Clinical trial NCT04404361
Conditions: COVID19 COVID-19 COVID
Keywords: COVID19 COVID-19 COVID
Sponsor: CTI BioPharma
Start date: 2020-05-22; Completion date: 2021-09-21
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pacritinib in hospitalized patients with severe COVID-19 with or without cancer.

Detailed description:
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of pacritinib in hospitalized patients with severe COVID-19 with or without cancer. Severe COVID-19 is defined as confirmed disease in patients who are hospitalized with hypoxia (blood oxygen saturation \[SpO2\] ≤93% on room air at sea level), respiratory rate \>30, arterial oxygen partial pressure \[PaO2\]/ fraction of inspired oxygen \[FiO2\] \<300, or lung infiltrates \>50% but do not require IMV.

Patients will be randomized 1:1 to receive pacritinib (400 mg once daily \[QD\] on Day 1, then 200 mg twice daily \[BID\] from Day 2 to Day 14) + SOC or placebo + SOC.

Assigned treatment will continue for up to Day 14 or until the patient experiences intolerable adverse events (AEs), withdraws consent, or initiates another investigational therapy or until the study is terminated. Assigned therapy may be given for an additional 7 days (for a total of 21 days) with the approval of the Medical Monitor if, in the opinion of the investigator, the patient's clinical signs and symptoms are improving and the potential benefit outweighs the potential risk.In the event of hospital discharge, patients will complete treatment with the assigned therapy as an outpatient.

Arms: arm 1: Pacritinib 400 mg once daily \[QD\] on Day 1, then 200 mg twice daily \[BID\] from Day 2 to Day 14) + SOC arm 2: 4 capsules once daily \[QD\] on Day 1, then 2 capsules twice daily \[BID\] from Day 2 to Day 14) + SOC
Interventions: intervention 1: Pacritinib intervention 2: Placebo
Intervention descriptions: intervention 1: 100 mg capsules intervention 2: Placebo capsules matching pacritinib 100 mg capsules

Protocol documents:
Prot_000.pdf: 
CTI BioPharma Corp. 
PRE-VENT Phase 2 Protocol Amendment 4 
 
 
Page 1 of 81 
 
 
 
CTI BioPharma Corp. 
 
PRE-VENT Phase 2 
 
A Phase 2 Randomized, Double-blind, Placebo-controlled, 
Multicenter Study of Pacritinib Plus Standard of Care Versus 
Placebo and Standard of Care in Hospitalized Patients With Severe 
COVID-19 With or Without Cancer 
 
PAC319 
IND # 149,611 
 
Amendment 4 
11 August 2021 
Sponsor: 
CTI BioPharma Corp. 
3101 Western Avenue, Suite 800 
Seattle, WA 98121 
 
Medical Monitor 
Sarah Buckley, MD 
Medical Director 
206-272-4541 
 
Chief Medical Officer 
Adam Craig, MD, PhD, MBA 
646-637-1916 
 
 
© CTI BioPharma Corp. all rights reserved.  This document and its contents are the property of CTI BioPharma Corp.  Unauthorized copying or 
use of this information is prohibited. This document or information within may not be used, divulged, published, or otherwise disclosed without 
the written consent of CTI 


CTI BioPharma Corp. 
PRE-VENT Phase 2 Protocol Amendment 4 
 
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Signature Page 
 
 
Approved: 
 
 
 
 
 
 
Sarah Buckley, MD 
Medical Director 
 
 
 
 
 
 
 
Date 
Adam Craig, MD, PhD, MBA 
Medical Director 
 
 
 
 
 
 
 
Date 
Jennifer Smith, PhD 
Senior Vice President, Biometrics 
 
 
 
 
 
 
 
Date 
John Volpone 
Senior Vice President,  
Strategic Operations 
 
 
 
Date 
 


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Table of Contents 
Signature Page ....................................................................................................................2 
Table of Contents ...............................................................................................................3 
List of Tables ......................................................................................................................6 
List of Figures .....................................................................................................................7 
Protocol Synopsis .............................................................................................................11 
1 
Background Information .........................................................................................25 
1.1 
COVID-19 .............................................................................................................25 
1.1.1 
Clinical Presentation and Disease-Related Symptoms ...............................25 
1.1.2 
Current Strategies for Prevention and Treatment of COVID-19 .............25 
1.1.3 
Pacritinib as a Therapeutic Strategy for COVID-19-Related ARDS and 
Cytokine Storm ..............................................................................................26 
1.2 
Pacritinib ..............................................................................................................27 
1.2.1 
Pharmacology .................................................................................................27 
1.2.2 
Preclinical Toxicology ....................................................................................28 
1.2.3 
Summary of Clinical Pharmacology and Early Phase Studies With 
Healthy Subjects of Pacritinib ......................................................................28 
1.2.4 
Overview of Clinical Safety of Pacritinib ....................................................29 
2 
Study Rationale and Objectives ..............................................................................30 
2.1 
Justification of Included Patient Population .....................................................31 
2.2 
Independent Data Monitoring Committee ........................................................31 
2.3 
Study Objectives...................................................................................................31 
2.3.1 
Primary Objective ..........................................................................................31 
2.3.2 
Secondary Objectives.....................................................................................32 
2.3.3 
Tertiary Objectives ........................................................................................32 
3 
Study Design ..............................................................................................................33 
3.1 
Rationale for Dosage Selection ...........................................................................34 
4 
Patient Selection and Withdrawal ...........................................................................35 
4.1 
Target Population ................................................................................................35 
4.1.1 
Inclusion Criteria ...........................................................................................35 
4.1.2 
Exclusion Criteria ..........................................................................................36 
4.2 
Withdrawal of Patients from Study ...................................................................37 
4.3 
Study Termination ................................................... Error! Bookmark not defined. 
5 
Method of Treatment Assignment and Blinding ...................................................37 
6 
Study Treatment .......................................................................................................38 
6.1 
Study Treatment Administration .......................................................................38 
6.2 
Study Treatment Description and Storage ........................................................38 
6.2.1 
Pacritinib ........................................................................................................38 
6.2.2 
Placebo ............................................................................................................38 
6.3 
Dosage, Route, and Mode of Administration ....................................................39 
6.4 
Drug Accountability.............................................................................................39 
6.5 
Pacritinib Treatment Adjustments for Adverse Events ...................................39 
6.5.1 
Treatment Interruption and Discontinuation .............................................39 
6.5.2 
Dosage Management Guidelines for Adverse Events .................................39 
6.5.3 
Dosage Management Guidelines for Bleeding and Thrombocytopenia....40 
6.5.4 
Dosage Management Guidelines for QTcF Interval Prolongation............41 


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6.5.5 
Dosage Management Guidelines for Diarrhea ............................................42 
6.5.6 
Dosage Management Guidelines for Treatment-Related Toxicities Other 
than QTcF Prolongation, Diarrhea, Bleeding, or Thrombocytopenia ......43 
6.6 
Concomitant and Excluded Therapies ...............................................................44 
6.6.1 
Management of Gastrointestinal Toxicity ...................................................45 
7 
Study Assessments ....................................................................................................45 
7.1 
Criteria for Evaluation ........................................................................................45 
7.1.1 
Efficacy............................................................................................................45 
7.1.1.1 
7-Point Ordinal Scale of Clinical Status ................................................45 
7.1.1.2 
Immunomodulatory Agents ....................................................................46 
7.1.1.3 
Lung Function Assessments ....................................................................46 
7.1.2 
Safety ...............................................................................................................46 
7.1.2.1 
Adverse Events .........................................................................................46 
7.1.2.2 
Hematology ...............................................................................................46 
7.1.2.3 
Coagulation Testing .................................................................................47 
7.1.2.4 
Serum Chemistry .....................................................................................47 
7.1.2.5 
Liver Function Panel ...............................................................................47 
7.1.2.6 
ECG Assessment ......................................................................................47 
7.1.2.7 
Markers of Disease Severity ....................................................................48 
7.1.3 
Informed Consent, Screening, and Washout of Prohibited Concomitant 
Medications Before Beginning Pacritinib/placebo ......................................48 
7.1.4 
Summary of Study Assessments and Events by Day ..................................48 
7.1.4.1 
Screening (Study Day -1 or 1) .................................................................48 
7.1.4.2 
Randomization (Study Day -1 or 1) ........................................................50 
7.1.4.3 
Study Day 1 (Pre-dose) ............................................................................50 
7.1.4.4 
Daily Assessment (Day 2 to Day 28) .......................................................51 
7.1.4.5 
End of Treatment .....................................................................................53 
7.1.4.6 
30-day Post-EOT Follow-up (± 3 days) ..................................................55 
7.1.4.7 
Day of Hospital Discharge .......................................................................55 
7.1.4.8 
Outpatient Assessments ...........................................................................56 
8 
Assessment of Safety .................................................................................................57 
8.1 
Adverse Events .....................................................................................................57 
8.1.1 
Definition of an Adverse Event .....................................................................57 
8.1.2 
Reporting Adverse Events .............................................................................57 
8.1.3 
Criteria for Assessing Adverse Events .........................................................58 
8.1.3.1 
Severity......................................................................................................58 
8.1.3.2 
Relationship ..............................................................................................59 
8.1.3.3 
Outcome ....................................................................................................59 
8.1.3.4 
Action Taken With Pacritinib/placebo ..................................................60 
8.1.4 
Serious Adverse Events .................................................................................60 
8.1.4.1 
Definition of a Serious Adverse Event ...................................................60 
8.1.4.2 
Exceptions .................................................................................................61 
8.1.4.3 
Reporting Serious Adverse Events to the Sponsor ...............................61 
8.1.4.4 
Reporting Serious Adverse Events to the Regulatory Agencies, 
Institutional Review Boards, and/or Ethics Committees .....................62 
8.2 
Laboratory Evaluation ........................................................................................63 


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8.3 
Vital Signs and Physical Examination ...............................................................63 
8.4 
Safety Surveillance ...............................................................................................63 
8.4.1 
Routine Pharmacovigilance Monitoring ......................................................63 
9 
Markers of Disease Severity ....................................................................................64 
9.1 
Blood Sample Collection, Handling, and Shipping ...........................................64 
9.2 
Disease Severity Assessments ..............................................................................64 
10 Data Management .....................................................................................................64 
10.1 
Data Collection .....................................................................................................65 
10.2 
Data Entry and Quality Control .........................................................................65 
11 Statistical Methods and Sample Size Determination .............................................65 
11.1 
Endpoints for the Analysis ..................................................................................65 
11.1.1 
Efficacy............................................................................................................65 
11.1.2 
Safety Endpoints ............................................................................................67 
11.2 
Analysis Populations ............................................................................................67 
11.2.1 
Primary Analysis Intent-to-Treat Population .............................................67 
11.2.2 
Safety Population ...........................................................................................67 
11.3 
Efficacy Analysis ..................................................................................................67 
11.4 
Safety Analysis .....................................................................................................68 
11.5 
Subgroup Analysis ...............................................................................................69 
11.6 
Multiplicity ............................................................... Error! Bookmark not defined. 
11.7 
Determination of Sample Size .............................................................................69 
11.8 
Analysis of Markers of Disease Severity ............................................................69 
11.9 
Interim Analysis ....................................................... Error! Bookmark not defined. 
12 Independent Data Monitoring Committee .............................................................69 
13 Study Administration and Investigator Obligations .............................................69 
13.1 
Pacritinib Accountability ....................................................................................70 
13.2 
Informed Consent ................................................................................................70 
13.3 
Disclosure of Data ................................................................................................70 
13.4 
Case Report Forms ..............................................................................................71 
13.5 
Study Monitoring .................................................................................................71 
13.6 
Record Retention .................................................................................................71 
14 Ethics ..........................................................................................................................71 
14.1 
Good Clinical Practice .........................................................................................71 
14.2 
Institutional Review Board/Research Ethics Board/Independent Ethics 
Committee .............................................................................................................72 
15 Termination of Study ...............................................................................................72 
16 Study Amendments ...................................................................................................73 
17 Use of Information and Publication ........................................................................73 
18 References ..................................................................................................................74 
19 Appendices.................................................................................................................76 
Appendix 1 - Selected Strong Inhibitors of CYP3A4 ...................................................77 
Appendix 2 – Selected Strong Inducers of CYP450 ......................................................78 
Appendix 3 - Common Terminology Criteria for Adverse Events: Diarrhea (Version 
4.03) ............................................................................................................................79 
Appendix 4 - Investigator Responsibilities, Required Documentation, and Signature80 
 


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List of Tables 
Table 1 
PRE-VENT Phase 2 (PAC319) Schedule of Assessments ..........................19 
Table 2. 
Study Treatments ...........................................................................................38 
Table 3. 
Treatment-Related Thrombocytopenia and Bleeding ................................40 
Table 4. 
QTcF Prolongation ........................................................................................42 
Table 5. 
Dosage Management for Treatment-Related Diarrhea..............................43 
Table 6. 
Treatment Toxicity and Dosage Management: Treatment-Related 
Toxicities Other than QTcF Prolongation, Diarrhea, or Thrombocytopenia 44 
Table 7. 
Outcomes of Adverse Events.........................................................................59 
 


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List of Figures 
Figure 1 
Simulated Median Concentration-Time Course in Myelofibrosis 
Patients (Day 1 to Day 8) .....................................................................................35 
 


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Abbreviations 
Abbreviation 
Full Term 
AE 
adverse event 
ABG 
arterial blood gas 
ALT 
alanine aminotransferase 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
BAT 
best available therapy 
BID 
twice daily 
BiPAP 
bilevel positive airway pressure 
BNP 
brain natriuretic peptide 
CBC 
complete blood count 
CD4 
cluster of differentiation 4 
CK 
creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CPAP 
continuous positive airway pressure 
CRP 
C-reactive protein 
CSF-1R 
colony‑stimulating factor 1 receptor 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
cytochrome P450 3A4 
CYP450 
cytochrome P450 
DC 
dendritic cell 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End of Treatment 
ER 
emergency room 
FiO2 
fraction of inspired oxygen 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR 
hazard ratio 


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Abbreviation 
Full Term 
HRmax 
maximum documented heart rate during calendar day 
IC50 
half maximum inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IL 
interleukin 
IMV 
invasive mechanical ventilation 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRAK1 
interleukin-1 receptor-associated kinase-1  
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
PaO2 
arterial oxygen partial pressure 
PD 
pharmacodynamic(s) 
PEEP 
positive end-expiratory pressure 
PK 
pharmacokinetic(s) 
PT 
preferred term 
PTT 
partial thromboplastin time 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QT corrected by the Fridericia method 
RBC 
red blood cell 
REB 
Research Ethics Board 
RT-PCR 
reverse transcriptase polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SOC 
standard of care 
SpO2 
blood oxygen saturation 
STAT 
signal transducer and activator of transcription 


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Abbreviation 
Full Term 
TEAE 
treatment-emergent adverse event 
Th17 
T helper 17 
Tmax 
maximum documented temperature during calendar day 
TSS 
total symptom score 
TYK 
cytoplasmic tyrosine kinase 
US 
United States 
WOCBP 
Woman of child-bearing potential 
WBC 
white blood cell 


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Protocol Synopsis 
Name of Investigational Drug 
Pacritinib 
Protocol ID 
PRE-VENT Phase 2 Study 
PAC319, IND # 149,611 
Protocol Title 
A Phase 2 Randomized, Double-blind, Placebo-controlled, Multicenter 
Study of Pacritinib Plus Standard of Care Versus Placebo and Standard of 
Care in Hospitalized Patients with Severe COVID-19 With or Without 
Cancer 
Version 
Amendment 4 
Primary Objective 
To compare the efficacy of pacritinib + standard of care (SOC) versus placebo + SOC in hospitalized patients 
who have severe COVID-19 with or without cancer, as the proportion of patients who require invasive 
mechanical ventilation (IMV) and/or extracorporeal membrane oxygenation (ECMO) or die by Day 28. 
Secondary Objectives 
1. To compare the number of ventilator-free days, defined as the number of days that patients are alive and 
not intubated, from randomization to Day 28 between pacritinib + SOC versus placebo + SOC 
2. To compare the mortality rate between pacritinib + SOC versus placebo + SOC at Day 28 
3. To compare the mortality rate between pacritinib + SOC versus placebo + SOC at Day 15 
4. To compare the time to improvement by at least 2 points relative to Baseline on the 7-point ordinal scale 
of clinical status between pacritinib + SOC versus placebo + SOC 
5. To compare the clinical status assessed by the 7-point ordinal scale of clinical status at Days 8, 15, 22, 
and 28 between pacritinib + SOC versus placebo + SOC 
6. To compare the rate of use of immunomodulatory agents as treatment for COVID-19 during the 28 days 
following randomization between pacritinib + SOC versus placebo + SOC 
7. To evaluate the toxicity profile of pacritinib therapy in hospitalized patients with severe COVID-19 with 
or without cancer 
Tertiary Objectives 
To evaluate the treatment effects of pacritinib + SOC on the following markers of disease severity: 
• 
C-reactive protein (CRP) 
• 
Ferritin  
• 
D-dimer  
• 
Interleukin-6 (IL-6) 
• 
Troponin-I 
• 
Lactate dehydrogenase (LDH) 
• 
Brain natriuretic peptide (BNP) 
• 
Procalcitonin 
• 
Triglycerides 
• 
Creatine kinase (CK) 
 


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Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and 
safety of pacritinib in hospitalized patients with severe COVID-19 with or without cancer.  Severe COVID-19 is 
defined as confirmed disease in patients who are hospitalized with hypoxia (blood oxygen saturation [SpO2] 
≤93% on room air at sea level), respiratory rate >30, arterial oxygen partial pressure [PaO2]/fraction of inspired 
oxygen [FiO2] <300, but do not require IMV.   
Patients will be randomized 1:1 to receive pacritinib (400 mg once daily [QD] on Day 1, then 200 mg twice daily 
[BID] from Day 2 to Day 14) + SOC or placebo + SOC.   
Assigned treatment will continue for up to Day 14 or until the patient experiences intolerable adverse events 
(AEs), withdraws consent, or initiates another investigational therapy or until the study is terminated.  Assigned 
therapy may be given for an additional 7 days (for a total of 21 days) with the approval of the Medical Monitor if, 
in the opinion of the investigator, the patient’s clinical signs and symptoms are improving and the potential 
benefit outweighs the potential risk.  In the event of hospital discharge, patients will complete treatment with the 
assigned therapy as an outpatient. 
The primary endpoint is the effect of treatment on the proportion of patients who require IMV and/or ECMO or 
die by Day 28.  
Data analyses will be conducted during the study by an Independent Data Monitoring Committee (IDMC).  The 
membership, roles, and responsibilities of the IDMC will be fully defined by an IDMC charter.   
Safety will be monitored with physical examinations, clinical laboratory assessments, and electrocardiogram 
(ECG) monitoring.  Specified pacritinib/placebo dosage modifications will be followed to address identified 
abnormalities.  AE data will be collected from the time of randomization through 30 days following the last dose 
of pacritinib/placebo.  Serious adverse events (SAEs) assessed as related to pacritinib/placebo or study procedure 
by the investigator or Sponsor shall be followed until the event resolves, stabilizes, or the patient is lost to 
follow-up.  SAEs assessed as unrelated to pacritinib/placebo or study procedures shall be followed for 30 days 
after the last dose of pacritinib/placebo, or until the event resolves, returns to baseline, stabilizes, or the patient is 
lost to follow-up, whichever comes first. 
At the request of an investigator, and with agreement of the Chief Medical Officer at CTI, the assigned treatment 
for an individual patient may be unblinded for the purposes of discussing the ongoing care of that patient. 
The approximate study duration for each patient will be 8 weeks.  The estimated duration of the entire study is 
approximately 1 year if the maximum number of patients are enrolled. 
The schedule of study assessments for all patients is provided in Table 1. 
Number of Centers 
Approximately 21 centers in the United States (number of centers and countries may be 
reassessed as patient enrollment increases) 
Number of Patients 
Approximately 200 patients  
Randomization 
1:1 to either pacritinib + SOC or placebo + SOC 
Stratification 
Age (< 60 years, ≥ 60 years) 
7-point ordinal scale of clinical status scale (baseline 3 or 4 versus 5) 


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Inclusion/ 
Exclusion Criteria 
Inclusion Criteria 
1. Hospitalized or will be hospitalized prior to randomization for the treatment of 
severe COVID-19 with SARS-CoV-2 infection confirmed by either a) a positive 
reverse transcriptase polymerase chain reaction (RT-PCR) or b) an antigen-based 
test from any respiratory, nasopharyngeal, saliva, blood, or stool specimen at 
Screening or documented within 1 week prior to the start of Screening (Severe 
COVID-19 is defined as confirmed disease in patients who are hospitalized with 
hypoxia [SpO2 ≤93% on room air], respiratory rate >30, PaO2/FiO2 <300, but do 
not require IMV). 
2. Age ≥ 18 years 
3. Platelet count ≥ 50,000/µL 
4. If fertile, willing to use effective birth control methods during the study 
5. Provision of informed consent within 96 hours after hospitalization 
Exclusion Criteria 
1. In the opinion of the investigator, progression to death is imminent and 
inevitable within the next 24 hours, irrespective of the provision of treatments 
2. Currently intubated or intubated between screening and randomization 
3. Suspected active uncontrolled bacterial, fungal, viral, or other infection (besides 
COVID-19) 
4. Prior allogenic hematopoietic stem cell transplantation 
5. Active lung cancer or history of lung cancer within the past 12 months 
6. Any active grade 2 or higher hemorrhage 
7. Any active gastrointestinal or metabolic condition that could interfere with 
absorption of oral medication 
8. Uncontrolled intercurrent illness that, in the judgment of the treating physician, 
would limit compliance with study requirements 
9. Known seropositivity for human immunodeficiency virus with cluster of 
differentiation 4 (CD4) count < 200/mm3 within 3 months prior to 
randomization 
10. Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination 
11. Concurrent enrollment in another interventional trial (investigational COVID-19 
antiviral studies are permitted) 
12. Serum creatinine > 2.5 mg/dL 
13. Total bilirubin > 4× the upper limit of normal 
14. QT corrected by the Fridericia method (QTcF) prolongation > 480 msec 
15. Known history of New York Heart Association Class II, III, or IV congestive 
heart failure prior to hospital admission 
16. Known allergic reaction to any Janus kinase 2 (JAK2) inhibitor 
17. Exposure to any JAK2 inhibitor within 28 days 
18. Currently receiving a strong CYP3A4 inhibitor or strong P450 inducer 
(Appendix 1 and Appendix 2, respectively) and unable to stop the medication 


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prior to the first dose of study drug and throughout the duration of study drug 
administration 
19. Treatment with cytoreductive chemotherapy administered within 14 days prior 
to randomization 
20. Administration of an IL-1 or IL-6 blocking immunomodulatory agent (such as 
tocilizumab, canakinumab, sarilumab, anakinra) within 48 hours prior to 
randomization  
21. Currently receiving therapeutic anticoagulation or anti-platelet medication and 
unable to stop the medication prior to randomization.  Prophylactic anticoagulation 
therapy or aspirin (≤ 100mg) are permitted. 
22. Unable to ingest capsules or tablets at randomization 
Study Treatments 
Pacritinib: 
Dosage Form: 100 mg capsules 
Dose Regimen: 4 capsules QD on Day 1 followed by 2 capsules BID.  Administered 
orally or via oro/nasogastric tube. 
Placebo: 
Dosage Form: Placebo capsules matching pacritinib 100 mg capsule  
Dose Regimen: 4 capsules QD on Day 1 followed by 2 capsules BID.  Administered 
orally or via oro/nasogastric tube. 
Concomitant and 
Excluded 
Therapies, 
Including 
Procedures 
Treatment with cytoreductive therapy is not permitted during the assigned treatment 
period.  Pacritinib is metabolized by the P450 system, including cytochrome P450 3A4 
(CYP3A4).  Use of strong CYP3A4 inhibitors is not permitted as these can lead to 
significantly increased concentrations of pacritinib.  Use of strong cytochrome P450 
(CYP450) inducers is not permitted as these can lead to significantly reduced 
concentrations of pacritinib.  Lists of selected strong CYP3A4 inhibitors and P450 
inducers are found in Appendix 1 and Appendix 2, respectively. 
Concomitant use of investigational agents (those administered as part of a clinical trial) 
for the treatment of COVID-19 is prohibited with the exception of antiviral agents.  The 
use of IL-1 or IL-6 blocking immunomodulatory agents (such as tocilizumab, 
canakinumab, sarilumab, anakinra) is allowed if, in the opinion of the investigator, a 
patient is clinically deteriorating.  However, patients who require IL-1 or IL-6 blocking 
agents must be discontinued from study drug.  Hydroxychloroquine, chloroquine, 
azithromycin, corticosteroids, and antiviral agents are permitted concomitant 
medications. 
Treatment-dose anticoagulation and anti-platelet therapy may be administered after 
randomization, if required; patients do not need to discontinue pacritinib/placebo if one 
of these medications is initiated. However, patients should not receive such agents 
concomitant with study drug administration if their platelet counts drop to < 50,000/µL. 
Cytotoxic chemotherapy or cancer-directed immunotherapy is prohibited during the 
pacritinib/placebo treatment period (14 or 21 days). 
Efficacy 
Assessments 
7-point ordinal scale of clinical status (adapted from Cao et al 2020) 
 
The following 7-point ordinal scale of clinical status will be used to assess the ordinal 
scale secondary endpoints.  The ordinal scale score is to be documented daily on study 
through Day 28 for all patients, including those who have been discharged from the 
hospital:  
1. Not hospitalized with resumption of normal activities 
2. Not hospitalized but unable to resume normal activities 
3. Hospitalization, not requiring supplemental oxygen 


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4. Hospitalization, requiring supplemental oxygen not meeting criteria for 
categories 5 or 6 
5. Hospitalization, on non-invasive positive pressure ventilation or high-flow nasal 
cannula 
6. Hospitalization, requiring IMV and/or ECMO 
7. Death 
Immunomodulatory Agents 
The use of other immunomodulatory agents as treatment for COVID-19, such as 
corticosteroids, tocilizumab, anakinra, or eculizumab, will be assessed as a secondary 
endpoint. 
Safety Assessments 
Adverse Events 
AEs will be collected during the clinical study from the time the patient is randomized 
through 30 days following the last dose of pacritinib/placebo.  AEs will be identified and 
reported to the Sponsor, in addition to any clinically indicated diagnostic, monitoring, 
treatment, and follow-up measures used to manage the reported AE.  Pregnancy alone 
will not be considered as an AE.  Pregnancy will be reported on a Pregnancy Reporting 
Form (Section 8.1.4.4).  Abnormal pregnancy outcomes and/or any AE for the child or 
fetus (including miscarriage) will be reported as SAEs.  Occurrences of overdose will be 
reported as SAEs. 
 
