics will be presented by treatment 
group and study day. The changes or percent changes from baseline to each subsequent day will 
be calculated for each subject and descriptive statistics will be presented. Treatment differences 
between groups will be assessed using a mixed-effects model for repeat measures (MMRM). The 
model will include group, study day as fixed effects, baseline value as a covariate, interaction 
between study day and group, interaction between study day and baseline, and subject as a 
random effect. 
• Percent change from baseline in C-reactive protein (CRP) at Days 3, 5, 7, 10, 14, 28  
• Relative change from baseline in oxygenation index (PaO2/FiO2) up to Day 5 
For each “number of days” endpoint listed below, descriptive statistics will be presented by 
treatment group. Treatment differences between groups will be assessed using analysis of 
variance (ANOVA) model with group as a fixed effect.  
• Number of days alive and free of respiratory failure at Day 28 


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• Number of days with respiratory failure up to Day 28 
• Number of days hospitalized up to Day 28 
• Number of days in intensive care unit (ICU) (length of stay) up to Day 90 
• Number of days alive outside of hospital up to Day 28 
• Number of days alive outside of hospital up to Day 90 
9.2.4 Time-to-Event Endpoint 
For the time from randomization to first occurrence of respiratory failure or death on study due 
to any cause up to Day 28, the Kaplan-Meier method will be applied. Subjects will be censored 
at the time of last follow-up. For each group, the 25th percentile, median and 75th percentile will 
be presented, if possible. Treatment differences between groups will be assessed by the log-rank 
test. 
9.3 
Exploratory Endpoints 
For the following exploratory endpoints, descriptive statistics will be presented by treatment 
group and study day. The changes from baseline to each subsequent day will be calculated for 
each subject and descriptive statistics will be presented. Treatment differences between groups 
will be assessed using a mixed-effects model for repeat measures (MMRM). The model will 
include group, study day as fixed effects, baseline value as a covariate, interaction between study 
day and group, interaction between study day and baseline, and subject as a random effect. 
• Change from baseline in absolute lymphocyte counts at Days 3, 5, 7, 10, 14, 28  
• Change from baseline in serum ferritin at Days 3, 5, 7, 10, 14, 28 
• Change from baseline in vascular endothelial growth factor (VEGF-A) at Days 3, 5, 7, 
10, 14, 28 
• Change from baseline for inflammatory cytokines (IL-6, TNF-α, IFNγ, IL1β, IL-7, IL-8, 
IL-10, IL-12, IL-17, IL-18, IP-10) at Days 3, 5, 7, 10, and 28 
10.0 
SAFETY EVALUATION 
10.1 
Adverse Events 
Treatment-emergent adverse events (TEAE) will be defined as any AE occurring post first 
administration of study drug. AEs will be coded using the MedDRA dictionary. 
A summary of TEAEs will be presented as the number and percentage of subjects with at least 
one of the following: 
• Any AE 
• Any TEAE 
• TEAE by Severity 
• TEAE by Causality 
• TEAEs leading to study discontinuation 


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• TEAEs leading to death (with outcome of Fatal) 
• SAEs 
• SAEs by Causality 
AEs and TEAEs will be summarized by SOC and preferred term by treatment group. For 
subjects with the same SOC and preferred term occurring more than once, the first occurrence 
will be tabulated. AEs and TEAEs will also be presented for each preferred term by maximum 
severity, by nearest relationship to study drug, and for serious AEs. 
10.2 
Laboratory Results 
For each continuous laboratory parameter (chemistry, coagulation, hematology), descriptive 
statistics will be presented for each study day collected and for the changes from baseline for by 
treatment group.  
Categorical urinalysis parameters will be presented as the number and percentage of subjects per 
category for each study day collected by treatment group.  
For laboratory parameters with normal ranges, the shift from Baseline (low, normal, high) to 
each subsequent study day (low, normal, high) will be presented by treatment group. 
10.3 
Respiratory Status 
Respiratory status data collected will be provided in a subject listing. 
10.4 
Vital Signs Measurements 
Vital signs measurement [body temperature (F), respiratory rate, radial pulse rate, systolic and 
diastolic blood pressure, and oxygen saturation (pulse oximetry will be summarized descriptively 
by treatment group for each study day collected. Additionally, the changes from baseline will be 
calculated and descriptive statistics presented.  
10.5 
Electrocardiogram (ECG) Results 
For each ECG parameter, descriptive statistics will be presented for each cohort by treatment 
group for values collected. 
10.6 
Physical Examination 
The results of the physical examination will be listed for each subject and study day collected. 
10.7 
Pregnancy Test for FCBP 
The results of the pregnancy test will be listed for each assessment visit day collected. 
11.0 
CHANGES TO THE PLANNED ANALYSES 
During the analysis and reporting process, any deviations from the statistical plan designed for 
this protocol will be described and justified in the clinical study report.   
 


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12.0 
APPENDICES 
12.1 
Appendix 1: Schedule of Assessments 
  
 


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