Hematology 
Hematology parameters, (complete blood count [CBC], white blood cell count [WBC], 
hemoglobin, hematocrit, and platelet count), will be evaluated at Screening (may be 
performed within 24 hours prior to the start of Screening) and daily from Days 2 through 
28 or EOT, and on the day of hospital discharge.  WBC differential will be evaluated at 
Screening (may be performed within 24 hours prior to the start of Screening), Day 8, 
Day 15 or EOT, Day 22, Day 28, and on the day of hospital discharge.  Hematology tests 
are not required after hospital discharge.  Results from unscheduled hematology tests 
should be entered into the electronic database using an Unscheduled Hematology case 
report form (CRF).  Analysis of CBC results will be performed at local laboratories.  
Pacritinib/placebo dosage modifications will be implemented for clinically significant 
AEs identified with this testing per the guidelines for “Treatment-Related 
Thrombocytopenia and Bleeding” (Section 6.5.3). 
 
Coagulation Assessments 
Coagulation testing will include international normalized ratio, partial thromboplastin 
time, and fibrinogen at Screening (may be performed within 24 hours prior to the start of 
Screening), Day 8, Day 15 or EOT, Day 22, Day 28, and on the day of hospital 
discharge.  Coagulation tests are not required after hospital discharge.  Results from 
unscheduled coagulation tests should be entered into the electronic database using an 
Unscheduled Coagulation Test CRF.  Analysis of serum chemistry results will be 
performed at local laboratories. 
 
Serum Chemistry 
Serum chemistry parameters (sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose, calcium, and magnesium) will be evaluated at Screening 
(may be performed within 24 hours prior to the start of Screening) and daily from Days 2 
through 28 or EOT and on the day of hospital discharge.  Serum chemistry tests are not 
required after hospital discharge.  Results from unscheduled serum chemistry tests 
should be entered into the electronic database using an Unscheduled Serum Chemistry 
CRF.  Analysis of serum chemistry results will be performed at local laboratories.  


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Pacritinib/placebo dosage modifications will be implemented for clinically significant 
AEs identified with serum chemistry testing per the guidelines for “Treatment-Related 
Toxicities Other than QTcF Prolongation, Diarrhea, Bleeding, or Thrombocytopenia” 
(Section 6.5.6). 
 
Liver Function Panel 
Liver function parameters (aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, total bilirubin, and albumin) will be evaluated at Screening (may be 
performed within 24 hours prior to the start of Screening) and Day 8, Day 15 or EOT, 
Day 22, Day 28 and on the day of hospital discharge.  Liver function panel tests are not 
required after hospital discharge.  Results from unscheduled liver function panel tests 
should be entered into the electronic database using an Unscheduled Liver Function 
Panel CRF.  Analysis of serum chemistry results will be performed at local laboratories.  
Pacritinib/placebo dosage modifications will be implemented for clinically significant 
AEs identified with serum chemistry testing per the guidelines for “Treatment-Related 
Toxicities Other than QTcF Prolongation, Diarrhea, Bleeding, or Thrombocytopenia” 
(Section 6.5.6). 
 
ECG 
An ECG will be performed at Screening (may be performed within 48 hours prior to the 
start of Screening), Day 3, Day 8, Day 15 or EOT, Day 22, and Day 28, and on the day 
of hospital discharge if before EOT.  Eligibility is to be based on mean QTcF of 
≤ 480 msec.  An ECG will also be performed on the day of hospital discharge if the 
patient will be continuing pacritinib/placebo as an outpatient; however, ECGs do not 
need to be assessed after hospital discharge.  Results from unscheduled ECG assessments 
should be entered into the electronic database using an Unscheduled ECG CRF.  ECGs 
should be assessed using at least 3 leads; rhythm strips from telemetry monitoring are 
acceptable.  Pacritinib/placebo modifications and follow-up monitoring for clinically 
significant ECG changes will be implemented as per the guidelines for “Dosage 
Management Guidelines for QTcF Interval Prolongation” (Section 6.5.4).  Additional 
ECG testing shall be done as clinically indicated. 
Markers of disease 
severity  
 
Blood samples for analysis of markers of disease severity (CRP, ferritin, D-dimer, IL-6, 
troponin-I, LDH, BNP, procalcitonin, CK, and triglycerides ) will be collected at 
Screening (may be performed within 24 hours prior to the start of Screening), before the 
morning dose Day 3, Day 8, Day 15 or EOT, Day 22, Day 28 and on the day of hospital 
discharge.  These markers do not need to be assessed after hospital discharge.  The 
assessments for markers of disease severity are required if they can be performed at a 
local laboratory or if the study center has access to an external laboratory where the 
samples can be sent for analysis.  If a study center does not have access to a local or 
external laboratory that can perform these assessments, the Investigator must provide 
written confirmation of the inability to perform the assessment(s), and approval from the 
CTI Medical Monitor is required to omit the assessment(s).  Results from unscheduled 
tests for markers of disease severity should be entered into the electronic database using 
an Unscheduled Markers of Disease Severity CRF. 
Pacritinib Dosage 
Modifications 
Pacritinib/placebo may be interrupted or the dosage may be modified for treatment-
related hematologic toxicities, bleeding, severe infections, cardiac toxicities (including 
QTcF interval prolongation), diarrhea, and other treatment-related non-hematologic 
toxicities.  Pacritinib/placebo may also be held for invasive procedures or at the 
discretion of the investigator.  Refer to Section 6.5 for treatment dosage management 
guidelines. 


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STATISTICAL METHODS 
 
Sample Size 
The study sample size will be approximately 200 patients (randomized in a 1:1 ratio).  This provides 80% power 
to detect at least 13% treatment difference in the proportion of patients who progress to IMV and/or ECMO or 
die by Day 28, assuming that the response rate is 13.5% in the pacritinib and SOC arm and 26.5% in the placebo 
and SOC arm, with a one-sided Type I error rate of 0.10. 
 
 
Analysis Populations 
The Intent-to-treat population is defined as all patients randomized.  Patients in this population will be analyzed 
according to the treatment arm to which they were assigned at randomization.  This population will be used for 
efficacy analyses. 
The Safety population is defined as all randomized patients who received at least one dose of study treatment.  
Patients in this population will be analyzed according to the treatment actually received.  This population will be 
used for the analysis of safety endpoints. 
 
Efficacy 
Primary Endpoint 
The primary efficacy endpoint is the proportion of patients who progress to IMV and/or ECMO or death during 
the 28 days following randomization. 
Secondary Efficacy Endpoints 
1. The number of ventilator-free days, defined as the number of days that patients are alive and not 
intubated, from randomization to Day 28 
2. The 28-day mortality rate, defined as the proportion of patients with outcome of death during the 28 
days following randomization 
3. The 15-day mortality rate, defined as the proportion of patients with outcome of death during the 15 
days following randomization 
4. The time to improvement by at least 2 points relative to Baseline on the 7-point ordinal scale of clinical 
status 
5. The clinical status as assessed by the 7-point ordinal scale of clinical status at Days 8, 15, 22, and 28  
6. The rate of use of immunomodulatory agents as treatment for COVID-19 is defined as the proportion of 
patients reporting use of medications such as corticosteroids, tocilizumab, anakinra, or eculizumab as 
treatment for COVID-19, during 28 days following randomization. 
Tertiary Endpoints 
• 
CRP 
• 
Ferritin  
• 
D-dimer  
• 
IL-6 
• 
Troponin-I 
• 
LDH 
• 
BNP 
• 
Procalcitonin 
• 
Triglycerides 
• 
CK 
Safety Endpoints 


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Safety will be assessed through 30 days of follow-up after the last dose of study treatment by the cumulative 
incidence, severity and seriousness of treatment-emergent AEs, drug discontinuations, laboratory values, and 
clinical assessments.  SAEs assessed as related to pacritinib/placebo or study procedure by the investigator or 
Sponsor shall be followed until the event resolves, stabilizes, or the patient is lost to follow-up.  SAEs assessed as 
unrelated to pacritinib/placebo or study procedures shall be followed for 30 days after the last dose of 
pacritinib/placebo, or until the event resolves, returns to baseline, stabilizes, or the patient is lost to follow-up, 
whichever comes first. 
 
References 
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 
[published online ahead of print, 2020 Mar 18]. N Engl J Med. 2020;NEJMoa2001282. 
doi:10.1056/NEJMoa2001282 
 


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Table 1 
PRE-VENT Phase 2 (PAC319) Schedule of Assessments 
Study Day 
Screening 
Window1 
Pre-Dose 
(Day 1) 
Inpatient 
Assessment 
EOT  
(For Inpatients 
Only) 
Day of Hospital 
Discharge2 
Outpatient3 
Assessment 
30-day 
Post-EOT 
Follow-up 
Window 
 
± 0 days 
 
 
 
 
± 3 days 
Informed consent1 
x 
 
 
 
 
 
 
Demographics 
(age, sex, race, and 
ethnicity) 
x 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
Vital signs4 
x 
 
 
 
 
 
 
Clinical status 
assessment 
(7-point ordinal 
scale)3,5 
x 
x  
(Unless the same 
time point as 
Screening) 
Daily 
(Days 2 through 
28) 
x 
x 
x 
 
Physical 
examination 
 
X6 
Days 8, 15, 22, 
and 28 
x 
x 
 
 
Tmax 
 
x 
Daily 
(Days 2 through 
28) 
x 
x 
 
 
HRmax 
 
x 
Daily 
(Days 2 through 
14) 
x 
x 
 
 
SpO2 in ambient 
air (if possible) 
x 
 
Daily 
(Days 2 through 
28) 
x 
x 
 
 
SpO2 with oxygen 
supplementation (if 
applicable) 
x 
 
Daily 
(Days 2 through 
28) 
x 
x 
 
 


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Table 1 
PRE-VENT Phase 2 (PAC319) Schedule of Assessments 
Study Day 
Screening 
Window1 
Pre-Dose 
(Day 1) 
Inpatient 
Assessment 
EOT  
(For Inpatients 
Only) 
Day of Hospital 
Discharge2 
Outpatient3 
Assessment 
30-day 
Post-EOT 
Follow-up 
Window 
 
± 0 days 
 
 
 
 
± 3 days 
ECG7 
x 
 
Days 3, 8, 15, 
22, and 28  
x 
x  
(only if 
continuing 
pacritinib/ 
placebo as an 
outpatient) 
 
 
Serum chemistry8 
x 
 
Daily 
(Days 2 through 
28) 
x 
x 
 
 
Liver function 
panel9 
x 
 
Days 8, 15, 22, 
and 28;  
x 
x 
 
 
CBC10 
x 
 
Daily 
(Days 2 through 
28) 
x 
x 
 
 
WBC differential11 
x 
 
Days 8, 15, 22, 
and 28  
x 
x 
 
 
RT-PCR test or 
antigen-based test 
for SARS-CoV-212 
x 
 
 
 
 
 
 
Coagulation tests13 
x 
 
Days 8, 15, 22, 
and 28  
x 
x 
 
 
Markers of disease 
severity14 
x 
 
Days 3, 8, 15, 
22, and 28  
x 
x 
 
 
Serum pregnancy 
test15 
x  
 
 
 
 
 
 
Chest imaging16 
x 
 
 
 
 
 
 


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Table 1 
PRE-VENT Phase 2 (PAC319) Schedule of Assessments 
Study Day 
Screening 
Window1 
Pre-Dose 
(Day 1) 
Inpatient 
Assessment 
EOT  
(For Inpatients 
Only) 
Day of Hospital 
Discharge2 
Outpatient3 
Assessment 
30-day 
Post-EOT 
Follow-up 
Window 
 
± 0 days 
 
 
 
 
± 3 days 
Documentation of 
oxygen delivery 
method17 
x 
x  
(Unless the same 
time point as 
Screening) 
Daily 
(Days 2 to 28) 
x 
x 
 
 
Highest oxygen 
delivery flow rate 
(if on non-invasive 
oxygen) 
 
x 
Daily 
(Days 2 to 28) 
x 
x 
 
 
Highest %FiO2 (if 
on CPAP, BiPAP, 
or IMV) 
x 
x 
Daily 
(Days 2 to 28) 
x 
 
 
 
Highest PEEP (if 
on positive 
pressure 
ventilation) 
x 
x 
Daily 
(Days 2 to 28) 
x 
 
 
 
Lowest PaO2:FiO2 
ratio (if applicable)  
 
 
Daily 
(Days 2 to 28) 
x 
x 
 
 
Randomization 
 
x 
 
 
 
 
 
Administer 
pacritinib/placebo3,
18 
 
x 
Daily 
(Days 2 through 
14)18 
x 
x 
(If on Days 2 to 
14)18 
 
 
Documentation of 
pacritinib/placebo 
dosing18 
 
x 
Daily 
(Days 2 through 
14) 
x 
x18 
x 
 
Adverse events3,19 
 
x 
Daily 
(Days 2 through 
28) 
x 
x  
x 
x 


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Table 1 
PRE-VENT Phase 2 (PAC319) Schedule of Assessments 
Study Day 
Screening 
Window1 
Pre-Dose 
(Day 1) 
Inpatient 
Assessment 
EOT  
(For Inpatients 
Only) 
Day of Hospital 
Discharge2 
Outpatient3 
Assessment 
30-day 
Post-EOT 
Follow-up 
Window 
 
± 0 days 
 
 
 
 
± 3 days 
Concomitant 
medications3,20 
x 
x 
Daily 
(Days 2 through 
28) 
x 
x 
x 
x 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BiPAP = bilevel positive airway pressure; CBC = complete blood count; 
CK = creatine kinase; CPAP = continuous positive airway pressure; CRF = case report form; CRP=C-reactive protein; ECG = electrocardiogram; ECMO = 
extracorporeal membrane oxygenation; EOT = End of Treatment; FiO2 = fraction of inspired oxygen; HRmax = maximum documented heart rate during 
calendar day; IMV = invasive mechanical ventilation; ICF = informed consent form; INR = international normalized ratio; PaO2 = partial pressure of 
oxygen; PEEP = positive end-expiratory pressure; PTT = partial thromboplastin time; RT-PCR = reverse transcriptase polymerase chain reaction; 
SARS-CoV-2 = severe acute respiratory distress syndrome coronavirus 2; SpO2 = blood oxygen saturation; Tmax = maximum documented temperature 
during calendar day; WBC = white blood cell WOCBP = women of child-bearing potential. 
  Note: Screening and randomization may occur on either Day -1 or Day 1.  Patients may be screened, randomized, and start treatment on the same day 
(Day 1).  Patients must provide informed consent within 96 hours after hospital admission. 
• 
Clinical laboratory assessments (serum chemistry, liver function panel tests, CBC with differential, and coagulation tests) obtained within 24 hours 
prior to the start of Screening may be used in determination of eligibility and do not need to be repeated. 
• 
ECG assessments performed within 48 hours prior to the start of Screening may be used in determination of eligibility and do not need to be 
repeated. 
• 
Chest imaging (performed in the ER or upon hospital admission) may be used for documentation and does not need to be repeated. 
  Assessments required on the day of hospital discharge do not need to be repeated if they are already performed that day as part of the protocol-defined 
inpatient assessments for that study day. 
  Outpatient assessments should be based on weekly telephone/videoconference communication with the patient to document an evaluation of the daily 
7-point ordinal scale score for the days between contacts confirmation of pacritinib/ placebo dosing if continuing on treatment as an outpatient, AEs, and the 
use of concomitant medications.  More frequent telephone/videoconference contact may occur as needed to supplement the above assessments.  Review of 
medical records may also be performed as needed to supplement these assessments; medical records should be reviewed for patients who cannot be reached 
by telephone/videoconference. 
  Vital signs include blood pressure, pulse, respiratory rate, temperature, SpO2, and body weight. 
  The 7-point ordinal scale of clinical status is as follows: category 7 = death; 6 = hospitalization, requiring IMV and/or ECMO; 5 = hospitalization, on 
non-invasive positive pressure ventilation or high-flow nasal cannula; 4 = hospitalization, requiring supplemental oxygen not meeting the criteria for 
categories 5 or 6; 3 = hospitalization, not requiring supplemental oxygen; 2 = not hospitalized but unable to resume normal activities; 1 = not hospitalized 
with resumption of normal activities. 
  Any physical examination performed as part of routine care on Day 1 prior to signing of informed consent may be used for documentation 


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  ECG will be performed at Screening (may be performed within 48 hours prior to the start of Screening), Day 3, Day 8, Day 15 or EOT, Day 22, Day 28, and 
on the day of hospital discharge if before EOT.  ECGs are not required after hospital discharge but must be performed on the day of discharge if the patient 
will be continuing pacritinib/placebo as an outpatient.  Results from unscheduled ECG assessments should be entered into the electronic database using an 
Unscheduled ECG CRF.  ECGs should be assessed using at least 3 leads; rhythm strips from telemetry monitoring are acceptable. 
  Serum chemistry, which includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, and magnesium, will be 
evaluated at Screening (the results of laboratory assessments performed in the ER or upon hospital admission that are relevant for the determination of 
eligibility may be used to confirm eligibility provided that they have been performed within 24 hours prior to the start of Screening) and daily from Days 2 
to 28 or EOT, and on the day of hospital discharge.  Serum chemistry tests are not required after hospital discharge.  Results from unscheduled serum 
chemistry tests should be entered into the electronic database using an Unscheduled Serum Chemistry CRF.    
  Liver function panel, which includes AST, ALT, alkaline phosphatase, total bilirubin, and albumin will be evaluated at Screening (the results of laboratory 
assessments performed in the ER or upon hospital admission that are relevant for the determination of eligibility may be used to confirm eligibility provided 
that they have been performed within 24 hours prior to the start of Screening), Day 8, Day 15 or EOT, Day 22, Day 28, and on the day of hospital discharge.  
Liver function panel tests are not required after hospital discharge.  Results from unscheduled liver function panel tests should be entered into the electronic 
database using an Unscheduled Liver Function Panel CRF. 
  CBC, which includes WBC count, hemoglobin, hematocrit, and platelet count, will be evaluated at Screening (the results of laboratory assessments 
performed in the ER or upon hospital admission that are relevant for the determination of eligibility may be used to confirm eligibility provided that they 
have been performed within 24 hours prior to the start of Screening) and daily from Days 2 to 28 or EOT, and on the day of hospital discharge.  Hematology 
tests are not required after hospital discharge.  Results from unscheduled hematology tests should be entered into the electronic database using an 
Unscheduled Hematology CRF. 
  WBC differential will be evaluated at Screening (the results of laboratory assessments performed in the ER or upon hospital admission that are relevant for 
the determination of eligibility may be used to confirm eligibility provided that they have been performed within 24 hours prior to the start of Screening), 
Day 8, Day 15 or EOT, Day 22, Day 28, and on the day of hospital discharge. 
  SARS-CoV-2 RT-PCR test or an antigen-based test from a respiratory, nasopharyngeal, saliva, blood, or stool specimen at Screening or documented within 
1 week prior to the start of Screening. 
  Coagulation tests (INR, PTT, and fibrinogen) will be performed at Screening (the results of laboratory assessments performed in the ER or upon hospital 
admission that are relevant for the determination of eligibility may be used to confirm eligibility provided that they have been performed within 24 hours 
prior to the start of Screening), Day 8, Day 15 or EOT, Day 22, Day 28, and the day of hospital discharge.  Coagulation testing does not need to be 
performed after hospital discharge.  Results from unscheduled coagulation tests should be entered into the electronic database using an Unscheduled 
Coagulation CRF. 
  Blood samples for markers of disease severity (CRP, ferritin, D-dimer, IL-6, troponin I, LDH, BNP, procalcitonin, CK, and triglycerides) will be collected at 
Screening (may be performed within 24 hours prior to the start of Screening), before the morning dose on Day 3, Day 8, Day 15 or EOT, Day 22, Day 28, 
and the day of hospital discharge.  These markers do not need to be assessed after hospital discharge.  The assessments for markers of disease severity are 
required if they can be performed at a local laboratory or if the study center has access to an external laboratory where the samples can be sent for analysis.  
If a study center does not have access to a local or external laboratory that can perform these assessments, the investigator must provide written confirmation 
of the inability to perform the assessment(s), and approval from the CTI Medical Monitor is required to omit the assessment(s).  Results from unscheduled 
tests for markers of disease severity should be entered into the electronic database using an Unscheduled Markers of Disease Severity CRF. 
  WOCBP must have a serum pregnancy test prior to randomization, which may be performed at any time after arrival to the emergency room or hospital 
admission. 
  Chest imaging assessments performed in the ER or upon hospital admission may be used for screening documentation. 


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  Oxygen delivery method may include nasal cannula, non-rebreather, non-invasive positive-pressure ventilation (eg, CPAP or BiPAP), or IMV.  If multiple 
delivery methods were used, the method that provides the highest concentration of oxygen will be documented. 
  Patients will receive pacritinib/placebo from Day 1 through Day 14.  Assigned therapy may be given for an additional 7 days (for a total of 21 days), with the 
approval of the Medical Monitor if, in the opinion of the investigator, the patient’s clinical signs and symptoms are improving and the potential benefit 
outweighs the potential risk.  In the event of hospital discharge, patients will complete treatment with the assigned therapy as an outpatient and 
documentation of dosing is to recorded during outpatient assessment via telephone/videoconference. 
  AEs will be documented during the clinical study from the time the patient is randomized through 30 days following the last dose of pacritinib/placebo. 
  Concomitant medications will be documented from the time of consent through 30 days following the last dose of pacritinib/placebo. 
 


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1 BACKGROUND INFORMATION 
1.1 
COVID-19 
1.1.1 
Clinical Presentation and Disease-Related Symptoms 
Coronavirus disease 2019 (COVID-19) is a viral infection due to the severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2), a positive-sense, single-stranded, enveloped RNA virus 
that can cause life-threatening infection, and has recently become a global pandemic.  Overall 
mortality rate from COVID-19 is approximately 3% but reaches approximately 25% in patients 
who require hospitalization (Zhou et al 2020).  Mortality from COVID-19 is largely due to the 
development of two sequelae: acute respiratory distress syndrome (ARDS), a syndrome of 
widespread pulmonary inflammation leading to severe hypoxemia, and cytokine storm, an 
exaggerated systemic inflammatory response that can lead to shock and multiorgan failure.  To 
date, no therapy has proven effective for treating or preventing these complications of 
COVID‑19 beyond supportive care.  Thus, there is an urgent unmet need for novel therapies to 
treat or prevent the inflammatory sequelae of COVID-19. 
ARDS is mediated by cellular infiltration and inflammation of the lung, causing hypoxemic 
respiratory failure (Zhou et al 2020).  The interleukin (IL)-6 is an important inflammatory 
mediator that has been linked to the pathogenesis of both ARDS and cytokine storm 
(Meduri et al 1995).  Patients with COVID-19 have markedly increased plasma levels of IL-6.  
Based on the published experience of cases from Wuhan, China, elevated levels of ferritin, a 
blood protein containing iron, and IL-6 were both associated with mortality, suggesting that 
death may be driven by a hyperinflammatory response to the virus. 
IL-6 induces differentiation of T helper 17 (Th17) cells.  Th17 cells are critical players in cellular 
host defense against extracellular pathogens such as viruses, as they mediate the recruitment of 
neutrophils and macrophages to infected tissues.  Emerging evidence implicates Th17 cells in the 
pathogenesis of ARDS (Yu et al 2015; Mikacenic et al 2016; Li et al 2015).  Supporting 
evidence includes an autopsy study of victims of COVID-19 that showed classic histological 
findings of ARDS and markedly increased concentrations of Th17 cells (Xu et al 2020).  Th17 
activation may potentiate the cytokine storm and macrophage activation phenotypes seen in 
patients with COVID-19 who have elevated levels of ferritin, IL-2, IL-6, IL-7, IL-10, 
granulocyte-macrophage colony-stimulating factor, interferon-gamma inducible protein 10, 
macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha (Ruan et al 2020; 
Huang et al 2020). 
These novel findings suggest that blocking IL-6 signaling and attenuating Th17 cell 
differentiation could prevent or mitigate ARDS and cytokine storm due to COVID-19.  Thus, a 
targeted immunomodulatory strategy is necessary. 
1.1.2 
Current Strategies for Prevention and Treatment of COVID-19 
There is currently no vaccine available to protect from SARS-CoV-2 infections and no approved 
treatments of COVID-19 (Zhou et al 2020).  Rigorous self-isolation and preventative lockdown 
measures have been put in place to mitigate the rate of SARS-CoV-2 infections, and patients 
with COVID‑19 are mainly administered supportive care.  Therapeutic interventions are usually 
used only in symptomatic patients with COVID-19, since asymptomatic patients demonstrate 


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better survival and are asked to self-isolate.  Current therapeutic approaches are aimed at 
mitigating specific COVID-19 symptoms, such as ARDS by placing patients on mechanical 
ventilatory support, and at evaluating novel antivirals to treat the cytokine storm. 
1.1.3 
Pacritinib as a Therapeutic Strategy for COVID-19-Related ARDS and 
Cytokine Storm 
The Janus kinases (JAKs) are a family of cytoplasmic tyrosine kinases (TYKs) consisting of 
JAK1, JAK2, JAK3, and TYK2.  They play a pivotal role in the signaling pathways of numerous 
cytokines, hormones, and growth factors.  Their intracellular substrates include the signal 
transducer and activator of transcription (STAT) family of proteins.  The JAK/STAT pathways, 
through the proper actions of the ligands, regulate important physiological processes, such as the 
immune response to viruses, hematopoiesis, among others. 
Pacritinib is a highly selective inhibitor of JAK2, with no off-target effects on JAK1 (Singer et al 
2016).  The major advantage of pacritinib for the treatment of patients with COVID-19 is its 
ability to block IL-6 downstream signaling and prevent induction of Th17 cells, thereby 
potentially preventing the pathogenesis of both ARDS and cytokine storm while preserving 
antiviral immunity. 
The JAK2/STAT3 signaling pathway is necessary for the differentiation and function of Th17 
cells.  Selective JAK2 inhibition decreases IL-17 production by dendritic cell 
(DC)‑allostimulated cluster of differentiation 4 (CD4+) T cells and suppresses expression of the 
retinoic acid receptor-related orphan receptor gamma t, a key Th17 cell differentiation factor 
(Betts et al 2011).  A recent study demonstrated that JAK2 inhibition can selectively inhibit the 
Th17 cell response in COVID-19 (Wu et al 2020).  Furthermore, JAK2/STAT3 is required for 
IL-6 signaling (Johnson et al 2018), which stimulates Th17 cell response and which has been 
implicated in the pathogenesis of COVID-19 (Gong et al 2020).  IL-6 blockade via JAK2 
inhibition may have several salubrious effects in patients with COVID-19.  JAK2 inhibitors have 
been used to abrogate the Th17 cell pathway in the setting of acute graft-versus-host disease 
(GVHD), which is characterized by elevated levels of Th17 cells in affected organs.  Ruxolitinib, 
a JAK2 inhibitor, has been successful in treating steroid-refractory acute GVHD (Meduri et al 
1995) and has been proposed as a novel treatment for COVID-19.  Similarly, pacritinib has 
shown potential efficacy in reducing GVHD in early phase studies, with reduction in Th17 cell 
cytokines (Betts et al 2011). 
As a non-selective JAK1 and JAK2 inhibitor, ruxolitinib may be associated with reduced 
antiviral response and viral clearance (Heine et al 2013a; Heine et al 2013b).  In contrast to 
JAK2/STAT3 signaling, JAK1/STAT1 is necessary for interferon-γ production, which is 
important in containing infections.  Inhibitors of JAK1 therefore may increase the risk of 
infection.  Multiple studies have demonstrated increased risk of fungal, bacterial, and viral 
infections in the setting of JAK1 inhibitors, including tofacitinib (which has a black box warning 
for increased risk of infection) and ruxolitinib (Sant'Antonio et al 2019).  Pacritinib, as a 
selective JAK2 inhibitor without effects on JAK1, was not associated with an excess in 
infections compared to best available therapy (BAT) in two large Phase 3 myelofibrosis trials, 
nor was it associated with opportunistic infections (Mascarenhas et al 2018; Mesa et al 2017).  In 
addition, stimulation of DCs with influenza virus peptide in the presence of selective JAK2 
inhibition elicited an intact cytotoxic T cell response, leading to the conclusion that, in contrast 


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to nonselective JAK inhibitors, JAK2 selective inhibitors did not increase the risk of viral 
infection (Betts et al 2011). 
In addition to its desirable selective kinase inhibition profile on the JAKs, pacritinib also inhibits 
interleukin-1 receptor-associated kinase-1 (IRAK1) and colony‑stimulating factor 1 receptor 
(CSF1R), both of which may be targets of interest in COVID-19 (Singer et al 2016; Singer et al 
2018).  IRAK1 is a key component of the inflammatory cascade that acts downstream of IL-1 
and toll-like receptor (TLR) and potentiates IL-6.  IRAK1 is an emerging target for inflammatory 
and malignant diseases, including sepsis.  In fact, among patients with sepsis, those with a 
variant haplotype of IRAK1 leading to elevated levels of the nuclear factor kappa-light chain-
enhancer of activated B cells transcription factor were more likely to develop shock, prolonged 
respiratory failure, and death (Arcaroli et al 2006).  CSF-1R is a cell surface receptor for the 
colony-stimulating factor 1, a cytokine that controls production, function, and differentiation of 
macrophages, and therefore a potential target in the setting of viral-induced macrophage 
activation, which is thought to occur in COVID-19 (Mehta et al 2020). 
Pacritinib represents a potential treatment for the pathologic inflammation associated with 
COVID-19 leading to ARDS.  As a selective JAK2 inhibitor, pacritinib may ameliorate the 
effects of cytokine storm via inhibition of Th17 cell differentiation and IL-6 blockade while 
permitting antiviral response via JAK1.  Additional potential therapeutic pathways exist via 
inhibition of IRAK1 and CSF-1R.  We proposed a randomized placebo-controlled study of 
standard-of-care with or without pacritinib to treat and prevent worsening of COVID-19 in 
hospitalized patients with severe disease with or without cancer.  
1.2 
Pacritinib 
Pacritinib is a novel JAK2/IRAK1/CSF-1R inhibitor that is being developed as a treatment for 
advanced myelofibrosis.  It has been studied in one Phase 2 dose-ranging study (PAC203) and 
two large randomized Phase 3 studies (PERSIST-1 and PERSIST-2).  In all studies, pacritinib 
has demonstrated clinical efficacy based on spleen volume response and a reduction in total 
symptom scores (TSS).  A randomized Phase 3 trial of pacritinib for the treatment of 
myelofibrosis and severe thrombocytopenia (PACIFICA) is currently enrolling.  In the Phase 2 
PAC203 study, the most common nonhematologic adverse events (AEs) were gastrointestinal, 
including diarrhea (30%), and nausea (28%); these were largely low grade and manageable with 
standard antidiarrheal medications.  The most common hematologic event reported was 
thrombocytopenia (35%), which was manageable with dose modifications and which was not 
associated with serious bleeding events (Gerds et al 2019). 
1.2.1 
Pharmacology 
Pooled Pharmacokinetic/Pharmacodynamic Modeling 
Population pharmacokinetics (PK) for pacritinib was established based on pooled data from 
16 studies including 630 patients who received pacritinib at total daily doses ranging from 100 to 
600 mg.  Pacritinib population PK was characterized by a two-compartment disposition model 
with first-order absorption and elimination.  Systemic exposure (area under the 
concentration-time curve, maximum concentration, and minimum concentration) for the 100 mg 
once daily (QD) and 100 mg twice daily (BID) regimens was generally lower than that achieved 
with higher doses (200 mg BID and 400 mg QD), although there was an overlap.  Population 
PK/pharmacodynamics (PD) modeling and exposure-response analysis confirmed that higher 


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pacritinib doses and exposures were associated with greater reductions in both spleen volume 
and TSS. 
The half maximum inhibitory concentration (IC50) of pacritinib against the key kinases it inhibits 
is as follows: JAK2 (6 nM), IRAK1 (13.6 nM), and CSF-1R (39.5 nM).  Pacritinib does not 
inhibit JAK1 at physiologic doses.  Oral dosing of 200 mg BID of pacritinib provides more than 
200 nM free drug concentration, which is many fold higher than the IC50. 
As some patients with COVID-19 may be unable to swallow or intubated, pacritinib/placebo 
may require administration via an oro- or nasogastric tube.  Currently, there are no data available 
regarding administration of pacritinib as a suspension via enteral tube.  However, currently 
available PK data and physicochemical properties do not suggest any untoward effects with 
enteral administration of pacritinib in suspension.  Pacritinib is a conventional 
immediate-release, non-granulated powder mixed with excipients in a capsule dosage form; 
hence it is suitable for opening the capsule and flushing down enteral tubes after mixing with 
water or commonly used liquids without substantially impacting safety and efficacy.  Pacritinib 
is poorly soluble in water in the pH range of 3.0-9.0; thus, suspension of the capsule contents in 
liquid before dosing is expected to have a minimal effect on the rate and extent of drug 
absorption. 
1.2.2 
Preclinical Toxicology 
The adverse effects of pacritinib were evaluated in 30-day repeated oral dose toxicity studies, 
with 14-day recovery in both mice and dogs, and in 26- and 39-week chronic toxicity studies in 
mice and dogs, respectively.  Key findings included dose-dependent leukopenia accompanied by 
neutropenia (dog) and neutrophilia (mice) that partially reversed during recovery.  Mice also 
showed dose-dependent but reversible thrombocytosis and anemia.  In the chronic toxicity 
studies, low-magnitude decreases in neutrophils and red blood cell (RBC) parameters were 
observed.  No treatment-related hepatic changes were observed, with the exception of increased 
aspartate transaminase (to +109%, male dogs) and increased triglycerides (to +57%, male and 
female dogs).   
In the 30-day study in dogs, animals receiving mid and high dosages of pacritinib experienced 
vomiting and diarrhea that increased in severity despite treatment with antiemetic and 
antidiarrheal medication.  Similarly, in the 39-week study in dogs, an increased incidence of 
nausea and vomiting was observed at dosages of 20 mg/kg/day and higher.  Periods of low food 
consumption in individual animals receiving 40 and 50 mg/kg/day were accompanied by rapid 
weight loss, which was controlled and reversed with subcutaneous fluid and supplemental food, 
and were considered treatment related and adverse. 
Based on these studies, the no observed adverse effect level was determined to be 100 mg/kg 
BID in mice and 10 mg/kg BID in dogs. 
Please refer to the IB for available information concerning the nonclinical safety of pacritinib. 
1.2.3 
Summary of Clinical Pharmacology and Early Phase Studies With 
Healthy Subjects of Pacritinib 
Two PK studies for pacritinib have been completed in healthy subjects, including a food effect 
study (SB1518-2010-006) characterizing the effects of a high-calorie, high-fat meal on the 
bioavailability and PK of pacritinib and a study assessing inter- and intra-individual variability of 


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oral pacritinib in healthy subjects under fasted conditions at 100, 200, and 400 mg doses 
(SB15182010-004).  In addition, the single- and multiple-dose population PK of pacritinib has 
been characterized following multiple-dose administration of pacritinib in two studies 
(SB1518-2007-001 and SB1518-2008-003) in patients with advanced myeloid malignancies.  
After administration of single doses of pacritinib in a randomized, three-treatment, three-period 
crossover study (SB1518-2010-004) in healthy subjects under fasted conditions, peak plasma 
concentrations were reached at a median time of maximum concentration (Tmax) ranging from 
4.5 to 5.5 hours across the 100 to 400 mg dose range.  While between-patient variability was 
relatively high (28% to 45%), the within-patient variability was low (13% to 15%), highlighting 
the consistent systemic exposure for pacritinib in individual patients.  The mean elimination 
half-life was approximately 34 hours and was not dependent on dose.  After oral administration 
of single 200 mg doses of pacritinib under fed and fasted conditions, no effect of food on 
absorption of pacritinib was observed.  Given these data, pacritinib can be orally administered 
without regard to timing of meals. 
Pooled analyses of PK assessments from the two clinical studies in patients at pacritinib dosages 
up to 600 mg QD showed slow absorption (Tmax 4 to 6 hours) and dose-related increases in 
systemic exposure up to 400 mg QD.  The rate of absorption was linear at doses up to 300 mg 
and thereafter appeared to be rate limited.  Therefore, modeling suggested that, at doses of over 
200 mg per day, divided doses would yield increased steady study blood levels.  Beyond the 
400 mg QD dosage, there was a minimal increase in exposure with doses up to 600 mg QD, 
suggesting the involvement of a saturable process in oral absorption of pacritinib. 
On the basis of these studies, a total daily dose of 400 mg was selected for future study.  
Subsequent Phase 3 studies, described in Section 1.2.4, used 400 mg QD and 200 mg BID 
dosing.  
1.2.4 
Overview of Clinical Safety of Pacritinib 
Approximately 1128 patients have received pacritinib in 16 completed studies, including 
713 patients with myelofibrosis who were assigned to a pacritinib arm.  Completed studies 
include two controlled studies in myelofibrosis (PERSIST-1 and PERSIST-2), five uncontrolled 
clinical studies in patients with cancer (including the PAC203 Phase 2 dose finding study in 
patients with myelofibrosis), and nine clinical pharmacology/PK studies. 
Among the patients with myelofibrosis treated with pacritinib in the completed controlled and 
uncontrolled studies, the most commonly (> 10% of all patients) reported treatment-emergent 
adverse events (TEAEs) related to study drug, by preferred term (PT), were in the system organ 
class of gastrointestinal (GI) disorders, including diarrhea (56%), nausea (34%), and vomiting 
(20%), and the System Organ Class of blood and lymphatic system disorders, including 
thrombocytopenia (25%) and anemia (25%).  Although GI-related events were common, they 
were generally reversible, were of low grade, and rarely led to treatment discontinuation. 
Overview of the PAC203 Phase 2 Dose-Finding Study in Patients with Myelofibrosis 
PAC203 was a dose-finding study in patients with advanced myelofibrosis who experienced 
intolerance or treatment failure with ruxolitinib.  Compared to the PERSIST studies, PAC203 
included additional eligibility and monitoring guidelines to mitigate the risk of cardiac and 
bleeding events.  Enrollment was not restricted based on platelet count.  The primary objective of 
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for safety and efficacy established in previous phase 1/2 clinical studies and the phase 3 
PERSIST-1 and PERSIST-2 studies.  Patients were randomized 1:1:1 to pacritinib 200 mg BID, 
pacritinib 100 mg BID, or pacritinib 100 mg QD.  Of the 161 patients who were randomized and 
who received treatment, median platelet count was 55,000/µL, and hemoglobin was < 10 g/dL in 
70.8% of patients (n = 114).  Median duration of treatment was 23 weeks (100 mg QD), 20 
weeks (100 mg BID), and 21 weeks (200 mg BID). 
At Week 24, the spleen volume reduction response rate (35% reduction) was highest in the 
200 mg BID arm (9.3%) compared to lower dose arms (100 mg QD: 0% and 100 mg BID: 
1.8%).  The TSS response rate (50% reduction) was similar across all arms (100 mg QD: 7.7%, 
100 mg BID:  7.3%, and 200 mg BID: 7.4%), with deepest responses in questions relating to 
spleen symptoms (satiety, abdominal discomfort, and left rib pain) and cytokine-related 
symptoms (night sweats, itching, and bone pain), particularly at 200 mg BID.  The percentage of 
patients describing at least minimal improvement of their symptoms based on the Patient Global 
Impression Assessment (PGIA) at Week 24 was greatest in the 200 mg BID arm (33.3%, 
n = 18/54) compared with 100 mg BID (23.6%, n = 13/55) or 100 mg QD (19.2%, n = 10/52). 
The majority of non-hematologic AEs was mild or moderate in severity, and rates were generally 
similar across dosing arms with the exception of gastrointestinal events, which occurred more 
commonly in patients treated at 200 mg BID (39/54, 72.2%) than in patients treated at lower 
doses (100 mg QD: 26/52, 50.0%; 100 mg BID: 30/55, 54.5%).  These events were largely grade 
1 or 2 and usually occurred within the first 8 weeks on treatment.  Diarrhea was common but 
generally manageable with standard antidiarrheal agents and tended to be short-lived: the median 
duration of pacritinib-related diarrhea was 2 weeks.  The most common hematologic AEs were 
thrombocytopenia and anemia, both of which occurred more frequently in patients treated at 
200 mg BID (40.7% and 24.1% respectively).  Cardiac events were more common in patients 
treated at 200 mg BID (40.7%, n = 22) than in patients treated at lower doses (100 mg QD: 
21.2%, n = 11; 100 mg BID: 21.8%, n = 12) but were largely grade 1 or 2 in severity, with the 
most common being peripheral edema (200 mg BID: 16.7%) and QT prolongation (200 mg BID: 
7.4%).  There was no excess in grade 3 or 4 cardiac events in patients treated at the highest dose 
(100 mg QD: 5.8%, n = 3; 100 mg BID: 5.5%, n = 3; and 200 mg BID: 3.7%, n = 2; no grade 4 
events).  The mean change in corrected QT interval (QTc) between Baseline and Week 24 was 
roughly +10 msec on all arms; no patient had a QTc > 500 msec.  Bleeding events were more 
common in patients treated at 200 mg BID (42.6%, n = 23) than in patients treated at lower doses 
(100 mg QD: 36.5%, n = 19; 100 mg BID: 25.5%, n = 14) but were largely grade 1 or 2 in 
severity, with the most common being epistaxis (200 mg BID: 14.8%) and bruising (200 mg 
BID: 9.3%).  There was no excess in grade 3 or 4 bleeding events in patients treated at the 
highest dose (100 mg QD: 7.7%, n = 4; 100 mg BID: 3.6%, n = 2; and 200 mg BID: 5.6%, n = 3; 
no grade 4 events).  The rate of fatal events was similar across all arms: 100 mg QD: 7.7%, n = 4 
(sepsis, disease progression, tuberculosis, and general state deterioration); 100 mg BID: 5.5%, 
n = 3 (myelofibrosis, subdural hemorrhage, and heart failure); and 200 mg BID: 5.6%, n = 3 
(sepsis, respiratory failure, and subdural hematoma). 
2 STUDY RATIONALE AND OBJECTIVES 
This study is being conducted to establish the safety and efficacy of pacritinib + standard of care 
(SOC) compared to placebo + SOC in hospitalized patients with severe COVID-19 with or 
without cancer as the proportion of patients who progress to IMV and/or ECMO or die by 


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Day 28.  This study will additionally confirm the safety and efficacy of pacritinib administered at 
400 mg QD on Day 1 followed by 200 mg BID for up to 14 days, with the option of extending an 
additional 7 days (for a total of 21 days) with the approval of the Medical Monitor if, in the 
opinion of the investigator, the patient’s clinical signs and symptoms are improving and the 
potential benefit outweighs the potential risk.  Determination of the selected dose is detailed in 
Section 3.1. 
2.1 
Justification of Included Patient Population 
The study population will consist of hospitalized adult patients with severe COVID-19 with or 
without cancer.  Severe COVID-19 is defined as confirmed disease in patients who are 
hospitalized with hypoxia [SpO2 ≤93% on room air], respiratory rate >30, PaO2/FiO2 <300, but 
do not require IMV (NIH COVID-19 Treatment Guidelines 2020).  Patients with moderate 
COVID-19 are not eligible for the study because it is likely that they will not be receiving 
supplemental oxygen and will not be hospitalized.  Patients with critical COVID-19 are not 
included because the goal of pacritinib therapy is to prevent patients from progressing to the 
acute respiratory distress syndrome associated with COVID-19. 
2.2 
Independent Data Monitoring Committee 
This study will be monitored by an Independent Data Monitoring Committee (IDMC).  The 
IDMC will comprise a multidisciplinary group of at least three voting members in the fields of 
hematology, infectious disease, and biostatistics.  Additional personnel may be added to the 
IDMC at the request of the IDMC membership.  The membership, roles, and responsibilities of 
the IDMC will be fully defined by the IDMC charter. 
The IDMC will make independent recommendations to the Sponsor on study continuation 
(continue without modification, continue with modification, or terminate) and on patient 
enrollment (hold or stop enrollment or enroll additional patients). 
The IDMC charter will be written in collaboration between the Sponsor and members of the 
IDMC.  In keeping with the terms of the charter, each IDMC meeting will have an open and 
closed session. 
The IDMC will convene for a formal safety review after the first 40 patients (approximately 
20 patients per arm) have completed treatment and then quarterly thereafter.  Subsequent 
meetings will be triggered at the interim analysis.  Ad hoc meetings can be called at any time by 
either the IDMC or by CTI. 
Meeting minutes will be generated from each IDMC meeting and provided to the Food and Drug 
Administration (FDA) within 10 business days of the meeting conclusion. 
2.3 
Study Objectives 
2.3.1 
Primary Objective 
To compare the efficacy of pacritinib + standard of care (SOC) versus placebo + SOC in 
hospitalized patients with severe COVID-19 with or without cancer, as the proportion of patients 


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who require invasive mechanical ventilation (IMV) and/or extracorporeal membrane 
oxygenation (ECMO) or die by Day 28. 
Severe COVID-19 is defined as confirmed disease in patients who are hospitalized with hypoxia 
(SpO2 ≤93% on room air at sea level), respiratory rate >30, PaO2/FiO2 <300, but do not require 
IMV.   
2.3.2 
Secondary Objectives 
1. To compare the number of ventilator-free days, defined as the number of days that 
patients are alive and not intubated, from randomization to Day 28 between pacritinib + 
SOC versus placebo + SOC 
2. To compare the mortality rate between pacritinib + SOC versus placebo + SOC at Day 28 
3. To compare the mortality rate between pacritinib + SOC versus placebo + SOC at Day 15 
4. To compare the time to improvement by at least 2 points relative to Baseline on the 
7-point ordinal scale of clinical status between pacritinib + SOC versus placebo + SOC 
5. To compare the clinical status assessed by the 7-point ordinal scale of clinical status at 
Days 8, 15, 22, and 28 between pacritinib + SOC versus placebo + SOC 
6. To compare the rate of use of immunomodulatory agents as treatment for COVID-19 
during the 28 days following randomization between pacritinib + SOC versus placebo + 
SOC 
7. To evaluate the toxicity profile of pacritinib therapy in hospitalized patients with severe 
COVID-19 with or without cancer 
2.3.3 
Tertiary Objectives 
To evaluate the treatment effects of pacritinib + SOC on the following markers of disease 
severity: 
• C-reactive protein (CRP) 
• Ferritin  
• D-dimer  
• IL-6 
• Troponin-I 
• Lactate dehydrogenase (LDH) 
• Brain natriuretic peptide (BNP) 


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• Procalcitonin 
• Triglycerides 
• Creatine kinase (CK) 
3 STUDY DESIGN 
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of pacritinib in hospitalized patients with severe COVID-19 with or without 
cancer.  Severe COVID-19 is defined as confirmed disease in patients who are hospitalized with 
hypoxia (SpO2 ≤93% on room air), respiratory rate >30, PaO2/FiO2 <300, but do not require 
IMV. 
Patients will be randomized 1:1 to receive pacritinib (400 mg QD on Day 1, then 200 mg BID 
from Day 2 to Day 14) + SOC or placebo + SOC stratified by age (< 60 years versus ≥ 60 years) 
and the 7-point ordinal scale of clinical status scale (baseline 3 or 4 versus 5).  The study 
duration will be 8 weeks. 
Assigned treatment will continue for up to Day 14 or until the patient experiences intolerable 
adverse events (AEs), withdraws consent, or initiates another investigational therapy, or until the 
study is terminated.  Assigned therapy may be given for an additional 7 days (for a total of 
21 days) with the approval of the Medical Monitor if, in the opinion of the investigator, the 
patient’s clinical signs and symptoms are improving and the potential benefit outweighs the 
potential risk.  In the event of hospital discharge, patients will complete treatment with the 
assigned therapy as an outpatient. 
The primary endpoint is the effect of treatment on the proportion of patients who require IMV 
and/or ECMO or die by Day 28.  
The study will be monitored by an IDMC comprising a multidisciplinary group of at least three 
voting members in the fields of hematology, infectious disease, and biostatistics.  Additional 
personnel may be added to the IDMC at the request of the IDMC membership.  The membership, 
roles, and responsibilities of the IDMC will be fully defined by an IDMC charter.   
Safety will be monitored with physical examinations, clinical laboratory assessments, and 
electrocardiogram (ECG) monitoring for inpatients.  Patients who are discharged from the 
hospital while still on study will be monitored weekly.  Outpatient monitoring will include 
telephone/videoconference contact and may also include review of the patient's electronic 
medical record.  Laboratory and ECG assessments will not be required for monitoring 
outpatients, including those completing their course of study drug.  Specified pacritinib/placebo 
dosage modifications will be followed to address identified abnormalities.  AE data will be 
collected from the time of randomization through 30 days following the last dose of 
pacritinib/placebo.  Serious adverse events (SAEs) assessed as related to pacritinib/placebo or 
study procedure by the investigator or Sponsor shall be followed until the event resolves, 
stabilizes or the patient is lost to follow-up.  SAEs assessed as unrelated to pacritinib/placebo or 
study procedures shall be followed for 30 days after the last dose of pacritinib/placebo, or until 


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the event resolves, returns to baseline, stabilizes, or the patient is lost to follow-up, whichever 
comes first. 
At the request of an investigator, and with agreement of the Chief Medical Officer at CTI, the 
assigned treatment for an individual patient may be unblinded for the purposes of discussing the 
ongoing care of that patient. 
The approximate study duration for each patient will be 8 weeks.  The estimated duration of the 
entire study is approximately 1 year and is subject to increase as patient enrollment increases. 
The schedules of study assessments for all patients are provided in Table 1. 
3.1 
Rationale for Dosage Selection 
The pacritinib IC50 for the therapeutic targets is as follows: 
• JAK2: 6 nM 
• IRAK-1: 13.6 nM 
• CSF-1R: 39.5 nM 
Inhibition of these targets is thought to mediate the cytokine storm and development of acute 
respiratory distress syndrome seen in patients with COVID-19.  The goal of dose selection in this 
study is to rapidly achieve many-fold higher free pacritinib plasma concentrations than the IC50.  
Following oral administration of 200 mg BID and 400 mg QD, free plasma drug concentration 
observed is about 200 nM and 250 nM, respectively.  As COVID-19 is a rapidly progressing 
disease with significant cytokine storm, the treatment goal should be rapid control of cytokine 
storm; hence, the dosage regimen that provides rapid plasma concentration many folds higher 
than IC50 is desired.  Therefore, dosing 400 mg QD on Day 1 followed by 200 mg BID provides 
steady-state equivalent plasma concentration on Day 1, which is similar to the steady-state 
concentration seen with 200 mg BID (Figure 1). 


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Figure 1 
Simulated Median Concentration-Time Course in Myelofibrosis 
Patients (Day 1 to Day 8) 
 
Abbreviations:  BID = twice daily; QD = once daily. 
Based on all available data from pre-clinical studies to clinical data in both healthy subjects and 
patients with hematologic malignancies including myelofibrosis, pacritinib 400 mg QD on Day 1 
followed by 200 mg BID dosing starting on Day 2 has been selected as the dosing for the PRE-
VENT study. 
4 PATIENT SELECTION AND WITHDRAWAL 
4.1 
Target Population 
4.1.1 
Inclusion Criteria  
1. Hospitalized or will be hospitalized prior to randomization for the treatment of severe 
COVID-19 with SARS-CoV-2 infection confirmed by either a) a positive reverse 
transcriptase polymerase chain reaction (RT-PCR) or b) an antigen-based test from any 
respiratory, nasopharyngeal, saliva, blood, or stool specimen at Screening or documented 
within 1 week prior to the start of Screening (Severe COVID-19 is defined as confirmed 
disease in patients who are hospitalized with hypoxia [SpO2 ≤93% on room air], respiratory 
rate >30, PaO2/FiO2 <300, but do not require IMV). 
2. Age ≥ 18 years 
3. Platelet count ≥ 50,000/µL 
4. If fertile, willing to use effective birth control methods during the study 
5. Provision of informed consent within 96 hours after hospitalization 


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4.1.2 
Exclusion Criteria  
1. In the opinion of the investigator, progression to death is imminent and inevitable within 
the next 24 hours, irrespective of the provision of treatments 
2. Currently intubated or intubated between screening and randomization 
3. Suspected active uncontrolled bacterial, fungal, viral, or other infection (besides 
COVID-19) 
4. Prior allogenic hematopoietic stem cell transplantation 
5. Active lung cancer or history of lung cancer within the past 12 months 
6. Any active grade 2 or higher hemorrhage 
7. Any active gastrointestinal or metabolic condition that could interfere with absorption of 
oral medication 
8. Uncontrolled intercurrent illness that, in the judgment of the treating physician, would 
limit compliance with study requirements  
9. Known seropositivity for human immunodeficiency virus with CD4 count < 200/mm3 
within 3 months prior to randomization 
10. Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination 
11. Concurrent enrollment in another interventional trial (investigational COVID-19 antiviral 
studies are permitted) 
12. Serum creatinine > 2.5 mg/dL  
13. Total bilirubin > 4× the upper limit of normal  
14. QT corrected by the Fridericia method (QTcF) prolongation > 480 msec 
15. Known history of New York Heart Association Class II, III, or IV congestive heart 
failure prior to hospital admission  
16. Known allergic reaction to any JAK2 inhibitor  
17. Exposure to any JAK2 inhibitor within 28 days 
18. Currently receiving a strong CYP3A4 inhibitor or strong P450 inducer (Appendix 1 and 
Appendix 2, respectively) and unable to stop the medication prior to the first dose of 
study drug and throughout the duration of study drug administration 
19. Treatment with cytoreductive chemotherapy administered within 14 days prior to 
randomization 


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20. Administration of an IL-1 or IL-6 blocking immunomodulatory agent (such as 
tocilizumab, canakinumab, sarilumab, anakinra) within 48 hours prior to randomization 
21. Currently receiving therapeutic anticoagulation or anti-platelet medication and unable to 
stop the medication prior to randomization.  Prophylactic anticoagulation therapy or 
aspirin (≤ 100mg) are permitted. 
22. Unable to ingest capsules or tablets at randomization 
4.2 
Withdrawal of Patients from Study 
Patients have the right to stop study participation at any time and for any reason without 
prejudice to his or her future medical care.  Patients (or a legally acceptable representative) may 
decline to continue receiving pacritinib/placebo and/or other protocol-required therapies or 
procedures at any time during the study.  Patients will be encouraged to allow continued follow-
up for study procedures and safety monitoring; however, patients may withdraw consent for all 
study procedures or for specific study procedures.  Data collected up to the date of withdrawal of 
consent will be included in the analysis of the study.  The Investigator is to discuss with the 
patient the appropriate procedures for withdrawal from the study.  The Investigator or Sponsor 
has the right to discontinue any patient from study participation. 
Reasons for patient discontinuation may include, but are not limited to, the following: 
• Patient’s request, with or without a stated reason 
• Noncompliance 
• Physician’s decision 
• Sponsor’s discretion 
• Lost to follow-up 
5 METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Eligible patients will be centrally randomized in a 1:1 allocation ratio to receive pacritinib 
(400 mg QD on Day 1, then 200 mg BID from Day 2 to Day 14) + SOC or placebo + SOC 
according to a stratified permuted block design stratified by age (< 60 years versus ≥ 60 years) 
and the 7-point clinical status scale (baseline 3 or 4 versus 5).  Assigned therapy may be given 
for an additional 7 days (for a total of 21 days) with the approval of the Medical Monitor if, in 
the opinion of the investigator, the patient’s clinical signs and symptoms are improving and the 
potential benefit outweighs the potential risk.   
This study is double-blind; the Sponsor, study patients, and Investigators will be blinded to 
treatment assignments.  The IDMC will have access to unblinded data.  Individual patient 
unblinding may occur at the request of the Investigators if necessary for medical reasons and to 
assess suspected unexpected serious adverse reactions. 


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6 STUDY TREATMENT 
6.1 
Study Treatment Administration 
Patients will be supplied with blinded pacritinib 100 mg capsules or matching placebo.  
Table 2. 
Study Treatments 
Treatment 
Dosage/Regimen 
Pacritinib + SOC 
400 mg (4 capsules) QD on Day 1, then 200 mg (2 capsules) BID from Day 2 to 
Day 14 + SOC.  Pacritinib/placebo is administered orally or via oro/nasogastric tube.  
Assigned therapy may be given for an additional 7 days (for a total of 21 days) with 
the approval of the Medical Monitor if, in the opinion of the investigator, the patient’s 
clinical signs and symptoms are improving and the potential benefit outweighs the 
potential risk.  
Placebo + SOC 
4 capsules QD on Day 1, then 2 capsules BID from Day 2 to Day 14 + SOC.  
Pacritinib/placebo is administered orally or via oro/nasogastric tube.  Assigned 
therapy may be given for an additional 7 days (for a total of 21 days) with the 
approval of the Medical Monitor if, in the opinion of the investigator, the patient’s 
clinical signs and symptoms are improving and the potential benefit outweighs the 
potential risk. 
Abbreviations:  BID = twice daily; QD = once daily; SOC = standard of care. 
6.2 
Study Treatment Description and Storage  
6.2.1 
Pacritinib 
Pacritinib for oral or oro/nasogastric tube administration is supplied in capsules containing 
100 mg (as the free base) in body size 0, red cap/gray opaque hard gelatin capsules.  The inactive 
ingredients are microcrystalline cellulose, magnesium stearate, and polyethylene glycol 8000. 
Each capsule contains 146 mg of pacritinib citrate, which is equivalent to 100 mg pacritinib free 
base. 
Direct contact of the powder in pacritinib capsules with the skin or mucous membranes should 
be avoided.  If such contact occurs, affected areas should be washed thoroughly with water. 
Pacritinib capsules should be stored at controlled room temperature 20°C to 25°C or 68°F to 
77°F, with excursions allowed from 15°C to 30°C or 59°F to 86°F.  All pacritinib supplies must 
be kept in a restricted access area. 
6.2.2 
Placebo 
Placebo for oral or oro/nasogastric tube administration will be supplied as capsules that match 
the pacritinib 100 mg capsules in appearance. 
The excipients, container, handling instructions, and storage conditions are the same as those 
described for the pacritinib capsules (Section 6.2.1). 


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6.3 
Dosage, Route, and Mode of Administration 
Patients will take 4 capsules of pacritinib/placebo at one time on Day 1 and two capsules BID 
from Day 2 to Day 14.  Assigned therapy may be given for an additional 7 days (for a total of 
21 days) with the approval of the Medical Monitor if, in the opinion of the investigator, the 
patient’s clinical signs and symptoms are improving and the potential benefit outweighs the 
potential risk.  Pacritinib/placebo will be taken orally or via oro/nasogastric tube at the same time 
of day, with or without food.   
Any missed or vomited doses should not be retaken or replaced. 
6.4 
Drug Accountability 
At the Day 15 or EOT assessment, any unused pacritinib/placebo capsules will be returned to the 
pharmacy.  Compliance with pacritinib/placebo will be reported by the site as the number of 
missed doses.  
6.5 
Pacritinib Treatment Adjustments for Adverse Events 
6.5.1 
Treatment Interruption and Discontinuation 
Safety parameters including AEs, complete blood count (CBC) with differential, serum 
chemistry, and ECGs will be assessed according to protocol.   
Pacritinib/placebo should be interrupted in the setting of certain AEs described below.  Where 
possible, pacritinib/placebo should be held if an invasive procedure, including central venous 
catheter insertion, is performed; drug should be restarted after 24 hours without signs or 
symptoms of active bleeding.  Pacritinib/placebo may also be held at the discretion of the 
investigator. The Medical Monitor should be notified of all such drug holds. 
Pacritinib/placebo should be discontinued in the setting of intolerable AEs described below, or if 
the patient withdraws consent to continue pacritinib/placebo.  Pacritinib/placebo may also be 
discontinued at the discretion of the investigator; the Medical Monitor should be notified of all 
such drug discontinuations. 
6.5.2 
Dosage Management Guidelines for Adverse Events 
In prior studies, pacritinib has been associated with diarrhea, nausea, anemia, thrombocytopenia, 
QTc prolongation (generally mild), and risk of bleeding.  Safety assessments will include 
hematologic parameters (CBC with differential), assessment of organ function (serum 
chemistry), monitoring for QTc prolongation, and general AE monitoring. 
Patients who develop worsening gastrointestinal symptoms with the initiation of 
pacritinib/placebo treatment may be treated with standard antidiarrheal and/or anti-emetic 
medications. 
Patients receiving study drug may also receive treatment-dose anticoagulants or anti-platelet 
agents, if required; patients do not need to discontinue study drug if one of these medications is 


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initiated. However, patients should not receive such agents concomitant with study drug 
administration if their platelet counts drop to < 50,000/µL; prophylaxis-dose anticoagulants are 
permitted for all patients on study.  Treatment-dose anticoagulants and anti-platelet agents may 
be administered at any dose after the study drug treatment period has ended. 
Additional dose modifications for treatment-related AEs are described in this section.  Dose 
modifications for any instance of QTcF prolongation (irrespective of relationship to study drug) 
are also described in this section.  AEs are deemed treatment-related if they are considered 
possibly related to pacritinib/placebo; AEs that are considered unlikely related to 
pacritinib/placebo do not require dose modification.  Dose levels referenced in the following 
tables refer to the following available doses: 200 mg BID, 100 mg BID, and 100 mg QD. 
Patients who require dose reduction may not subsequently re-escalate the dose. 
6.5.3 
Dosage Management Guidelines for Bleeding and Thrombocytopenia 
Hematology parameters, including CBC (which includes white blood cell [WBC] count, 
differential, hemoglobin count, hematocrit, and platelet count), will be evaluated for inpatients 
during the study.  These parameters should be monitored more frequently if clinically required. 
Table 3 indicates the required dose interruptions and modifications for treatment-related bleeding 
and thrombocytopenia.  Of note, if more than one toxicity is experienced simultaneously, the 
higher-grade toxicity should determine the dose interruption/modification.  
Table 3. 
Treatment-Related Thrombocytopenia and Bleeding 
Event 
CTCAE (v4.03) Grade 
Management/Action 
Thrombocytopenia 
2 
 
(Management required only 
for patients starting with 
normal platelet counts; 
patients starting with grade 1 
or 2 thrombocytopenia at 
Baseline do not require dose 
adjustments) 
• 
Reduce to 50% of the prior dose 
3 
 
(Management required only 
for patients starting with 
normal platelet count or grade 
1 thrombocytopenia; patients 
starting with grade 2 or 3 
thrombocytopenia at Baseline 
do not require dose 
adjustments) 
• 
Hold pacritinib/placebo.  If the toxicity 
resolves to Baseline grade within 7 days, 
treatment may be resumed at the same level or at 
50% of the dose.  If the toxicity does not resolve 
or if it occurs at the lowest dose level, 
pacritinib/placebo must be discontinued. 
• 
If criterion is met on the day of hospital 
discharge, pacritinib/placebo should not be 
administered as an outpatient. 
4 
 
(Management required only 
for patients starting with 
normal platelet count or grade 
• 
Hold pacritinib/placebo.  If the toxicity 
resolves to Baseline grade within 7 days, 
treatment may be resumed at the same level or at 
50% of the dose.  If the toxicity does not resolve 


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Table 3. 
Treatment-Related Thrombocytopenia and Bleeding 
Event 
CTCAE (v4.03) Grade 
Management/Action 
1 or 2 thrombocytopenia; 
patients starting with grade 3 
or 4 thrombocytopenia at 
Baseline do not require dose 
adjustments) 
or if it occurs at the lowest dose level, 
pacritinib/placebo must be discontinued. 
• 
If criterion is met on the day of hospital 
discharge, pacritinib/placebo should not be 
administered as an outpatient. 
Bleeding 
 
1 
• 
No change 
2 
• 
Hold pacritinib/placebo until bleeding 
resolves for up to 2 days.  Restart 
pacritinib/placebo at the same dose.  If bleeding 
recurs, hold again for up to 2 days and restart at 
50% of the prior dose. 
• 
If bleeding is ongoing after 2 days, 
discontinue pacritinib/placebo. 
• 
If treatment-related bleeding grade 2 or 
higher occurred on study, pacritinib/placebo 
should not be administered as an outpatient. 
3 
• 
Hold pacritinib/placebo until bleeding 
resolves for up to 2 days.  Restart 
pacritinib/placebo at 50% of the prior dose.  If 
bleeding recurs, hold again for up to 2 days and 
restart at 50% of the prior dose. 
• 
If bleeding is ongoing after 2 days, 
discontinue pacritinib/placebo. 
• 
If treatment-related bleeding grade 2 or 
higher occurred on study, pacritinib/placebo 
should not be administered as an outpatient. 
4 
• 
Discontinue pacritinib/placebo. 
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events. 
Dose interruptions and modifications for SOC agents will be based on the prescribing 
information described in the most current versions of the agents’ approved labeling.   
6.5.4 
Dosage Management Guidelines for QTcF Interval Prolongation 
An ECG will be performed at Screening (Baseline), Days 3, 8, 15 (or End of Treatment [EOT]), 
22, 28, and on the day of hospital discharge (for patients who will be continuing 
pacritinib/placebo as outpatient), and as clinically indicated. 
Treatment should be modified as shown in Table 4, as recommended by FDA in case of QTcF 
interval prolongation.  Dose modifications for any instance of QTcF prolongation (irrespective of 
relationship to study drug) are also described in this section.  Dose levels referenced in the 


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following tables refer to the following available doses: 200 mg BID, 100 mg BID, and 100 mg 
QD. 
Table 4. 
QTcF Prolongation 
CTCAE (v4.03) Toxicity 
Grade 
Management/Action 
1 
• 
No change 
2 
• 
No change 
3 
(including QTcF ≥ 501 on any 
occasion) 
• 
For QTcF ≥ 501 msec on any assessment, hold pacritinib/placebo and 
assess daily ECGs while inpatient until toxicity resolves to 
grade ≤ 2 (QTc ≤ 500 msec).  If toxicity resolves to grade ≤ 2, treatment 
may be resumed.  If this is the second occurrence, the dose must be 
reduced by 50%.  If already at the 100 mg QD dose, discontinue 
pacritinib/placebo. 
• 
If the QTcF on the date of discharge is >500 msec, pacritinib/placebo 
cannot be administered in an outpatient setting. 
4 
• 
Discontinue pacritinib/placebo 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; QD = once 
daily; QTcF = QT corrected by the Fridericia method. 
 
Electrolyte repletion should be considered for patients who have electrolyte levels below the 
lower limit of normal upon entry into the study or while receiving pactritinib/placebo. 
6.5.5 
Dosage Management Guidelines for Diarrhea 
Treatment with antidiarrheals such as loperamide (Imodium®) is advised for all patients who 
experience new onset diarrhea (Table 5).  Dose levels referenced in the tables refer to the 
following available doses: 200 mg BID, 100 mg BID, and 100 mg QD. 


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Table 5. 
Dosage Management for Treatment-Related Diarrhea 
CTCAE (v4.03) Toxicity 
Grade 
Management/Action 
1 or 2 
• 
No change 
3 
• 
Hold pacritinib/placebo.  If the toxicity resolves to grade ≤ 1 or to the 
Baseline grade within 7 days, treatment may be resumed at the same level 
or at 50% of the dose.  Concomitant antidiarrheal treatment is required 
for patients restarting pacritinib/placebo.  If the toxicity does not resolve 
or if it occurs at the lowest dose level, pacritinib/placebo must be 
discontinued. 
4 
• 
Hold pacritinib/placebo.  If the toxicity resolves to grade ≤ 1 or to the 
Baseline grade within 7 days, treatment may be resumed at 50% of the 
dose.  Concomitant antidiarrheal treatment is required for patients 
restarting pacritinib/placebo.  If the toxicity does not resolve or if it 
occurs at the lowest dose level, pacritinib/placebo must be discontinued. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events. 
6.5.6 
Dosage Management Guidelines for Treatment-Related Toxicities Other 
than QTcF Prolongation, Diarrhea, Bleeding, or Thrombocytopenia  
Treatment should be modified as shown in Table 6 in the event of related nonhematologic 
toxicities other than QTcF prolongation or diarrhea.  Dose levels referenced in the following 
tables refer to the following available doses: 200 mg BID, 100 mg BID, and 100 mg QD. 


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Table 6. 
Treatment Toxicity and Dosage Management: Treatment-Related 
Toxicities Other than QTcF Prolongation, Diarrhea, or 
Thrombocytopenia 
CTCAE (v4.03) Toxicity 
Grade 
Management/Action 
1 or 2 
• 
No change 
3 
• 
Hold treatment 
• 
If the toxicity resolves to grade ≤ 1 or to the Baseline grade within 
7 days, treatment may be resumed at the same level or at the 50% dose 
level, at the discretion of the investigator.  Otherwise, treatment should be 
discontinued. 
4 
• 
Hold treatment 
• 
If the toxicity resolves to grade < 1 or to the Baseline grade within 
7 days, treatment may be resumed, but dosage will be reduced to 50% 
from the level at which the toxicity was observed.  If grade 4 toxicity 
occurs at the lowest dosage of 100 mg QD or if there is no resolution 
within 7 days, the patient should be discontinued from pacritinib/placebo. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; QD = once daily; QTcF = QT 
corrected by the Fridericia method. 
6.6 
Concomitant and Excluded Therapies 
Treatment with cytoreductive therapy is not permitted during the assigned treatment period.  
Pacritinib is metabolized by the P450 system, including cytochrome P450 3A4 (CYP3A4).  Use 
of strong CYP3A4 inhibitors is not permitted as these can lead to significantly increased 
concentrations of pacritinib.  Use of strong cytochrome P450 (CYP450) inducers is not permitted 
as these can lead to significantly reduced concentrations of pacritinib.  Lists of selected strong 
CYP3A4 inhibitors and P450 inducers are found in Appendix 1 and Appendix 2, respectively. 
Concomitant use of investigational agents (those administered as part of a clinical trial) for the 
treatment of COVID-19 is prohibited with the exception of antiviral agents.  The use of IL-1 or 
IL-6 blocking immunomodulatory agents (such as tocilizumab, canakinumab, sarilumab, 
anakinra) is allowed if, in the opinion of the investigator, a patient is clinically deteriorating.  
However, patients who require IL-1 or IL-6 blocking agents must be discontinued from study 
drug.  Hydroxychloroquine, chloroquine, azithromycin, corticosteroids, and antiviral agents are 
permitted concomitant medications. 
Electrolyte repletion should be considered for patients who have electrolyte levels below the 
lower limit of normal upon entry into the study or while receiving pactritinib/placebo. 
Patients who develop worsening gastrointestinal symptoms with the initiation of 
pacritinib/placebo treatment may be treated with standard antidiarrheal and/or anti-emetic 
medications (Section 6.6.1). 


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Treatment-dose anticoagulation and anti-platelet therapy may be administered after 
randomization, if required; patients do not need to discontinue pacritinib/placebo if one of these 
medications is initiated.  However, patients should not receive such agents concomitant with 
study drug administration if their platelet counts drop to < 50,000/µL; prophylaxis-dose 
anticoagulants are permitted for all patients on study.  Treatment-dose anticoagulants and 
anti-platelet agents may be administered at any dose after the study drug treatment period has 
ended.  
Cytotoxic chemotherapy or cancer-directed immunotherapy is prohibited during the 
pacritinib/placebo treatment period (14 or 21 days).  Cancer-directed immunotherapy includes 
immune checkpoint inhibitors, antibody-based cancer therapy, and cell-based cancer therapy.   
6.6.1 
Management of Gastrointestinal Toxicity  
The need for managing gastrointestinal effects of pacritinib, particularly diarrhea, should be 
anticipated.  A careful Baseline evaluation of bowel habits (frequency and consistency of bowel 
movements) should be obtained prior to the first dose. 
Loperamide (Imodium®) or a similarly effective antidiarrheal drug may be administered at the 
Investigator’s discretion if changes in frequency or consistency of bowel movements occur after 
starting pacritinib/placebo.   
Early intervention for diarrhea should be initiated for patients with increases of one grade or 
more in diarrhea (Appendix 3).  Standard supportive care measures to control symptoms of 
gastrointestinal toxicity such as diarrhea, constipation, and nausea should be provided.   
7 STUDY ASSESSMENTS 
7.1 
Criteria for Evaluation 
7.1.1 
Efficacy 
7.1.1.1 
7-Point Ordinal Scale of Clinical Status 
The following 7-point ordinal scale of clinical status (Cao et al 2020) will be used to assess the 
ordinal scale secondary endpoints.  The ordinal scale score is to be documented daily on study 
through Day 28 for all patients, including those who have been discharged from the hospital. 
1. Not hospitalized with resumption of normal activities 
2. Not hospitalized but unable to resume normal activities 
3. Hospitalization, not requiring supplemental oxygen 
4. Hospitalization, requiring supplemental oxygen not meeting criteria for categories 5 or 6 
5. Hospitalization, on non-invasive positive pressure ventilation or high-flow nasal cannula 


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6. Hospitalization, requiring IMV and/or ECMO 
7. Death 
7.1.1.2 
Immunomodulatory Agents 
The use of other immunomodulatory agents as treatment for COVID-19, such as corticosteroids, 
tocilizumab, anakinra, or eculizumab, will be assessed as a secondary endpoint. 
7.1.1.3 
Lung Function Assessments 
Lung function will be assessed by SpO2 in ambient air (if possible), SpO2 with oxygen 
supplementation (if applicable), documentation of oxygen delivery method, highest oxygen 
delivery flow rate (if receiving non-invasive oxygen), highest fraction of inspired oxygen 
(%FiO2) (if on continuous positive airway pressure [CPAP], bilevel positive air pressure 
[BiPAP], or invasive mechanical ventilation [IMV] ), highest positive end-expiratory pressure 
(PEEP; if on positive pressure ventilation), and lowest PaO2:FiO2 ratio (if arterial blood gas 
[ABG] is obtained and the patient is on positive pressure ventilation). 
7.1.2 
Safety 
7.1.2.1 
Adverse Events 
AEs will be collected during the clinical study from the time the patient is randomized through 
30 days following the last dose of pacritinib/placebo.  AEs will be identified and reported to the 
Sponsor, in addition to any clinically indicated diagnostic, monitoring, treatment, and follow-up 
measures used to manage the reported AE.  Pregnancy alone will not be considered as an AE.  
Pregnancy will be reported on a Pregnancy Reporting Form (Section 8.1.4.4).  Abnormal 
pregnancy outcomes and/or any AE for the child or fetus (including miscarriage) will be reported 
as SAEs.  Occurrences of overdose will be reported as SAEs. 
7.1.2.2 
Hematology 
Hematology parameters, (CBC, WBC, hemoglobin, hematocrit, and platelet count), will be 
evaluated at Screening (may be performed within 24 hours prior to the start of Screening) and 
daily from Days 2 through 28 or EOT, and on the day of hospital discharge.  WBC differential 
will be evaluated at Screening (may be performed within 24 hours prior to the start of 
Screening), Day 8, Day 15 or EOT, Day 22, Day 28, and on the day of hospital discharge.  
Hematology tests are not required after hospital discharge.  Analysis of CBC results will be 
performed at local laboratories.  Results from unscheduled hematology tests should be entered 
into the electronic database using an Unscheduled Hematology case report form (CRF).  
Pacritinib/placebo dosage modifications will be implemented for clinically significant AEs 
identified with this testing per the guidelines for “Treatment-Related Thrombocytopenia and 
Bleeding” (Section 6.5.3).  


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7.1.2.3 
Coagulation Testing 
Coagulation testing will include international normalized ratio (INR), partial thromboplastin time 
(PTT), and fibrinogen at Screening (may be performed within 24 hours prior to the start of 
Screening), Day 8, Day 15 or EOT, Day 22, Day 28, and on the day of hospital discharge.  
Coagulation tests are not required after hospital discharge.  Results from unscheduled 
coagulation tests should be entered into the electronic database using an Unscheduled 
Coagulation CRF.  Analysis of coagulation results will be performed at local laboratories.  
7.1.2.4 
Serum Chemistry 
Serum chemistry parameters (sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, calcium, and magnesium) will be evaluated at Screening (may be performed 
within 24 hours prior to the start of Screening) and Day 2 through Day 28 or EOT, and on the 
day of hospital discharge.  Serum chemistry tests are not required after hospital discharge.  
Results from unscheduled serum chemistry tests should be entered into the electronic database 
using an Unscheduled Serum Chemistry CRF.  Analysis of serum chemistry results will be 
performed at local laboratories.  Pacritinib/placebo dosage modifications will be implemented for 
clinically significant AEs identified with serum chemistry testing per the guidelines for 
“Treatment-Related Toxicities Other than QTcF Prolongation, Diarrhea, Bleeding, or 
Thrombocytopenia” (Section 6.5.6).   
7.1.2.5 
Liver Function Panel 
Liver function parameters (aspartate aminotransferase [AST], alanine aminotransferase (ALT), 
alkaline phosphatase, total bilirubin, and albumin) will be evaluated at Screening (may be 
performed within 24 hours prior to the start of Screening), Day 8, Day 15 or EOT, Day 22, 
Day 28, and on the day of hospital discharge.  Liver function panel tests are not required after 
hospital discharge.  Results from unscheduled liver function panel tests should be entered into 
the electronic database using an Unscheduled Liver Function Panel CRF.  Analysis of serum 
chemistry results will be performed at local laboratories.  Pacritinib/placebo dosage 
modifications will be implemented for clinically significant AEs identified with serum chemistry 
testing per the guidelines for “Treatment-Related Toxicities Other than QTcF Prolongation, 
Diarrhea, Bleeding, or Thrombocytopenia” (Section 6.5.6). 
7.1.2.6 
ECG Assessment 
An ECG will be performed at Screening (may be performed within 48 hours prior to the start of 
Screening), Day 3, Day 8, Day 15 or EOT, Day 22, Day 28, and on the day of hospital discharge 
if before EOT.  Eligibility is to be based on QTcF of ≤ 480 msec.  An ECG will also be 
performed on the day of hospital discharge if the patient will be continuing pacritinib/placebo as 
an outpatient; however, ECGs are not required after hospital discharge.  Results from 
unscheduled ECG assessments should be entered into the electronic database using an 
Unscheduled ECG CRF. ECGs should be assessed using at least 3 leads; rhythm strips from 
telemetry monitoring are acceptable.  Pacritinib/placebo modifications and follow-up monitoring 
for clinically significant ECG changes will be implemented as per the guidelines for “Dosage 


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Management Guidelines for QTcF Interval Prolongation” (Section 6.5.4).  Additional ECG 
testing shall be done as clinically indicated. 
7.1.2.7 
Markers of Disease Severity 
Blood samples for analysis of markers of disease severity (CRP, ferritin, D-dimer, IL-6, 
troponin-I, LDH, BNP, procalcitonin, , triglycerides, and CK) will be collected from all patients 
at Screening (may be performed within 24 hours prior to the start of Screening), before the 
morning dose on Day 3, Day 8, Day 15 or EOT, Day 22, Day 28, and on the day of hospital 
discharge.  These markers do not need to be assessed after hospital discharge.  The assessments 
for markers of disease severity are required if they can be performed at a local laboratory or if 
the study center has access to an external laboratory where the samples can be sent for analysis.  
If a study center does not have access to a local or external laboratory that can perform these 
assessments, the Investigator must provide written confirmation of the inability to perform the 
assessment(s), and approval from the CTI Medical Monitor is required to omit the assessment(s).  
Results from unscheduled tests for markers of disease severity should be entered into the 
electronic database using an Unscheduled Markers of Disease Severity CRF. 
7.1.3 
Informed Consent, Screening, and Washout of Prohibited Concomitant 
Medications Before Beginning Pacritinib/placebo 
Informed consent must be obtained before any study procedures and Screening evaluations are 
performed, unless those evaluations are performed as part of SOC.  Patients must provide 
informed consent within 96 hours after hospital admission.  Patients who do not meet eligibility 
criteria at Screening may be rescreened at a later date. 
The informed consent process should be documented in the patient’s medical chart.   
7.1.4 
Summary of Study Assessments and Events by Day  
7.1.4.1 
Screening (Study Day -1 or 1) 
The Screening evaluations listed below are to be carried out between Day -1 and Day 1 (prior to 
the start of treatment).  Screening and randomization may occur on either Day -1 or Day 1.  
Patients may be screened, randomized, and started treatment on the same day (Day 1). 
• Signing of ICF within 96 hours after hospital admission 
• Demographics (age, sex, race, and ethnicity) 
• Medical history 
• Vital signs (blood pressure, pulse, respiratory rate, temperature, SpO2, and body weight) 
• 7-point ordinal scale of clinical status  
• SpO2 in ambient air (if possible) 


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• SpO2 with oxygen supplementation (if applicable) 
• Highest %FiO2 (if on CPAP, BiPAP, or IMV) 
• Highest PEEP)( if on positive pressure ventilation) 
• ECG (at least 3 leads; may be performed within 48 hours prior to the start of Screening) 
• Serum chemistry, including sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose, calcium, and magnesium (The results of laboratory 
assessments performed in the emergency room [ER] or upon hospital admission that are 
relevant for the determination of eligibility may be used to confirm eligibility provided 
that they have been performed within 24 hours prior to the start of Screening.) 
• Liver function panel, including aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and albumin (The 
results of laboratory assessments performed in the ER or upon hospital admission that are 
relevant for the determination of eligibility may be used to confirm eligibility provided 
that they have been performed within 24 hours prior to the start of Screening.) 
• CBC, including WBC count, hemoglobin, hematocrit, and platelet count (The results of 
laboratory assessments performed in the ER or upon hospital admission that are relevant 
for the determination of eligibility may be used to confirm eligibility provided that they 
have been performed within 24 hours prior to the start of Screening.) 
• WBC differential (The results of laboratory assessments performed in the ER or upon 
hospital admission that are relevant for the determination of eligibility may be used to 
confirm eligibility provided that they have been performed within 24 hours prior to the 
start of Screening.) 
• SARS-CoV-2 RT-PCR test or an antigen-based test from any respiratory, 
nasopharyngeal, saliva, blood, or stool specimen at Screening or documented within 1 
week prior to the start of Screening 
• Coagulation tests, including INR, PTT, and fibrinogen 
• CRP 
• Ferritin 
• D-dimer 
• IL-6 
• Troponin-I 
• LDH 


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• BNP 
• Procalcitonin 
• Triglycerides 
• CK 
• Serum pregnancy test for women of childbearing potential prior to randomization, which 
may be performed at any time after arrival to the emergency room or hospital admission 
• Chest imaging assessments performed in the ER or upon hospital admission may be used 
for screening documentation. 
• Documentation of oxygen delivery method, which may include nasal cannula, 
non-rebreather, non-invasive positive pressure ventilation (eg, CPAP or BiPAP), or IMV 
• Concomitant medications 
7.1.4.2 
Randomization (Study Day -1 or 1) 
Patients must have provided informed consent, then completed all Screening procedures, and met 
all eligibility criteria. 
Note: Screening and randomization may occur on either Day -1 or Day 1.  Patients may be 
screened, randomized, and start treatment on the same day (Day 1).   
• AE reporting will begin at the time of randomization 
7.1.4.3 
Study Day 1 (Pre-dose) 
Note: Patients may be screened, randomized and start treatment on the same day. 
• Randomization 
• 7-point ordinal scale of clinical status (unless the same time point as Screening) 
• Physical examination (any physical examination performed as part of routine care on 
Day 1 prior to signing of informed consent may be used for documentation) 
• Maximum documented temperature in the 24 hours prior to dose of pacritinib/placebo 
(Tmax) 
• Maximum documented heart rate in the 24 hours prior to dose of pacritinib/placebo 
(HRmax) 


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• Documentation of oxygen delivery method (unless the same time point as Screening).  If 
multiple delivery methods were used, the method that provides the highest concentration 
of oxygen will be documented. 
• Highest oxygen delivery flow rate (if on non-invasive oxygen) 
• Highest %FiO2 (if on CPAP, BiPAP, or IMV) 
• Highest PEEP (if on positive pressure ventilation) 
• Begin pacritinib/placebo dosing 
• Document pacritinib/placebo dosing 
• AEs 
• Concomitant medications 
7.1.4.4 
Daily Assessment (Day 2 to Day 28) 
Daily assessment evaluations listed below are to be carried out from Day 2 to Day 28 unless 
otherwise noted.  If patient is discharged, refer to Section 7.1.4.8 for outpatient assessments.  
• 7-point ordinal scale of clinical status 
• Physical examination (Day 8 [or on the day of hospital discharge if before EOT], Day 15 
or EOT, Day 22, and Day 28) 
• Maximum temperature documented during the calendar day (Tmax) 
• Maximum heart rate documented during the calendar day (HRmax) (Days 2 through 14) 
• SpO2 in ambient air (if possible) (lowest value documented during the calendar day) 
• SpO2 with oxygen supplementation (if applicable) (lowest value documented during the 
calendar day) 
• ECG (Day 3, Day 8, Day 15, Day 22, Day 28, and on the day of hospital discharge if 
before EOT; not required after hospital discharge but must be performed on the day of 
discharge if the patient will be continuing pacritinib/placebo as an outpatient) 
• Serum chemistry, including sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose, calcium, and magnesium 
• Liver function panel, including AST, ALT, alkaline phosphatase, total bilirubin, and 
albumin (Day 8, Day 15, Day 22, Day 28) 
• CBC, including WBC count, hemoglobin, hematocrit, and platelet count 


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• WBC differential (Day 8, Day 15, Day 22, and Day 28) 
• Coagulation tests, including INR, PTT, and fibrinogen (Day 8, Day 15, Day 22, and Day 
28; samples can be collected on other days as clinically indicated) 
• CRP (before the morning dose on Day 3, Day 8, Day 15 or EOT, Day 22, and Day 28; 
samples can be collected on other days as clinically indicated) 
• Ferritin (before the morning dose on Day 3, Day 8, Day 15, Day 22, and Day 28; samples 
can be collected on other days as clinically indicated) 
• D-dimer (before the morning dose on Day 3, Day 8, Day 15, Day 22, and Day 28; 
samples can be collected on other days as clinically indicated) 
• IL-6 (before the morning dose on Day 3, Day 8, Day 15 or EOT, Day 22, and Day 28; 
samples can be collected on other days as clinically indicated) 
• Troponin-I (before the morning dose on Day 3, Day 8, Day 15 or EOT, Day 22, and Day 
28; samples can be collected on other days as clinically indicated) 
• LDH (before the morning dose on Day 3, Day 8, Day 15, Day 22, and Day 28; samples 
can be collected on other days as clinically indicated) 
• BNP (before the morning dose on Day 3, Day 8, Day 15 or EOT, Day 22, and Day 28; 
samples can be collected on other days as clinically indicated) 
• Procalcitonin (before the morning dose on Day 3, Day 8, Day 15 or EOT, Day 22, and 
Day 28; samples can be collected on other days as clinically indicated) 
• Triglycerides (before the morning dose on Day 3, Day 8, Day 15, Day 22, and Day 28) 
• CK (before the morning dose on Day 3, Day 8, Day 15, Day 22, and Day 28; samples can 
be collected on other days as clinically indicated) 
• Documentation of oxygen delivery method, which may include nasal cannula, 
non-rebreather, non-invasive positive-pressure ventilation (eg, CPAP or BiPAP), or IMV.  
If multiple delivery methods were used, the method that provides the highest 
concentration of oxygen will be documented. 
• Highest oxygen delivery flow rate (if on non-invasive oxygen) 
• Highest %FiO2 (if on CPAP, BiPAP, or IMV) 
• Highest PEEP (if on positive pressure ventilation) 


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• Lowest partial pressure of oxygen (PaO2):FiO2 ratio (if applicable); if ABG has been 
assessed while the patient is on IMV, then the PaO2 should be documented along with 
the FiO2 set on the ventilator at the time of the ABG assessment 
• Administer pacritinib/placebo (Days 2 through 14; Pacritinib/placebo may be given for 
an additional 7 days [through Day 21] with the approval of the Medical Monitor if, in the 
opinion of the investigator, the patient’s clinical signs and symptoms are improving and 
the potential benefit outweighs the potential risk.) 
• Documentation of pacritinib/placebo dosing (Days 2 through 14; Pacritinib/placebo may 
be given for an additional 7 days [through Day 21] with the approval of the Medical 
Monitor if, in the opinion of the investigator, the patient’s clinical signs and symptoms 
are improving and the potential benefit outweighs the potential risk.) 
• AEs 
• Concomitant medications 
7.1.4.5 
End of Treatment 
• 7-point ordinal scale of clinical status 
• Physical examination 
• Tmax 
• HRmax  
• SpO2 in ambient air (if possible) (lowest value documented during the calendar day) 
• SpO2 with oxygen supplementation (if applicable) (lowest value documented during the 
calendar day) 
• ECG 
• Serum chemistry, including sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose, calcium, and magnesium 
• Liver function panel, including AST, ALT, alkaline phosphatase, total bilirubin, and 
albumin 
• CBC, including WBC count, hemoglobin, hematocrit, and platelet count 
• WBC differential 
• Coagulation tests, including INR, PTT, and fibrinogen 
• CRP 


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• Ferritin 
• D-dimer 
• IL-6 
• Troponin-I 
• LDH 
• BNP 
• Procalcitonin 
• Triglycerides 
• CK 
• Documentation of oxygen delivery method, which may include nasal cannula, 
non-rebreather, non-invasive positive pressure ventilation (eg, CPAP or BiPAP), or IMV.  
If multiple delivery methods were used, the method that provides the highest 
concentration of oxygen will be documented. 
• Highest oxygen delivery flow rate (if on non-invasive oxygen) 
• Highest %FiO2 (if on CPAP, BiPAP, or IMV) 
• Highest positive end-expiratory pressure (PEEP; if on positive pressure ventilation) 
• Lowest partial pressure of oxygen (PaO2):FiO2 ratio (if applicable); if arterial blood gas 
(ABG) has been assessed while the patient was on IMV, then the PaO2 should be 
documented along with the FiO2 set on the ventilator at the time of the ABG assessment 
• Administer pacritinib/placebo (Days 2 through 14; Pacritinib/placebo may be given for 
an additional 7 days [through Day 21] with the approval of the Medical Monitor if, in the 
opinion of the investigator, the patient’s clinical signs and symptoms are improving and 
the potential benefit outweighs the potential risk.) 
• Documentation of pacritinib/placebo dosing (Days 2 through 14; Pacritinib/placebo may 
be given for an additional 7 days [through Day 21] with the approval of the Medical 
Monitor if, in the opinion of the investigator, the patient’s clinical signs and symptoms 
are improving and the potential benefit outweighs the potential risk.) 
• AEs 
• Concomitant medications 


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7.1.4.6 
30-day Post-EOT Follow-up (± 3 days)  
AEs and concomitant medications are to be documented through 30 days after the last dose of 
pacritinib/placebo. 
• AEs 
• Concomitant medications 
7.1.4.7 
Day of Hospital Discharge  
• 7-point ordinal scale of clinical status 
• Physical examination 
• Maximum temperature documented during the calendar day (Tmax) 
• Maximum heart rate documented during the calendar day (HRmax) 
• SpO2 in ambient air (if possible) (lowest value documented during the calendar day) 
• SpO2 with oxygen supplementation (if applicable) (lowest value documented during the 
calendar day) 
• ECG (only if the patient will be continuing pacritinib/placebo as an outpatient) 
• Serum chemistry, including sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen, creatinine, glucose, calcium, and magnesium 
• Liver function panel, including AST, ALT, ALP, total bilirubin, and albumin 
• CBC, including WBC count, hemoglobin, hematocrit, and platelet count 
• WBC differential 
• Coagulation tests, including INR, PTT, and fibrinogen 
• CRP 
• Ferritin 
• D-dimer 
• IL-6 
• Troponin-I 
• LDH 


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• BNP 
• Procalcitonin 
• Triglycerides 
• CK 
• Documentation of oxygen delivery method, which may include nasal cannula, 
non-rebreather, non-invasive positive pressure ventilation (eg, CPAP or BiPAP), or IMV.  
If multiple delivery methods were used, the method that provides the highest 
concentration of oxygen will be documented.  
• Highest oxygen delivery flow rate (if on non-invasive oxygen) 
• Lowest partial pressure of oxygen (PaO2):FiO2 ratio (if applicable); if ABG has been 
assessed while the patient was on IMV, then the PaO2 should be documented along with 
the FiO2 set on the ventilator at the time of the ABG assessment 
• Administer pacritinib/placebo (Days 2 through 14; pacritinib/placebo may be given for an 
additional 7 days [through Day 21] with the approval of the Medical Monitor if, in the 
opinion of the investigator, the patient’s clinical signs and symptoms are improving and 
the potential benefit outweighs the potential risk.) 
• Documentation of pacritinib/placebo dosing (Days 2 through 14; pacritinib/placebo may 
be given for an additional 7 days [through Day 21] with the approval of the Medical 
Monitor if, in the opinion of the investigator, the patient’s clinical signs and symptoms 
are improving and the potential benefit outweighs the potential risk.) 
• AEs 
• Concomitant medications 
7.1.4.8 
Outpatient Assessments  
• 7-point ordinal scale of clinical status (Daily scores through Day 28 will be evaluated and 
will be based on weekly assessments performed on Day 8, Day15, Day 22, and Day 28 
[±2 days].) 
• Documentation of pacritinib/placebo dosing for patients who continue treatment after 
discharge from the hospital 
• AEs (will be documented through 30 days after the last dose of pacritinib/placebo and 
will be based on weekly assessments [±2 days] through 30 days after last dose) 


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• Concomitant medications (will be documented through 30 days after the last dose of 
pacritinib/placebo and will be based on weekly assessments [±2 days] through 30 days 
after last dose) 
Note: Outpatient assessments should be based on weekly telephone/videoconference 
communication with the patient and include an evaluation of the daily 7-point ordinal scale score 
for the days between contacts and daily pacritinib/placebo dosing as outlined in Table 1.  More 
frequent telephone/videoconference contact may occur as needed to supplement the above 
assessments.  Review of medical records may also be performed as needed to supplement these 
assessments; medical records should be reviewed for patients who cannot be reached by 
telephone/videoconference. 
8 ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
8.1.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have to have a causal 
relationship with this treatment.   
Examples of AEs are as follows: 
• Any unfavorable and unintended sign, including an abnormal laboratory finding, 
symptom, medical diagnosis, or concomitant disease temporally associated with the use 
of pacritinib/placebo, whether considered related to pacritinib/placebo or not 
• Abnormalities observed during the study that meet any of the criteria below: 
− A laboratory or other test result that is clinically significant or requires active 
intervention, retesting, or ongoing medical monitoring 
− Requires discontinuation, dosage reduction, or delay of pacritinib/placebo  
− Requires that the patient receive specific corrective or supportive therapy 
− Clinically significant changes noted during physical examinations, cardiac 
monitoring, imaging studies, biopsies, and other safety assessments, whether or not 
these procedures were required by the protocol 
Progressive disease and signs and symptoms of progressive disease should not be reported as 
AEs. 
8.1.2 
Reporting Adverse Events 
Baseline conditions and medical history will be collected at the time of informed consent.  AEs 
will be collected during the clinical study from the time of randomization through 30 days 


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following the last dose of pacritinib/placebo.  AEs that occur after the 30-day Post-EOT Visit 
that are considered possibly related to pacritinib/placebo or procedure should also be recorded. 
For screened patients who are not randomized, only SAEs occurring between the time of 
informed consent and determination of screen failure are reported.  
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of the patient or may be detected through a clinically meaningful procedure.  To 
prevent bias, patients should not be questioned regarding the specific occurrence of one or more 
AEs. 
The following information should be captured for all AEs: date of onset and resolution, severity 
per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, seriousness, the 
investigator’s assessment of relationship to pacritinib/placebo, event outcome, and action taken 
with study medication due to the reported event.  If concomitant treatment is given for the AE, 
this information should be captured on the appropriate electronic case report form (eCRF).   
When recording AEs, the diagnosis of the underlying illness or disorder should be used as the 
event term or description on the eCRF and symptoms of the illness or disorder should not be 
reported as separate AEs.  It is expected that whenever possible the clinical term, rather than the 
laboratory term, for the AE will be used by the reporting investigator (e.g., “anemia” versus “low 
hemoglobin value”). 
If an AE results in early termination of the patient’s pacritinib/placebo treatment period, “AE” 
should be selected as the reason for discontinuation on the eCRF.   
Special Considerations 
• Elective procedures or routinely scheduled treatments are not AEs.  However, any 
untoward medical event occurring during a prescheduled elective procedure or routinely 
scheduled treatment should be documented as an AE. 
• Baseline conditions are not AEs; however, worsening of a Baseline condition following 
pacritinib/placebo administration is an AE. 
• Death alone is not considered an AE; it can be an outcome of an AE.  Reports of death 
should be accompanied by the corresponding AE term for the event that led to the 
outcome of death.  However, sudden death or death due to unexplainable cause(s) should 
be reported as an SAE, while follow-up is pursued to determine the cause.  
8.1.3 
Criteria for Assessing Adverse Events 
8.1.3.1 
Severity 
The term “severe” is a measure of intensity; a severe event is not necessarily serious.   
The National Cancer Institute CTCAE version 4.03 should be used to assess and grade AE 
severity, including laboratory abnormalities identified as AEs.  A copy of these criteria is 


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provided in the study manual; however, minor version updates (i.e., 4.01, 4.02, and above) may 
be used at the discretion of the Sponsor.   
8.1.3.2 
Relationship 
The relationship of an AE to pacritinib/placebo will be assessed using the guidelines described 
below.  Any AE for which there is no assessed causal relationship shall be assessed by the 
Sponsor as related and will require immediate follow-up with the site to determine the 
investigator’s assessment.   
Possibly 
There is a reasonable causal relationship between the event and pacritinib/placebo, the event 
occurred within a plausible time relationship to pacritinib/placebo administration, but the event 
could also possibly be explained by the condition under study, concurrent disease, other drugs or 
chemicals, or other circumstances.  Dechallenge information is lacking or unclear. 
Unlikely 
There is a temporal relationship of the event to pacritinib/placebo but not a reasonable causal 
relationship; there is no temporal relationship to pacritinib/placebo administration or the 
condition under study, concurrent disease, and other drugs or chemicals; or other circumstances 
provide a plausible explanation for the event. 
8.1.3.3 
Outcome 
AEs will be characterized according to the outcomes described in Table 7. 
Table 7. 
Outcomes of Adverse Events 
Outcome 
Description 
Recovered/Resolved 
One of the possible results of an adverse event outcome that indicates that the event 
has improved or recuperated 
Recovered/Resolved with 
Sequelae 
One of the possible results of an adverse event outcome where the patient 
recuperated but retained pathological conditions resulting from the prior disease or 
injury 
Recovering/Resolving 
One of the possible results of an adverse event outcome that indicates that the event 
is improving 
Not Recovered/Not 
Resolved 
One of the possible results of an adverse event outcome that indicates that the event 
has not improved or recuperated 
Fatal 
The termination of life as a result of an adverse event 
Unknown 
Not known, not observed, not recorded, or refused  


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8.1.3.4 
Action Taken With Pacritinib/placebo  
Action taken with pacritinib/placebo in relation to the AE will be characterized as follows: 
• Dosage not changed 
• Dosage reduced (includes dose holds followed by dose reduction) 
• Drug interrupted (and resumed at the same dose) 
• Drug withdrawn 
• Not applicable (patients who did not receive a dose of pacritinib/placebo) 
• Unknown 
8.1.4 
Serious Adverse Events 
8.1.4.1 
Definition of a Serious Adverse Event 
An SAE is an AE that, at any dosage, suggests a significant hazard or side effect, regardless of 
its relationship to pacritinib/placebo.  An AE is serious if it meets any of the criteria below:  
1. Results in death 
2. Is life-threatening: in the view of the investigator, the event placed the patient at 
immediate risk of death.  This does not include an AE that, had it occurred in a more 
severe form, might have caused death. 
3. Requires rehospitalization after discharge from the hospital or prolongation of an existing 
hospitalization (see Section 8.1.4.2) 
4. Results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
5. Is a congenital anomaly/birth defect 
6. Is an important medical event that is not fatal, life threatening, or requiring 
hospitalization but may be considered serious if, based on appropriate medical judgment, 
the event jeopardized the patient and required medical or surgical intervention to prevent 
one of the outcomes listed above (Items 1 to 5) 
7. Cancer/overdose: All cases of new cancers and drug overdose (defined as accidental or 
intentional ingestion of any dosage of a product that is considered both excessive and 
medically important) must be reported immediately using the SAE form.  All cases of 
drug overdose, irrespective of seriousness or association with AE(s), must be reported to 
the Sponsor within 24 hours.  Determination of seriousness will be reached in 
consultation with the Safety Physician, CTI BioPharma Corp.  Pharmacovigilance United 


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States (US) Headquarters or designee.  Additional instructions for reporting 
cancer/overdose information will be provided by the Sponsor in the study binder. 
8.1.4.2 
Exceptions 
Re-hospitalizations not reported as SAEs include admissions for the following:  
1. Planned, non-life-threatening medical/surgical procedures (e.g., admission for transfusion 
as required per local medical practice) 
2. Routine health assessments requiring admission for health status documentation 
(e.g., routine gastroscopy, and colonoscopy) 
3. Other life circumstances that have no bearing on health status and require no 
medical/surgical intervention (e.g., lack of housing and family circumstances) 
4. Administration of study medication 
8.1.4.3 
Reporting Serious Adverse Events to the Sponsor 
SAEs, irrespective of causal relationship, will be collected during the clinical study from the time 
the patient provides informed consent through 30 days following the last dose of 
pacritinib/placebo.  The site must send the paper SAE form via email 
(SAE@CTIbiopharma.com) within 24 hours of the site’s first awareness of an SAE.   
Special Considerations: 
• SAEs considered to be possibly related to pacritinib/placebo or study procedure by the 
investigator or Sponsor shall be followed until the event resolves, stabilizes or the patient 
is lost to follow-up.  
• SAEs assessed as unlikely related to pacritinib/placebo or study procedures shall be 
followed for 30 days after the last dose of pacritinib/placebo, or until the event resolves, 
returns to Baseline, stabilizes, or the patient is lost to follow-up, whichever comes first.  
• For screened patients who are not randomized, only SAEs occurring between the time of 
informed consent and determination of screen failure are reported.  
• All SAEs for randomized patients must have a corresponding AE recorded on the eCRF 
with an exact match to the event term or description.  
• An SAE form should be completed for any event for which doubt exists regarding its 
seriousness. 
• If an ongoing SAE changes in intensity, relationship to pacritinib/placebo, or as new 
information becomes available and/or known for the event, a follow-up SAE report 


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should be completed and sent to the Sponsor within 24 hours of the change in SAE 
assessment.   
• Any SAE that occurs after treatment completion and is considered by the investigator to 
be related to pacritinib should be reported to the Sponsor. 
A brief narrative outlining the details of the SAE and treatment and outcome is to be included on 
the SAE form.  Follow-up information, such as laboratory reports, discharge summaries, autopsy 
reports, and information concerning outcome of the event, should be provided, as soon as the 
information becomes available and provided to CTI Pharmacovigilance via email at 
SAE@CTIbiopharma.com or fax (1-866-660-8967).  
Source documents should be submitted in English.  If source documents are not in English, the 
investigator must summarize the source documents and provide a complete English narrative that 
includes a description of the event as it evolved, the results of all diagnostic procedures 
performed and treatments administered, and the outcome of the event. 
8.1.4.4 
Reporting Serious Adverse Events to the Regulatory Agencies, 
Institutional Review Boards, and/or Ethics Committees 
The Sponsor will assess SAEs for expedited reporting against the most current approved version 
of the Investigator Brochure.  Until an AE is identified in the Reference Safety Information of 
the Investigator’s Brochure or Summary of Product Characteristics, it is considered unexpected, 
regardless of whether the AE has been submitted previously as an expedited report. 
Expedited reporting will be performed by the Sponsor in accordance with regulatory 
requirement.   
Upon receiving an expedited report, the investigator must review and retain the notice with the 
Investigator Brochure and shall be responsible for submitting expedited reports to their 
Institutional Review Board (IRB)/Ethics Committee (EC) in accordance with institutional 
guidelines.  Regardless of institutional guidelines, investigators shall submit expedited reports to 
their IRB/EC in the event that the Sponsor identifies an expedited report to represent a new 
and/or unforeseen risk.  
In support of required progress reports, the Sponsor will provide the investigator and/or EC with 
a summary of all SAEs reported for the study at predefined intervals (e.g., quarterly) and/or upon 
request. 
Pregnancy 
Pregnancy alone is not considered as an AE.  However, if a patient becomes pregnant or causes a 
pregnancy during treatment and/or within 3 months of ending treatment even if the patient is 
withdrawn from study, this must be reported to the Sponsor immediately on the Pregnancy 
Reporting Form.  The investigator must obtain written authorization (medical records release) 
from a female partner of a male patient prior to obtaining follow-up.   


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The investigator must follow the pregnancy either to term or termination and will collect data on 
both maternal and fetal outcome.  All pregnancy outcomes will be recorded on the Pregnancy 
Reporting Form.  Additional instructions for reporting pregnancy information will be provided 
by the Sponsor in the study binder. 
Normal outcomes will be communicated to the Sponsor within 30 calendar days of 
birth/delivery.  Abnormal pregnancy outcomes and/or any AE for the child or fetus (including 
miscarriage) will also be recorded in the AE eCRF and on the SAE form.  The associated SAE 
Report Form should be sent to the Sponsor per the procedure and timelines described within 
Section 8.1.4.3.  
Overdose 
Overdose is defined as any deviation from the defined or prescribed use of pacritinib/placebo as 
applicable for the drug and study design.  Occurrences of overdose should be reported to the 
Sponsor on an SAE Report Form.  Reports of overdose will be evaluated on a case by case basis.  
Additional instructions for reporting overdose information will be provided by the Sponsor in the 
study binder. 
Deaths 
All deaths that occur during the study must be recorded on the appropriate eCRF.  As described 
in Sections 8.1.2 and 8.1.3.1, death alone is not considered as an AE; it is an outcome of an AE.  
Reports of death should be accompanied by the corresponding AE term for the event that led to 
the outcome of death. 
Sudden death or death due to unexplainable cause(s) should be reported as an SAE, while 
follow-up is pursued to determine the cause. 
8.2 
Laboratory Evaluation 
All clinical laboratory test values collected during the study will be evaluated by local 
laboratories and entered into the electronic data capture (EDC).  In addition, any unscheduled 
laboratory test results must be entered into the EDC using an Unscheduled Local Laboratory 
CRF. 
8.3 
Vital Signs and Physical Examination 
Vital signs (blood pressure, pulse, respiratory rate, temperature, SpO2, and body weight) and 
physical examinations will be obtained at Screening. 
8.4 
Safety Surveillance 
8.4.1 
Routine Pharmacovigilance Monitoring 
The Sponsor will monitor safety data during the clinical study by examining the incidence and 
severity of AEs and changes in laboratory results.  Clinically important increases in the rate of 
serious adverse reactions will be communicated to the IDMC (see Section 2.2), investigators, and 


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regulatory agencies, as appropriate.  A clinically important increase will be considered an 
increase in frequency and/or severity in an event that leads to a serious outcome and exceeds the 
rate(s) of the reported event listed in the Investigator Brochure reference safety information.  In 
addition, if the sponsor observes a difference of > 6% in the frequency (and a difference of ≥ 2 
patients between the 2 arms) of grade 4 or 5 treatment-related AEs in the pacritinib arm 
compared to the placebo + SOC arm, the IDMC will be convened to review the risk profile and 
render a recommendation regarding study continuation.  The FDA and other Competent 
Authorities will be notified of any IDMC meeting that is convened under these circumstances, 
and the resultant decision will be reported to the FDA within 2 business days. 
Single events assessed as serious, unexpected, and related will continue to be reported on an 
expedited basis per regulatory requirement.   
9 MARKERS OF DISEASE SEVERITY 
9.1 
Blood Sample Collection, Handling, and Shipping 
Blood samples for analysis of markers of disease severity should be collected in appropriate 
blood collection tubes as defined in the study manuals.  Analyses will be performed in local or 
external laboratories.  The time/date when the prior dose was administered must be recorded in 
the source documents and on the appropriate CRF page. 
9.2 
Disease Severity Assessments 
Blood samples for analysis of markers of disease severity will be collected from all patients at 
Screening (may be performed within 24 hours prior to the start of Screening), before the morning 
dose on Day 3, Day 8, Day 15 or EOT, Day 22, Day 28, and on the day of hospital discharge.  
Samples may be collected on other days as clinically indicated.  These markers do not need to be 
assessed after hospital discharge.  The assessments for markers of disease severity are required if 
they can be performed at a local laboratory or if the study center has access to an external 
laboratory where the samples can be sent for analysis.  If a study center does not have access to a 
local or external laboratory that can perform these assessments, the Investigator must provide 
written confirmation of the inability to perform the assessment(s), and approval from the CTI 
Medical Monitor is required to omit the assessment(s).  Results from unscheduled tests for 
markers of disease severity should be entered into the electronic database using an Unscheduled 
Markers of Disease Severity CRF. 
Markers of disease severity will be analyzed for Baseline characteristics and changes over time.   
10 DATA MANAGEMENT 
The CTI BioPharma Corp. Clinical Data Management Department or its designee will prepare 
guidelines for data entry and data handling, which will include procedures for data verification 
and electronic edit checks.  The complete data management process will be described in the Data 
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10.1 Data Collection 
An EDC system will be used for this study.  Designated site personnel will enter patient data 
required by the protocol into eCRFs based on source documents.  Personnel will not receive 
access to the EDC system until they have completed all training requirements.  The EDC system 
will provide an automatic audit trail of all changes made to the clinical database. 
10.2 Data Entry and Quality Control 
Data items will be entered directly from source documents by designated site personnel using 
single data entry.  Concomitant medications entered into the database will be encoded using the 
World Health Organization Drug Reference Dictionary.  AEs, coexisting disease, and other data 
items will be encoded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
CTI BioPharma Corp. staff or designees will review the data on a periodic basis to ensure 
validity, accuracy, and completeness.  Data suspected to be discrepant or incomplete will be 
questioned using data queries.  Data queries resulting from these reviews will be sent to the study 
sites via the EDC system.  The staff at the study sites will respond to the queries in the EDC 
system, and these responses will be reviewed by CTI BioPharma Corp. staff or designee.   
11 STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
Statistical analysis of the study data will be the responsibility of CTI BioPharma Corp. 
Biostatistics Department or its designee.  This section describes the statistical methodology used 
in the analysis of the primary and secondary safety and efficacy endpoints. Details of the 
analyses will be specified in a separate statistical analysis plan (SAP).   
Categorical and nominal variables will be summarized by frequency and percentage.  Continuous 
variables will be summarized by descriptive statistics such as n, mean, median, standard 
deviation, minimum, and maximum.  Ordinal variables will be summarized by frequency 
distribution of scores and by summary statistics on the scores or shift tables, as appropriate.  
Where appropriate, 95% confidence intervals around point estimates will be presented. 
11.1 Endpoints for the Analysis 
11.1.1 
Efficacy 
Primary Endpoint 
The primary efficacy endpoint is the proportion of patients who progress to IMV and/or ECMO 
or death during the 28 days following randomization.  The proportion is calculated as the number 
of patients who progress divided by the total number of patients in the ITT population. 


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Secondary Endpoints 
1. The number of ventilator-free days, defined as the number of days that patients are alive 
and not intubated, from randomization to Day 28 
2. The mortality rate at Day 28 is defined as the number of patients with outcome of death 
during the 28 days following randomization divided by the total number of patients in the 
ITT population 
3. The mortality rate at Day 15 is defined as the number of patients with outcome of death 
in the 15 days following randomization divided by the total number of patients in the ITT 
population. 
4. The time to improvement by at least 2 points relative to Baseline on the 7-point ordinal 
scale of clinical status.  All enrolled patients will have a score between 3 and 5 by virtue 
of being hospitalized and non-intubated; therefore, patients who progress from 3 to 1, 
from 4 to 2, or from 5 to 3 will have met the definition of improvement. 
5. The clinical status as assessed by the 7-point ordinal scale of clinical status at Days 8, 15, 
22, and 28.   
6. The rate of use of immunomodulatory agents as treatment for COVID-19 is defined as 
the proportion of patients reporting use of medications such as corticosteroids, 
tocilizumab, anakinra, or eculizumab as treatment for COVID-19, during 28 days 
following randomization divided by the patients in the ITT population. 
Tertiary Endpoints 
• CRP 
• Ferritin  
• D-dimer  
• IL-6 
• Troponin-I 
• LDH 
• BNP 
• Procalcitonin 
• Triglycerides 


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• CK 
• Triglycerides 
11.1.2 
Safety Endpoints 
Safety will be assessed through 30 days of follow-up after the last dose of study treatment and 
assessed by the cumulative incidence, severity and seriousness of TEAEs, drug discontinuations, 
laboratory values, and clinical assessments. 
11.2 Analysis Populations 
11.2.1 
Primary Analysis Intent-to-Treat Population 
The Intent-to-treat (ITT) population is defined as all patients randomized.  Patients in this 
population will be analyzed according to the treatment arm to which they were assigned at 
randomization.  This population will be used for efficacy analyses. 
11.2.2 
Safety Population 
The Safety population is defined as all randomized patients who received at least one dose of 
study treatment.  Patients in this population will be analyzed according to the treatment actually 
received.  This population will be used for the analysis of safety endpoints. 
11.3 Efficacy Analysis 
All efficacy analyses will be performed using the ITT population.   
Primary Endpoint 
The primary efficacy endpoint of proportion of patients with progression to IMV and/or ECMO 
or death will be compared between treatment arms using the Cochran-Mantel-Haenszel (CMH) 
test stratified by age (< 60 years versus ≥ 60 years) and baseline 7-point clinical status scale 
(baseline 3 or 4 versus 5).  The point estimates and 95% confidence intervals of the proportion of 
patients who progress to IMV and/or ECMO or death will be presented by treatment arm.  The 
CMH odds ratio, difference in progression rates, and associated 95% confidence intervals will be 
presented. 
Secondary Endpoints 
The number of ventilator-free days will be presented by treatment arm using descriptive statistics 
including mean, median, standard deviation, interquartile range, and may include frequency 
distributions. 
The mortality rate at Day 28 will be compared between treatment arms using the CMH test 
stratified by age (< 60 years versus ≥ 60 years) and baseline 7-point clinical status scale (baseline 
3 or 4 versus 5).  The point estimates and 95% confidence intervals of the mortality rates at 


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Day 28 will be presented by treatment arm.  The CMH odds ratio, difference in mortality rates at 
Day 28, and associated 95% confidence intervals will be presented. 
The mortality rate at Day 15 will be compared between treatment arms using the CMH test 
stratified by age (< 60 years versus ≥ 60 years) and baseline 7-point clinical status scale (baseline 
3 or 4 versus 5).  The point estimates and 95% confidence intervals of the mortality rates at 
Day 15 will be presented by treatment arm.  The CMH odds ratio, difference in mortality rates at 
Day 15, and associated 95% confidence intervals will be presented. 
The time from randomization to improvement by at least 2 points relative to Baseline on the 
7-point clinical status will be compared between treatment arms using a stratified log-rank test 
stratified by age (< 60 years versus ≥ 60 years) and baseline 7-point clinical status scale (baseline 
3 or 4 versus 5).  All enrolled patients will have a score between 3 and 5 by virtue of being 
hospitalized and non-intubated; therefore, patients who progress from 3 to 1, from 4 to 2, or from 
5 to 3 will have met the definition of improvement.  Kaplan-Meier methods will be used to 
estimate time to improvement by treatment arm. Summary statistics, including median time to 
improvement and corresponding 95% confidence intervals, will be presented by treatment arm.  
The hazard ratio (HR) for time to improvement by treatment arm will be estimated using a 
stratified Cox proportional hazards model stratified by age (< 60 years versus ≥ 60 years) and 
baseline 7-point clinical status scale (baseline 3 or 4 versus 5). 
The clinical status assessed by the 7-point ordinal scale of clinical status at Days 8, 15, 22, 
and 28 will be presented by treatment arm using counts and percent of patients at each level of 
the 7-point scale score. 
The rate of use of immunomodulatory agents as treatment for COVID-19 will be compared 
between treatment arms using the CMH test stratified by age (< 60 years versus ≥ 60 years) and 
baseline 7-point clinical status scale (baseline 3 or 4 versus 5).  The point estimates and 95% 
confidence intervals of the rates of immunomodulatory agents use will be presented by treatment 
arm.  The CMH odds ratio, difference in rates of immunomodulatory agent use, and associated 
95% confidence intervals will be presented. 
Details of the analysis of tertiary endpoints will be specified in the SAP. 
11.4 Safety Analysis 
All safety analyses will be performed on the Safety population. 
Safety will be assessed through 30 days of follow-up after the last dose of study treatment and 
assessed by the cumulative incidence, severity and seriousness of TEAEs, drug discontinuations, 
laboratory values, and clinical assessments. 
TEAEs will be coded using MedDRA and summarized by SOC, PT, and treatment arm as the 
number and percentage of patients with an event.  The following subsets of TEAEs will also be 
summarized by treatment arm: AEs related to study treatment, AEs by CTCAE v4.03 grade, AEs 
leading to treatment discontinuation, and SAEs. 


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Clinical laboratory data will be assigned a CTCAE v4.03 grade and summarized with descriptive 
statistics and, where possible, in shift tables comparing the worst post-baseline shift relative to 
baseline. 
11.5 Subgroup Analysis 
The following subgroup analyses may be performed: 
• Age (< 60 years, ≥ 60 years) 
• Sex (male versus female) 
• Race (Caucasian versus all others) 
• Baseline 7-point ordinal scale of clinical status scale (baseline 3 or 4 versus 5) 
• Baseline IL-6 (normal versus elevated) 
• Procalcitonin (normal or indeterminate versus elevated) 
• Ferritin (< 500 ug/L versus ≥ 500 ug/L) 
• Other markers of disease severity (D-dimer, CRP, troponin-I, triglycerides) 
• History of invasive cancer (yes/no) 
11.6 Determination of Sample Size  
Our hypothesis is that pacritinib would reduce the risk of these events to 13.5% by Day 28.  The 
study sample size will be approximately 200 patients (randomized in a 1:1 ratio).  This provides 
80% power to detect at least 13% treatment difference in the proportion of patients who progress 
to IMV and/or ECMO or death by Day 28, assuming that the response rate is 13.5% in the 
pacritinib and SOC arm and 26.5% in the placebo and SOC arm, with a one-sided Type I error 
rate of 0.10. 
11.7 Analysis of Markers of Disease Severity 
Markers of disease severity data will be summarized using descriptive statistics.   
12 INDEPENDENT DATA MONITORING COMMITTEE 
See Section 2.2 for a description of the composition and responsibilities of the IDMC. 
13 STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
For studies conducted outside the US under a US Investigational New Drug (IND), the principal 
investigator must comply with US FDA IND regulations and with those of relevant national and 
local health authorities. 


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13.1 Pacritinib Accountability 
CTI BioPharma Corp. will provide pacritinib and matching placebo.  The recipient will 
acknowledge receipt of the drug by returning the appropriate shipping receipt form according to 
the study-specific pharmacy manual.  Damaged supplies will be replaced. 
Accurate records of all pacritinib/placebo dispensed from and returned to the study site should be 
recorded by using the Drug Inventory Log (refer to study-specific pharmacy manual). 
Pacritinib/placebo will be disposed of at the study site according to institutional standard 
operating procedures after study monitors have completed the drug inventory reconciliation.  If a 
site cannot or prefers not to dispose the clinical material locally, the pacritinib/placebo must be 
returned by the site to the clinical supplier, Almac.  The method of destruction must be 
documented.  A copy of the destruction certification along with the inventory of destroyed 
clinical material will be provided to CTI BioPharma Corp. 
13.2 Informed Consent 
CTI BioPharma Corp. will provide a sample ICF to each site for submission and approval by 
site’s IRB, Research Ethics Board (REB), or Independent Ethics Committee (IEC).  CTI 
BioPharma Corp. or its designee must review and approve any proposed deviations from the 
sample ICF.  Patients must be re-consented to the most current IRB/REB/IEC approved version 
of the ICF during their participation in the study.  The investigator must provide the final 
IRB/REC/IEC approved ICF to CTI BioPharma Corp. for regulatory purposes. 
The patient or the patient’s legally authorized representative must sign the ICF before his or her 
participation in the study.  The source record for each patient shall document that informed 
consent was obtained prior to participation in the study.  A copy of each signed ICF or 
Addendum to an existing ICF must be provided to the patient or the patient’s legally authorized 
representative.  If applicable, it will be provided in a certified translation of the local language. 
All signed consent forms must remain in each patient’s study file and must be available for 
verification by the study monitor, Sponsor representative, or regulatory agency at any time. 
13.3 Disclosure of Data 
Patient medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 
Upon the patient’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection upon request by representatives of 
the US FDA, national and local health authorities, CTI BioPharma Corp., its designees and the 
IRB/REB/IEC for each study site, if appropriate. 


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13.4 Case Report Forms  
CTI BioPharma Corp. will provide eCRFs, which should be completed in accordance with 
instructions from CTI BioPharma Corp. 
13.5 Study Monitoring 
Representatives of CTI BioPharma Corp. or their designee must be allowed to monitor all study 
site locations at appropriate intervals to assure compliance with Good Clinical Practice (GCP), 
satisfactory enrollment rate, data recording, and protocol adherence.  The frequency of 
monitoring may vary depending on enrollment rate and the quality of data collected.  The 
investigator and staff are expected to cooperate and provide all relevant study documentation in 
detail at each site visit on request for review.  The investigator agrees to cooperate with the 
monitor to ensure any problems detected in the course of these monitoring visits are resolved.  In 
addition to these visits, CTI BioPharma Corp. or designee may monitor each site by phone to 
keep abreast of patient status and to answer questions. 
In order for the investigator to participate in this study, the study monitor must be able to 
perform source data for verification remotely (ie, without having to physically visit the site).  
This will be done by comparing data from the eCRFs with data from the patient’s clinic or 
hospital records (permission will be sought from the patient as part of the consent process).  
In addition, CTI BioPharma Corp. internal auditors and government inspectors may evaluate the 
study.  They must be allowed access to eCRFs, source documents, and other study files.  CTI 
BioPharma Corp. audit reports will be kept confidential. 
The investigator should promptly notify CTI BioPharma Corp. of an audit scheduled by any 
regulatory authority, and immediately forward copies of audit reports. 
13.6 Record Retention 
US FDA regulations (21CFR§312.62[c]) and the International Council for Harmonisation (ICH) 
Guideline for GCP (see Section 4.9 of the guideline) require that the principal investigator retain 
records and documents pertaining to the conduct of the study and distribution of investigational 
drug, including eCRFs, consent forms, laboratory test results, radiographic assessments, and 
medication inventory records for 2 years after the last marketing application approval in an ICH 
region or after at least 2 years have elapsed since formal discontinuation of clinical development 
of the investigational product.  All state and local laws for retention of records also apply.  CTI 
BioPharma Corp. will notify the principal investigator of these events. 
No records should be disposed of without the written approval of CTI BioPharma Corp. 
14 ETHICS 
14.1 Good Clinical Practice 
The investigator and Sponsor will ensure that this study is conducted in full compliance with 
Declaration of Helsinki, ICH guidelines, US FDA regulations 21 CFR Parts 50, 56, and 312, and 


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with the laws and regulations of the country in which the research is conducted, whichever 
affords the greatest protection to the study patient. 
14.2 Institutional Review Board/Research Ethics Board/Independent Ethics 
Committee 
The appropriate IRB, REB, or IEC must approve in writing the protocol and ICF for this study in 
accordance with the laws and regulation of the country in which the research is conducted prior 
to any patient being registered in this study. 
Before the investigational drug will be shipped to the investigator, the investigator must provide 
CTI BioPharma Corp. with a copy of the IRB/REB/IEC approval letter stating that the study 
protocol and ICF have been reviewed and approved.  Original US FDA Form 1572 (for all 
studies conducted under US IND regulations) signed by the principal investigator, and a copy of 
the curriculum vitae for the principal investigator, and a copy of an IRB/REB/IEC approved ICF 
are also required. 
The investigator must also report all serious and medically significant AEs to the IRB/REB/IEC 
according to the local regulation. Appendix 4 lists the responsibilities of the investigator. 
15 TERMINATION OF STUDY  
CTI BioPharma Corp. will retain the right to terminate the study and remove all the study 
materials from the study site at any time.  Specific instances that may precipitate such 
termination are as follows: 
• Unsatisfactory enrollment with regard to quality or quantity 
• Deviations from GCP 
• Deviation from protocol requirements, without prior approval from CTI BioPharma Corp. 
• Inaccurate and/or incomplete data recording on a recurrent basis 
• The incidence and/or severity of adverse drug events in this or other studies indicating a 
potential health hazard caused by the treatment 
In addition, if the sponsor observes a difference of > 6% in the frequency (and a difference of 
≥ 2 patients between the 2 arms) of grade 4 or 5 treatment-related AEs in the pacritinib arm 
compared to the placebo + SOC arm, the IDMC will be convened to review the risk profile and 
render a recommendation regarding study continuation.  The FDA and other Competent 


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Authorities will be notified of any IDMC meeting that is convened under these circumstances, 
and the resultant decision will be reported to the FDA within 2 business days. 
In terminating the study, CTI BioPharma Corp. and the investigator will assure adequate 
consideration to the protection of the patients’ interest. 
16 STUDY AMENDMENTS 
Changes in any portion of this protocol must be documented in the form of an amendment from 
CTI BioPharma Corp. and must be approved by the site’s IRB/REB/IEC before the amendment 
can be implemented at the site.  The IRB/REB/IEC chairperson may approve minor changes, or 
may designate one or more regulatory members to approve revisions.  In addition, substantial 
amendments made to this protocol will require approval by the appropriate regulatory authority 
prior to implementation. 
17 USE OF INFORMATION AND PUBLICATION 
CTI BioPharma Corp. recognizes the importance of communicating medical study data and 
therefore encourages their publication in reputable scientific journals and at seminars or 
conferences.  The Clinical Study Agreement will describe the details of the processes of 
producing and reviewing reports, manuscripts, and presentations based on the data from this 
study. 


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18 REFERENCES 
Arcaroli J, Silva E, Maloney JP, et al. Variant IRAK-1 haplotype is associated with increased 
nuclear factor-kappaB activation and worse outcomes in sepsis. Am J Respir Crit Care Med. 
2006;173(12):1335–1341.  
Betts BC, Abdel-Wahab O, Curran SA, et al. Janus kinase-2 inhibition induces durable tolerance 
to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall 
antigen. Blood. 2011;118(19):5330–5339.  
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe 
Covid-19 [published online ahead of print, 2020 Mar 18]. N Engl J Med. 2020;NEJMoa2001282. 
doi:10.1056/NEJMoa2001282 
Gerds AT, Savona MR, Scott B, et al. Results of PAC203: A Randomized Phase 2 Dose-Finding 
Study and Determination of the Recommended Dose of Pacritinib. Blood. 2019;134(S1):667. 
Gong J, Dong H, Xia Q, et al. Correlation Analysis Between Disease Severity and Inflammation-
related Parameters in Patients with COVID-19 Pneumonia (Pre-print, not peer-reviewed). 
Accessed via https://www.medrxiv.org/content/10.1101/2020.02.25.20025643v1.full.pdf. 
Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell 
function in vitro and in vivo. Blood. 2013a;122(7):1192–1202. 
Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it time 
for anti-infective prophylaxis?. Blood. 2013b;122(23):3843–3844. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China [published correction appears in Lancet. 2020 Jan 30]. Lancet. 
2020;395(10223):497–506. 
Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signaling axis in cancer. 
Nat Rev Clin Oncol. 2018;15(4):234–248.  
Li JT, Melton AC, Su G, et al. Unexpected Role for Adaptive αβTh17 Cells in Acute Respiratory 
Distress Syndrome. J Immunol. 2015;195(1):87–95. 
Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs Best Available Therapy, Including 
Ruxolitinib, in Patients With Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 
2018;4(5):652–659. 
Meduri GU, Headley S, Kohler G, et al. Persistent elevation of inflammatory cytokines predicts a 
poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors 
of outcome over time. Chest. 1995;107(4):1062–1073. 
Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the 
treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, 
randomised, phase 3 trial. Lancet Haematol. 2017;4(5):e225–e236. 


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Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and 
immunosuppression. Lancet. 2020;395(10229):1033–1034. 
Mikacenic C, Hansen EE, Radella F, Gharib SA, Stapleton RD, Wurfel MM. Interleukin-17A Is 
Associated With Alveolar Inflammation and Poor Outcomes in Acute Respiratory Distress 
Syndrome. Crit Care Med. 2016;44(3):496–502. 
National Institute of Health COVID-19 Treatment Guidelines. 
https://covid19treatmentguidelines.nih.gov/overview/management-of-covid-19/(accessed 
4/24/2020). 
Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an 
analysis of data of 150 patients from Wuhan, China [published online ahead of print, 2020 Mar 
3] [published correction appears in Intensive Care Med. 2020 Apr 6]. Intensive Care Med. 
2020;1–3. 
Sant'Antonio E, Bonifacio M, Breccia M, Rumi E. A journey through infectious risk associated 
with ruxolitinib. Br J Haematol. 2019;187(3):286–295. 
Singer JW, Al-Fayoumi S, Ma H, et al. Comprehensive kinase profile of pacritinib, a 
nonmyelosuppressive Janus kinase 2 inhibitor. J Exp Pharmacol. 2016;8:11–19. 
Singer JW, Fleischman A, Al-Fayoumi S, et al. Inhibition of interleukin-1 receptor-associated 
kinase 1 (IRAK1) as a therapeutic strategy. Oncotarget. 2018;9(70):33416–33439. 
Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 
inhibitor Fedratinib [published online ahead of print, 2020 Mar 11]. J Microbiol Immunol Infect. 
2020;S1684-1182(20)30065-7. 
Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute 
respiratory distress syndrome [published correction appears in Lancet Respir Med. 2020 Feb 25]. 
Lancet Respir Med. 2020;8(4):420–422. 
Yu ZX, Ji MS, Yan J, et al. The ratio of Th17/Treg cells as a risk indicator in early acute 
respiratory distress syndrome. Crit Care. 2015;19(1):82.  
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study [published correction appears in 
Lancet. 2020 Mar 28;395(10229):1038]. Lancet. 2020;395(10229):1054–1062. 


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19 APPENDICES 
 
 


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Appendix 1 - Selected Strong Inhibitors of CYP3A4 
boceprevir 
ciprofloxacin 
clarithromycin 
conivaptan 
erythromycin 
fluconazole 
grapefruit 
grapefruit juice 
indinavir 
itraconazole 
ketoconazole 
lopinavir 
mibefradil 
nefazodone  
nelfinavir 
norfloxacin 
posaconazole 
quinidine 
ritonavir 
saquinavir 
Seville oranges 
star fruit 
telaprevir 
telithromycin 
troleandomycin 
voriconazole 
This list is not comprehensive. When considering using an agent that could be a potential CYP3A4 inhibitor, please discuss 
this with the medical monitor. 
Source: http://medicine.iupui.edu/clinpharm/ddis/table.asp and http://www.pharmacytimescom/issue/pharmacy/2008/2008-
09/2008-09-8687. 
 


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Appendix 2 – Selected Strong Inducers of CYP450 
carbamazepine 
efavirenz 
nevirapine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John's Wort 
troglitazone 
This list is not comprehensive. When considering using an agent that could be a potential CYP450 inducer, please discuss this 
with the medical monitor. 
Source: http://medicine.iupui.edu/clinpharm/ddis/table.asp and http://www.pharmacytimescom/issue/pharmacy/2008/2008-
09/2008-09-8687. 
 
 
 


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Appendix 3 - Common Terminology Criteria for Adverse Events: Diarrhea (Version 4.03) 
 
Definition: A Disorder Characterized by Frequent and Watery Bowel Movements. 
1 
Increase of  < 4 stools per day over Baseline; mild increase in ostomy output compared to Baseline 
2 
Increase of 4 – 6 stools per day over Baseline; moderate increase in ostomy output compared to Baseline 
3 
Increase of  > 7 stools per day over Baseline; incontinence; hospitalization indicated; severe increase in 
ostomy output compared to Baseline; limiting self-care ADL 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death 
 


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Appendix 4 - Investigator Responsibilities, Required Documentation, and Signature 
CTI BioPharma Corp. will select the investigator(s) on the basis of their expertise in the field of 
clinical studies in hematologic oncology and in the care and treatment of patients with chronic 
myeloproliferative diseases. Investigators will also be selected on the appropriateness of their 
facility to conduct a research study of this nature, and the characteristics of the patient population 
treated at the institution. The investigator will: 
• Obtain Institutional Review Board (IRB), Research Ethics Board (REB), or Independent 
Ethics Committee (IEC) approval of the protocol and amendments to the protocol and 
Informed Consent Form before initiation of the protocol or any amendments for the 
study, and obtain annual IRB or IEC renewal, as required.  
• Ensure that current FDA and/or ICH-E6 regulations are followed. 
• Select all patients in accordance with the selection criteria outlined in the study protocol. 
• Treat and follow patients as described in this research protocol. Complete all electronic 
case report forms (eCRFs) in a timely manner and review eCRFs for accuracy and 
completeness.  Provide the original clinical source documents to verify all data entered on 
eCRFs or SAE reports and all data that document the course of the patient throughout 
their participation on the study.  Provide a clinical summary to the Sponsor's clinical 
research monitor. 
• Report all adverse events to CTI BioPharma Corp. or designee, as required by the 
protocol. 
• Ensure that the investigational drug is kept in a secured, limited access area and stored 
under proper conditions. Ensure that all investigational drug receipt and dispensing 
information is recorded and all drug can be accounted for at all times. 
• Before initiation of the study, each participating investigator will submit to CTI: 
− FDA Form 1572 and, if applicable, other ministry of health required forms 
− Copies of the medical licenses of principal investigators and subinvestigators 
− Addresses and descriptions of all clinical laboratory facilities to be used 
− Laboratory certification and expiration dates 
− Normal ranges and effective dates for all required laboratory tests 
− IRB/REB/IEC approval letter referencing the protocol (and amendments, if 
applicable) 
− IRB/REB/IEC Membership List: A list of the IRB/REB/EC members, their 
respective titles or occupations, and their institutional affiliations 


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− A sample copy of the IRB/REB/IEC-approved Informed Consent Form 
− Curricula vitae: Curricula vitae for the principal investigator and all 
subinvestigators 
− Financial disclosure for the principal investigator and all subinvestigators 
− Protocol signature page, signed by the principal investigator 
Investigator Statement and Signature: 
I attest that I have read this protocol, understand and agree to the provisions of the protocol, and 
accept the responsibilities listed above in my role as principal investigator for the study. 
 
 
 
Principal Investigator Signature 
Date 
 
 
 
Principal Investigator Name, Printed 
 

SAP_001.pdf: 
CTI Biopharma 
PAC319 (PRE-VENT) Statistical Analysis Plan
Page 1
 
Statistical Analysis Plan  
 
 
CTI Biopharma Corp. 
PRE-VENT Phase 3 
 
 
 A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Multicenter Study of Pacritinib Plus Standard of Care Versus 
Placebo and Standard of Care in Hospitalized Patients With 
Severe COVID-19 With or Without Cancer  
 
Protocol Amendment 4 
 
 
Sponsor: 
CTI Biopharma Corp. 
3101 Western Avenue, Suite 800 
Seattle, WA 98121 
 
 
 
 
 
 
 
Statistical Analysis Plan Version: 
V1.0  
Date: 
13 September 2021 
 
 
 
 
 
 
Confidentiality Statement 
This document and its contents are the property of CTI BioPharma Corp. Unauthorized 
copying or use of this information is prohibited. This document or information within may not 
be used, divulged, published, or otherwise disclosed without the written consent of CTI.  


CTI Biopharma 
PAC319 (PRE-VENT) Statistical Analysis Plan
Page 2
 
CTI Biopharma Corp. 
PRE-VENT Phase 3 
 
 
 A Phase 3 Randomized, Double-blind, Placebo-controlled, 
Multicenter Study of Pacritinib Plus Standard of Care Versus 
Placebo and Standard of Care in Hospitalized Patients With 
Severe COVID-19 With or Without Cancer  
 
Protocol Amendment 4 
11 August 2021 
This Statistical Analysis Plan has been reviewed and approved by: 
 
 
 
 
 
Jirui Wang, PhD 
Date 
Biostatistician 
Medpace, Inc. 
 
 
 
 
 
 
Lyon Gleich, MD 
 
Date 
Vice President, Medical Department 
Medpace Inc. 
 
 
 
 
 
 
Herve Mommeja-Marin, MD 
 
Date 
Vice President, Medical Department 
Medpace Inc. 
 
 
 
 
 
 
Jennifer Smith, PhD 
 
Date 
Sr. VP, Biometrics 
CTI Biopharma Corp. 
 
 
 
 
 
 
Karisse Roman-Torres, MSPH 
 
Date 
Lead Statistician 
CTI Biopharma Corp. 
 


CTI Biopharma 
PAC319 (PRE-VENT) Statistical Analysis Plan
Page 3
 
TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................................... 7 
2 
STUDY OBJECTIVES .................................................................................................................... 7 
2.1 
Primary Objective .................................................................................................................. 7 
2.2 
Secondary Objectives ............................................................................................................. 7 
2.3 
Tertiary Objectives ................................................................................................................. 7 
3 
STUDY OVERVIEW ...................................................................................................................... 8 
3.1 
Study Design .......................................................................................................................... 8 
3.2 
Study Centers ......................................................................................................................... 9 
3.3 
Randomization and Blinding .................................................................................................. 9 
3.4 
Sample Size Determination .................................................................................................... 9 
3.5 
Duration of Study ................................................................................................................. 10 
3.6 
Schedule of Assessments (SoA) ........................................................................................... 10 
4 
ANALYSIS POPULATIONS ....................................................................................................... 10 
5 
STUDY ASSESSMENTS ............................................................................................................. 10 
5.1 
Efficacy Assessments ........................................................................................................... 10 
5.1.1 
Ordinal Scale of Clinical Status .............................................................................. 10 
5.1.2 
Marker of Disease Severity Assessments ................................................................ 11 
5.1.3 
Lung Function Assessment ..................................................................................... 11 
5.1.4 
Immunomodulatory Agents ..................................................................................... 12 
5.2 
Safety Assessments .............................................................................................................. 12 
5.2.1 
Adverse Events ........................................................................................................ 12 
5.2.2 
Laboratory Assessments .......................................................................................... 13 
5.2.3 
Vital Signs ............................................................................................................... 14 
5.2.4 
Electrocardiograms (ECGs) .................................................................................... 14 
5.2.5 
Physical Examinations ............................................................................................ 14 
6 
CLINICAL OUTCOME VARIABLES ......................................................................................... 14 
6.1 
Primary Efficacy Endpoint ................................................................................................... 14 
6.2 
Secondary Efficacy Endpoints ............................................................................................. 15 
6.2.1 
Number of Ventilator-Free Days ............................................................................. 15 
6.2.2 
Mortality Rate at Days 15 and 28 ............................................................................ 15 
6.2.3 
Time to Improvement in Clinical Status ................................................................. 15 
6.2.4 
Ordinal Scale of Clinical Status .............................................................................. 16 
6.2.5 
Rate of Use of Immunomodulatory Agents ............................................................ 16 
6.3 
Secondary Endpoints  Safety ............................................................................................. 16 
6.3.1 
Adverse Events ........................................................................................................ 16 
7 
STATISTICAL ANALYSES ........................................................................................................ 17 
7.1 
General Statistical Considerations ....................................................................................... 17 
7.1.1 
Baseline Definition .................................................................................................. 18 
7.1.2 
Covariate Adjustment .............................................................................................. 18 


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7.1.3 
Multicenter Studies ................................................................................................. 18 
7.1.4 
Handling of Dropouts or Missing Data ................................................................... 18 
7.1.4.1 
Partial or Missing AE Onset and Resolution Dates ............................................ 18 
7.1.5 
Subgroup Analyses .................................................................................................. 19 
7.2 
Study Population Data.......................................................................................................... 19 
7.2.1 
Patient Disposition .................................................................................................. 19 
7.2.2 
Demographics and COVID-19 Baseline Characteristics ........................................ 20 
7.2.3 
Medical History and Comorbidities ........................................................................ 20 
7.2.4 
Prior and Concomitant Medications ........................................................................ 20 
7.2.5 
Lung Function Assessment ..................................................................................... 21 
7.3 
Exposure to Pacritinib/Placebo ............................................................................................ 21 
7.4 
Efficacy Analyses................................................................................................................. 21 
7.4.1 
Primary Efficacy Analysis ...................................................................................... 21 
7.4.2 
Secondary Efficacy Analysis .................................................................................. 23 
7.4.2.1 
Number of Ventilator-Free Days ........................................................................ 23 
7.4.2.2 
Mortality Rate at Day 15 and 28 ........................................................................ 23 
7.4.2.3 
Clinical Status ..................................................................................................... 23 
7.4.2.4 
Time to Improvement in Clinical Status ............................................................. 24 
7.4.2.5 
Use of Immunomodulatory Agents .................................................................... 24 
7.4.3 
Tertiary Analyses .................................................................................................... 25 
7.4.3.1 
Markers of Disease Severity ............................................................................... 25 
7.5 
Safety Analyses .................................................................................................................... 25 
7.5.1 
Adverse Events ........................................................................................................ 25 
7.5.2 
Laboratory Assessments .......................................................................................... 26 
7.5.3 
Vital Signs ............................................................................................................... 26 
7.5.4 
Electrocardiograms.................................................................................................. 27 
7.5.5 
Other Safety Assessments ....................................................................................... 28 
8 
GENERAL INFORMATION ........................................................................................................ 28 
8.1 
Statistical Software............................................................................................................... 28 
8.2 
Format of Tables, Listings, and Figures ............................................................................... 28 
9 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSIS ........................................................ 28 
10 REFERENCES .............................................................................................................................. 28 
11 APPENDIX 1: IMMUNOMODULATORY AGENTS ................................................................ 29 
 
 
 
 
 
 


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Version History 
 
Version and Date 
Description 
Version 1.0, 13 September 2021 
Initial version 
 
 
 
 


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         Table 1: List of Abbreviations and Definitions of Terms 
 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
ADI 
Actual Dose Intensity 
AESI 
Adverse Event of Special Interest 
ATC 
Anatomical Therapeutic Chemical 
CI  
Confidence interval 
 
CK 
Creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
FiO2 
Fraction of inspired oxygen 
IDMC 
Independent Data Monitoring Committee 
IMV 
Invasive Mechanical Ventilation 
MedDRA 
Medical Dictionary for Regulatory Activities 
PaO2 
Arterial oxygen partial pressure 
PT 
Preferred Term 
RDI 
Relative Dose Intensity 
SAE 
Serious adverse advent 
SAP
Statistical Analysis Plan
SoA
Schedule of Assessments
SMQ
Standardised MedDRA Query
SOC
Standard of care
SpO2
Blood oxygen saturation
TEAE
Treatment-emergent adverse event
TESAE
Serious treatment-emergent adverse event
TFLs
Tables, Figures, and Listings
WHO
World Health Organization
WHODD
World Health Organization Drug Dictionary
WHO-DDE 
World Health Organization Drug Dictionary 
Enhanced
 
 


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1 
INTRODUCTION  
This Statistical Analysis Plan (SAP) describes the statistical analyses and data presentations to 
be performed for protocol PAC319
A Phase 2 Randomized, Double-blind, Placebo-
controlled, Multicenter Study of Pacritinib Plus Standard of Care Versus Placebo and Standard 
of Care in Hospitalized Patients With Severe COVID-19 With or Without Cancer  
(Amendment 4). 
 
This document provides additional details concerning the statistical analyses that were 
mentioned in the protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they will be identified as post hoc in the clinical study report.  
 
2 
STUDY OBJECTIVES  
2.1 
Primary Objective 
To compare the efficacy of pacritinib + standard of care (SOC) versus placebo + SOC in 
hospitalized patients with severe COVID-19 with or without cancer, as the proportion of 
patients who require invasive mechanical ventilation (IMV) and/or extracorporeal membrane 
oxygenation (ECMO) or die by Day 28. Severe COVID-19 is defined as confirmed disease in 
rate >30, PaO2/FiO2 <300 but do not require IMV. 
2.2 
Secondary Objectives 
1. To compare the number of ventilator-free days, defined as the number of days that patients 
are alive and not intubated, from randomization to Day 28 between pacritinib + SOC versus 
placebo + SOC  
2. To compare the mortality rate between pacritinib + SOC versus placebo + SOC at Day 28  
3. To compare the mortality rate between pacritinib + SOC versus placebo + SOC at Day 15  
4. To compare the time to improvement by at least 2 points relative to Baseline on the 7-point 
ordinal scale of clinical status between pacritinib + SOC versus placebo + SOC  
5. To compare the clinical status assessed by the 7-point ordinal scale of clinical status at Days 
8, 15, 22, and 28 between pacritinib + SOC versus placebo + SOC  
6. To compare the rate of use of immunomodulatory agents as treatment for COVID-19 during 
the 28 days following randomization between pacritinib + SOC versus placebo + SOC  
7. To evaluate the toxicity profile of pacritinib therapy in hospitalized patients with severe 
COVID-19 with or without cancer 
2.3 
Tertiary Objectives 
To evaluate the treatment effects of pacritinib + SOC vs. placebo + SOC on the following 
markers of disease severity:  


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-reactive protein (CRP)  
 
-dimer  
Interleukin 6 (IL-6) 
Serum troponin-I  
 
 
 
 
 
3 
STUDY OVERVIEW 
3.1 
Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy and safety of pacritinib in hospitalized patients with severe COVID-19 with or 
without cancer. Severe COVID-19 is defined as confirmed disease in patients who are 
hos
or lung infiltrates >50% but do not require IMV.  
Patients will be randomized 1:1 to receive pacritinib (400 mg QD on Day 1, then 200 mg BID 
from Day 2 to Day 14) + SOC o
years) and the 7-point ordinal scale of clinical status scale (baseline 3 or 4 versus 5). The study 
duration will be 8 weeks.  
Assigned treatment will continue for up to Day 14 or until the patient experiences intolerable 
adverse events (AEs), withdraws consent, or initiates another investigational therapy, or until 
the study is terminated. Assigned therapy may be given for an additional 7 days (for a total of 
21 days) with the approval of the Medical Monitor if, in the opinion of the investigator, the 
potential risk. In the event of hospital discharge, patients will complete treatment with the 
assigned therapy as an outpatient.  
The primary endpoint is the effect of treatment on the proportion of patients who require IMV 
and/or ECMO or die by Day 28. 
Ongoing safety monitoring will be conducted by an independent data monitoring committee 
(IDMC). The IDMC will comprise a multidisciplinary group of at least three voting members 
in the fields of hematology, infectious disease, and biostatistics. Additional personnel may be 


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added to the IDMC at the request of the IDMC membership. The membership, roles, and 
responsibilities of the IDMC will be fully defined by an IDMC charter. 
Safety will be monitored with physical examinations, clinical laboratory assessments, and 
electrocardiogram (ECG) monitoring for inpatients. Patients who are discharged from the 
hospital while still on study will be monitored weekly. Outpatient monitoring will include 
telephone contact and may also include review of the patient's electronic medical record. 
Laboratory and ECG assessments will not be required for monitoring outpatients, including 
those completing their course of study drug. Specified pacritinib/placebo dosage modifications 
will be followed to address identified abnormalities. AE data will be collected from the time 
of randomization through 30 days following the last dose of pacritinib/placebo. Serious adverse 
events (SAEs) assessed as related (i.e., possibly related per protocol) to pacritinib/placebo or 
study procedure by the investigator or Sponsor shall be followed until the event resolves, 
stabilizes or the patient is lost to follow-up. SAEs assessed as unrelated to pacritinib/placebo 
or study procedures shall be followed for 30 days after the last dose of pacritinib/placebo, or 
until the event resolves, returns to baseline, stabilizes, or the patient is lost to follow-up, 
whichever comes first. 
3.2 
Study Centers 
The study will take place at approximately 21 centers in the United States (number of centers 
and countries may be reassessed as patient enrollment increases).  
3.3 
Randomization and Blinding 
Eligible patients will be centrally randomized in a 1:1 allocation ratio to receive pacritinib (400 
mg QD on Day 1, then 200 mg BID from Day 2 to Day 14) + SOC or placebo + SOC according 
to a stratified permuted block design stratified by age (< 60 years v
7-point clinical status scale (baseline 3 or 4 versus 5).  
This study is double-blind; the Sponsor, study patients, and Investigators will be blinded to 
treatment assignments. The IDMC will have access to unblinded data. Individual patient 
unblinding may occur at the request of the Investigators if necessary for medical reasons and 
to assess suspected unexpected serious adverse reactions.  
3.4 
Sample Size Determination 
The study sample size will be approximately 200 patients (randomized in a 1:1 ratio). This 
provides 80% power to detect at least 13% treatment difference in the proportion of patients 
who progress to IMV and/or ECMO or die by Day 28, assuming that the response rate is 13.5% 
in the pacritinib + SOC arm and 26.5% in the placebo+SOC arm, with a one-sided Type I error 
rate of 0.10.  


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3.5 
Duration of Study 
The approximate study duration for each patient will be 8 weeks. The estimated duration of 
the entire study is approximately 1 year if the maximum number of patients are enrolled.  
3.6 
Schedule of Assessments (SoA) 
The Schedule of Assessments is presented in Protocol Table 1.  
4 
ANALYSIS POPULATIONS 
The study analysis populations and planned analysis for each population are as follows.  
Table 2  Analysis Populations 
Population Name 
Planned Analyses Definition 
 
Intent-to-Treat (ITT) 
Population 
Patient 
disposition, 
demographics, 
clinical baseline 
characteristics, 
and efficacy 
The Intent-to-treat (ITT) population is defined 
as all patients randomized.  
Note: Patients in this population will be 
analyzed according to the treatment arm to 
which they were assigned at randomization. 
This population will be used for efficacy 
analyses. 
Safety Population 
Safety  
The Safety population is defined as all 
randomized patients who received at least one 
dose of study treatment. 
Note: Patients in this population will be 
analyzed according to the treatment actually 
received. This population will be used for the 
analysis of safety endpoints.  
5 
STUDY ASSESSMENTS 
5.1 
Efficacy Assessments 
This section describes the assessments that will be performed to evaluate the efficacy 
endpoints. 
5.1.1 
Ordinal Scale of Clinical Status  
The following scale adapted from Cao et al. will be used in order to assess the clinical status 
for the derivation of primary and secondary endpoints.  


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Table 3  Ordinal Scale of Clinical Status (adapted from Cao et al.) 
Ordinal Value and Description 
1. Not hospitalized with resumption of normal activities  
2. Not hospitalized but unable to resume normal activities  
3. Hospitalization, not requiring supplemental oxygen  
4. Hospitalization, requiring supplemental oxygen not meeting criteria for categories 5 or 6  
5. Hospitalization, on non-invasive positive pressure ventilation or high-flow nasal cannula  
6. Hospitalization, requiring IMV and/or ECMO  
7. Death 
5.1.2 
Marker of Disease Severity Assessments 
The following markers of disease severity will be assessed: 
 
-reactive protein (CRP),  
 
-dimer,  
-6, 
-I,  
e (LDH),  
 
 
 
5.1.3 
Lung Function Assessment 
Lung function will be assessed by SpO2 in ambient air (if possible), SpO2 with oxygen 
supplementation (if applicable), documentation of oxygen delivery method, highest oxygen 
delivery flow rate (if receiving noninvasive oxygen), highest fraction of inspired oxygen 
(%FiO2) (if on continuous positive airway pressure ventilation [CPAP], bilevel positive air 
pressure (BiPAP), or invasive mechanical ventilation [IMV]), highest positive end-expiratory 
pressure (PEEP; if on positive pressure ventilation), and lowest PaO2:FiO2 ratio (if arterial 
blood gas [ABG] is obtained and the patient is on positive pressure ventilation). 


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5.1.4 
Immunomodulatory Agents 
The use of immunomodulatory agents as treatment for COVID-19 such as corticosteroids, 
tocilizumab, anakinra, or eculizamab, will be assessed. 
5.2 
Safety Assessments 
This section describes the assessments that will be performed to evaluate safety. 
Safety assessments include adverse event reporting, laboratory assessments, vital signs, ECG 
assessments, and physical examinations.  
5.2.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and that does not necessarily have to have a causal 
relationship with this treatment. 
AEs will be collected during the clinical study from the time of randomization through 30 days 
following the last dose of pacritinib/placebo. AEs that occur after the 30-Day Post EOT Visit 
that are considered possibly related to pacritinib/placebo or procedure should also be recorded. 
For screened patients who are not randomized, only SAEs occurring between the time of 
informed consent and determination of screen failure are reported. 
The following information should be captured for all AEs: date of onset and resolution, severity 
per Common Terminology Criteria for Adverse Events (CTCAE), seriousness, the 
with study medication due to the reported event. If concomitant treatment is given for the AE, 
this information should be captured on the appropriate electronic case report form (eCRF). If 
should be selected as the reason for discontinuation on the eCRF. 
The CTCAE version 4.03 will be used for the grading of adverse events.  
Table 4  Adverse Event Relationship to Pacritinib/Placebo 
Relationship Category 
Description 
Possible 
There is a reasonable causal relationship 
between the event and pacritinib/placebo, the 
event occurred within a plausible time 
relationship 
to 
pacritinib/placebo 
administration, but the event could also 
possibly be explained by the condition under 
study, concurrent disease, other drugs or 


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Relationship Category 
Description 
chemicals, 
or 
other 
circumstances. 
Dechallenge information is lacking or unclear.
Unlikely  
 
There is a temporal relationship of the event to 
pacritinib/placebo but not a reasonable causal 
relationship; there is no temporal relationship 
to pacritinib/placebo administration or the 
condition under study, concurrent disease, and 
other 
drugs 
or 
chemicals; 
or 
other 
circumstances provide a plausible explanation 
for the event. 
5.2.2 
Laboratory Assessments 
Clinical laboratory assessments will be performed at the times specified in protocol Table 1.   
The following clinical laboratory parameters will be evaluated during the study.  
Table 5  Laboratory Assessments and Parameters 
Laboratory Test 
Parameters 
 
Serum chemistry 
Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, glucose, calcium, and magnesium 
Liver Panel 
AST, ALT, alkaline phosphatase, total bilirubin, and albumin.  
Hematology 
WBC count, hemoglobin, hematocrit, and platelet count 
Note: WBC subsets may be reported as either differential or absolute 
counts on the eCRF. Additional white cell counts (e.g. bands) may 
also be reported if available.  
Coagulation 
INR, PTT, and fibrinogen  
Other  
Ferritin, LDH, CRP, IL-6, Troponin-I, LDH, BNP, procalcitonin, 
triglycerides, and CK 
Serum pregnancy test for women of childbearing potential 


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5.2.3 
Vital Signs 
Vital signs will be assessed at the times specified in protocol Table 1. The vital signs 
assessment will include recording of the systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), respiratory rate (breaths/minute),  maximum temperature, maximum heart 
rate, SpO2, and body weight.  
5.2.4 
Electrocardiograms (ECGs) 
The ECG assessment will be performed at the times specified in protocol Table 1.  
The Fridericia-Corrected QT interval (QTcF) and overall interpretation will be recorded.  
5.2.5 
Physical Examinations 
The Physical Examination assessment will be performed at the times specified in protocol 
Table 1. 
6 
CLINICAL OUTCOME VARIABLES 
This section describes the clinical outcomes and derivation of variables considered for this 
study.  
6.1 
Primary Efficacy Endpoint 
The primary endpoint is the proportion of patients with progression to IMV and/or ECMO or 
death by Day 28 (+/- 2 days) for the Intent-to-Treat (ITT) Population. Patients will be 
considered to have progression to IMV and/or ECMO or death based on the Cao et al. (Table 
3) clinical status assessment of 6 or 7. Specifically, the proportion of patients with progression 
to IMV and/or ECMO or death by Day 28 (+/- 2 days) will be calculated in each treatment arm 
as: 
(Number of patients with clinical status of 6 or 7 at any time on or before Day 28 (+/-
2 days) ) / (Number of patients in the ITT population) 
Patients who discontinued early and did not progress to IMV and/or ECMO or death (a clinical 
status of 6 or 7)  will be considered as having progression unless they were discharged from 
the clinical facility (discharge date is not missing), in which case they will be considered non-
progression. 
Patients will be summarized based on the randomized (planned) treatment arm. Patients can 
meet this endpoint in two ways by progressing to IMV and/or ECMO or dying.   


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6.2 
Secondary Efficacy Endpoints 
6.2.1 
Number of Ventilator-Free Days 
The number of total ventilator-free days is defined as the number of total days that patients are 
alive and not intubated, from Day 1 to Day 28. The number of total ventilator-free days will 
be calculated as: 
Number of ventilator free days = Number of total days with clinical status assessment 
of 5 or less from Day 1 until Day 28  
Ventilator-free days includes all episodes a patient is not on IMV and/or ECMO and report a 
clinical status form of 5 or less from Day 1 to Day 28. 
Patients who discontinued early will be considered as being ventilator-free up to Day 28 if they 
were discharged from the clinical facility (discharge date is not missing), in which case they 
will be considered as not having an event of IMV and/or ECMO up to Day 28.  Patients who 
discontinued early and were not discharged from the clinical facility will be considered as 
being ventilator-free up to the time of study discontinuation. 
6.2.2 
Mortality Rate at Days 15 and 28 
The 15-day mortality rate is defined as the proportion of patients with outcome of death during 
the 15 days following randomization. The Day 15 mortality rate is calculated as: 
 (Number of patients that die by Day 15) / (Number of patients in the ITT population) 
The 28-day mortality rate is defined as the proportion of patients with outcome of death during 
the 28 days following randomization. The Day 28 mortality rate is calculated as: 
(Number of patients that die by Day 28) / (Number of patients in the ITT population) 
6.2.3 
Time to Improvement in Clinical Status  
The time to improvement in clinical status from baseline will be calculated as: 
Time to Improvement in Clinical Status (days) = Date of improvement in clinical status 
 date of randomization + 1 
The date of improvement in clinical status is defined as the first ordinal scale assessment with 
a decrease of 2 or more points from the baseline clinical status assessment. For example, for a 
patient that has a baseline clinical status of 4, the date of improvement would be the first post-
baseline clinical status assessment of 2 or 1.   


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6.2.4 
Ordinal Scale of Clinical Status  
The clinical status adapted from Cao et al. (as described in Table 3), will be a secondary 
efficacy outcome variable. The 7-point clinical status score at Day 8, 15, 22 and 28 will be 
presented by treatment arm using the ITT population. 
6.2.5 
Rate of Use of Immunomodulatory Agents 
The use of other immunomodulatory agents as treatment for COVID-19, such as 
corticosteroids, tocilizumab, anakinra, or eculizumab, will be assessed as a secondary 
endpoint. These medications will be identified on the CRF as concomitant medications and 
defined by groups of certain WHODD preferred names. The list of WHODD terms is provided 
in Appendix 1. 
A patient will be considered to have used an immunomodulatory agent if any medication used 
by the patient between Day 1 and Day 28 is coded to the list of preferred names in Appendix 
1.  
The rate of use of immunomodulatory agents will be calculated as: 
(Number of patients using an immunomodulatory agent between Day 1 and Day 28) / 
(Number of patients in the ITT population) 
6.3 
Secondary Endpoints  Safety 
A secondary endpoint is to evaluate the toxicity profile of pacritinib therapy in hospitalized 
patients with severe COVID-19 with or without cancer. In general, this will be assessed 
through the analysis of treatment-emergent adverse events including incidence, seriousness, 
relatedness to pacritinib, and severity.  
6.3.1 
Adverse Events 
Adverse Events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
MedDRA v23.1. The severity of all adverse events will be graded according to NCI CTCAE 
version 4.03.  
A treatment-emergent adverse event (TEAE) is defined as an adverse event occurring on or 
after the first dose of study treatment and within 30 days after the last study treatment date.  
TEAEs will be summarized by presenting, for each treatment arm, the count and percentage of 
patients having any TEAE, having a TEAE in each system organ class, and having an 
individual event according to version 23.1 of the MedDRA dictionary (or later as specified in 
the Data Management Plan). The version of MedDRA used for the purpose of coding events 
in the clinical database will be static for the duration of the study.  CTCAE (version 4.03) 
grades and relationship to study drug will be summarized as appropriate. For summaries by 
CTCAE grade or relatedness, only the highest CTCAE grade or degree of relatedness of each 


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System Organ Class and/or preferred term (PT) will be summarized. A patient having the same 
event more than once will be counted only once and by greatest severity or closest relationship. 
Cardiac TEAEs are all the PTs in the Standardised MedDRA Queries (SMQs) of Cardiac 
Arrhythmias, Cardiac Failure, Ischaemic Heart Disease, and Embolic and Thrombotic Events.  
Haemorrhage TEAEs are all PTs in the SMQ of Haemorrhages.  
7 
STATISTICAL ANALYSES 
This section describes the statistical analyses to be conducted in relation to the primary, 
secondary, and exploratory objectives of the study.  
7.1 
General Statistical Considerations 
Unless specified otherwise, the analyses of data collected will be descriptive and summaries 
will be presented separately for each treatment arm and in total for the specified analysis 
population. Statistical analyses will be descriptive and no formal hypothesis testing or 
comparative analyses between treatment arms will be performed unless stated. Confidence 
intervals (CIs) will be constructed at the 95% confidence level where appropriate. For 
categorical variables, confidence intervals will be calculated using the Clopper-Pearson 
method where appropriate.  
For continuous variables, the number of observations (n), mean, standard deviation, median, 
q1, q3, minimum, and maximum will be provided as summary statistics. For categorical 
variables, the frequency and percentage in each category will be displayed.   
Sumary tables will in general display 2 treatment arms:   
Pacritinib 400 mg 
Placebo 
A total column will be added for table summaries if appropriate.  
Efficacy analyses will in general be based on the ITT Population according to the randomized 
(planned) treatment arm.  
Safety analyses will in general be performed using the Safety Population according to the 
treatment actually received.  
Subject disposition, demographics, and clinical baseline characteristics data will be 
summarized for the ITT Population. If the ITT Population differs from other defined analysis 
populations, additional patient characteristic summaries may be generated using other analysis 
populations.  


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7.1.1 
Baseline Definition 
The baseline value for analyses will be defined as the last assessment prior to the start of 
treatment, unless otherwise specified. 
Study Day 1 will be considered as the first dose of treatment. Note that randomization may 
occur before study Day 1.  
7.1.2 
Covariate Adjustment 
No adjustment for other covariates is planned.  
7.1.3 
Multicenter Studies 
The center effect will not be considered for this study. 
7.1.4 
Handling of Dropouts or Missing Data 
Unrecorded data values will be recorded as missing. Only recorded (i.e. complete) data values 
will be used for statistical analyses. In general, invalid or missing values will not be imputed 
in the data unless stated otherwise.  
In addition, analysis methods for handling dropouts are specified under the endpoint definition. 
7.1.4.1 
Partial or Missing AE Onset and Resolution Dates 
For AE summaries, the missing day of onset of an adverse event will conservatively be set to: 
First day of the month that the AE occurred if this is after the date of the start of first 
treatment. 
One day after the first treatment if this is the same month that the AE occurred. 
The 15th of the month and year if the AE month and year are before the month and 
year of the first treatment. 
If the onset date of an adverse event is missing both day and month, it will be set to: 
January 1 of the year of onset, as long as this is after the first study treatment. 
One day after the first study treatment if this is the same year that the AE occurred. 
July 1st of the year if the AE year is before the year of the first study treatment. 
If the day of resolution of an adverse event is missing, it will conservatively be set to the last 
day of the month or 30 days after the last dose of study treatment if this day is in the same 
month and year, whichever is earlier. If the day of resolution of an adverse event is missing 
both day and month, it will conservatively be set to the last day of the year or 30 days after the 
last dose of study treatment if this day is in the same year, whichever is earlier. 
 


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7.1.5 
Subgroup Analyses 
The following subgroup analyses of the primary endpoint may be performed: 
 Age (< 60 years, 
 60 years) 
 
 races) 
-point ordinal scale of clinical status scale (baseline 3 or 4 versus 5) 
e IL-6 (normal versus elevated) 
 
 Ferritin (< 500 ug/L versus 
 500 ug/L) 
-dimer, CRP, Troponin-I, triglycerides) 
Additional subgroups may be identified on the basis of other factors including, but not limited 
to, use of certain medications (e.g. immunomodulatory agents) or medical history.  
7.2 
Study Population Data 
7.2.1 
Patient Disposition 
Patient disposition will be summarized using counts and percentages for the ITT Population.   
The following patient disposition categories will be summarized: 
Patients screened; 
Patients randomized; 
Patients who received study treatment; 
Patients that completed planned study treatment; 
Patients discontinued from study treatment; 
Patients that completed the study; 
Patients who discontinued the study. 
For patients who discontinued study treatment and patients who discontinued the study, reason 
for discontinuation will be provided.   
The total number of patients in each defined analysis population will be tabulated. 


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7.2.2 
Demographics and COVID-19 Baseline Characteristics 
Descriptive summaries of demographic and COVID-19 disease criteria will be presented 
separately for the ITT Population. If other analysis populations differ form the ITT population 
then additional table summaries based on these populations may be presented.  
Demographic characteristics may include, but are not limited to: age, sex, race,  and ethnicity.  
COVID-19 baseline disease characteristics may include the following: percent of patients with 
hypoxemia (SpO2 
2 for both on room air and on supplemental oxygen, 
type of oxygen delivery devices used (percent of patients using each device type), percent of 
patients with tachypnea (RR>20 breaths/min), percent of patients with RR>30 breaths/min, 
percent of patients with P:F <300 (among patients in whom P:F ratio was calculable), percent 
of patients with fever (temperature >100.4F), percent of patients with tachycardia (HR>100 
beats/min), and baseline clinical status. 
Additional summaries of disease markers of severity at baseline (normal vs above upper limit 
of normal) may be presented.  
Demographics and COVID-19 disease criteria will be listed.  
7.2.3 
Medical History and Comorbidities 
Medical history items will be coded using MedDRA v23.1 (or later as specified in the Data 
Management Plan). Recorded medical history items will be summarized by System Organ 
Class and PT. A patient will be counted only once within each System Organ Class and PT but 
may contribute to more than one PT within a System Organ Class.  
The number of patients with pre-defined comorbidities (e.g. diabetes mellitus) will be 
summarized.  
Medical history and comorbidities will be listed.   
7.2.4 
Prior and Concomitant Medications 
Concomitant medications will be collected from the time of consent through 30 days following 
the last dose of pacritinib/placebo. 
Prior medications are medications that were started and stopped prior to the first dose of study 
drug. Concomitant medications are medications that were taken on or after the first dose of 
study drug. Recorded prior and concomitant medications will be coded using the WHO Drug 
Dictionary (version March 2020 or later as specified in the Data Management Plan).  
Recorded concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) levels and PT. Concomitant medications of special interest (e.g. immunomodulary 
agents/antiviral) will be summarized separately. A patient will be counted only once within 
each ATC level and PT but may contribute to more than one PT within an ATC.   


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Prior and concomitant medications  as well as concomitant medications of special interest 
(immunomodulary agents/ antiviral) will be listed.  
7.2.5 
Lung Function Assessment 
Descriptive statistics will be provided by timepoint for SpO2 in ambient air (if applicable), 
SpO2 with oxygen supplementation (if applicable), and oxygen delivery method.  
Lung function assessments will be listed by patient.  
7.3 
Exposure to Pacritinib/Placebo 
Exposure to study treatment will be evaluated by the duration of treatment, cumulative dose, 
actual dose intensity, and relative dose intensity in the Safety Population.  
Duration of treatment (days) is defined as the duration from first day of study treatment to the 
last day of study treatment, i.e., 
Duration of treatment (days) =  
Date of last dose of study treatment  date of first dose of study treatment + 1   
Descriptive statistics will be provided for duration of treatment by treatment arm. 
Cumulative dose (mg) is defined as the sum of all pacritinib doses of study treatment taken. 
Descriptive statistics will be provided for the cumulative dose. The counts and percentages of 
patients with any dose modifications will be provided by treatment arm. Reasons for dose 
modifications will also be summarized. In addition, the actual dose intensity (ADI) and relative 
dose intensity (RDI) will be defined as follows: 
ADI (mg/day) = (total dose taken in mg) ÷ (duration of treatment in days). 
RDI (%) = (ADI) ÷ (planned daily dose) × 100. 
The planned pacritinib dose is 400 mg/day. Descriptive statistics will be provided for both ADI 
and RDI.  
Exposure data will be listed.  
7.4 
Efficacy Analyses 
Efficacy analyses described in this section will performed using the ITT Population according 
to the randomized treatment arm.  
7.4.1 
Primary Efficacy Analysis 
The primary efficacy analysis is the proportion of patients with progression to IMV and/or 
ECMO or death by Day 28 in the Intent-to-Treat Population.  


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The primary efficacy endpoint of proportion of patients with progression to IMV and/or ECMO 
or death will be compared between treatment arms using the Cochran-Mantel-Haenszel (CMH) 
test stratified by randomization stratification factors age (< 
 60 years) and 7-
point clinical status scale (baseline 3 or 4 versus 5) as entered in the IXRS.  The point estimates 
and 95% confidence intervals of the proportion of patients who progress to IMV and/or ECMO 
or death will be presented by treatment arm.  The CMH odds ratio, difference in 
progressionrates, and associated 95% confidence intervals will be presented. 
Patients who discontinued early and did not progress to IMV and/or ECMO or death (a clinical 
status of 6 or 7)  will be considered as having progression unless they were discharged from 
the clinical facility (discharge date is not missing), in which case they will be considered non-
progression. 
To evaluate the impact of missing data on the primary analysis, two sensitivity analyses will 
be performed:  
1. A conservative analysis in the ITT population that considers all patients who 
discontinued early and did not progress to IMV and/or ECMO or death (a clinical status 
of 6 or 7)  as having progression regardless of hospital discharge status. 
2. An analysis in the ITT population that considers patients who discontinue early and did 
not progress to IMV and/or ECMO or death (a clinical status of 6 or 7) as having non-
progression. 
An additional analysis of the time to event (IMV/ECMO or Death ) will be performed.  
The time to IMV/ECMO or Death will be calculated as the earliest date of a clinical status 
assessment of 6 or 7  date of randomization + 1. Table 6 provides the rules for IMV/ECMO 
or death events and censoring for the time to event analysis. .  
Table 6  Event and Censoring Rules for IMV/ECMO 
 
Situation 
Date of Event or Censoring  
IMV/ECMO 
or 
Death
Event 
IMV/ECMO documented in 
the clinical status form (6)
Earliest date when IMV/ECMO is observed 
Death 
Date of death if no IMV/ECMO was observed 
Censor 
No post-baseline clinical 
status assessments
Randomization date 
No IMV/ECMO or death by 
Day 28
Date of last clinical status assessment  
Lost to follow-up 
Date of last clinical status assessment  
The rules apply to dates up to study Day 28 +2 day window (Day 30). 
 
Kaplan-Meier methods will be used to estimate the time to IMV/ECMO or death by treatment 
arm. Summary statistics, including median time to IMV/ECMO or death and corresponding 


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95% confidence intervals, will be presented by treatment arm. The time to IMV/ECMO or 
death will be analyzed using the log-rank test stratified by age (< 60 
 60 years) 
and baseline 7-point clinical status scale (baseline 3 or 4 versus 5).   
The hazard ratio (HR) of the time to IMV/ECMO or death by treatment arm will be estimated 
using a stratified Cox proportional hazards model stratified by age (< 60 years versus 
 60 years) and baseline 7-point clinical status scale (baseline 3 or 4 versus 5).  
Kaplan-Meier plots of the time to improvement in clinical status will be generated by treatment 
arm.  
The clinical status assessments will be listed. 
7.4.2 
Secondary Efficacy Analysis 
7.4.2.1 
Number of Ventilator-Free Days 
The number of ventilator-free days will be presented by treatment arm using descriptive 
statistics. The 95% confidence intervals will be provided.  The treatment arm comparison will 
be performed using the Wilcoxon rank sum test.  
In addition, the number of patients that remain ventilator-free for certain clinically significant 
thresholds (e.g. 21 days) may be summarized.   
7.4.2.2 
Mortality Rate at Day 15 and 28 
The Day 15 and Day 28 mortality rates and associated 95% confidence interval will be 
summarized by treatment arm.  
The mortality rate at Day 15 and Day 28 will be compared between treatment arms using the 
CMH test stratified by age (< 60 years versus 
 60 years) and baseline 7-point clinical status 
scale (baseline3 or 4 versus 5). The point estimates and 95% confidence intervals of the 
mortality rates at Day 15 and Day 28 will be presented by treatment arm. The CMH odds ratio, 
difference in mortality rates at Day 15 and Day 28, and associated 95% confidence intervals 
will be presented.  
7.4.2.3 
Clinical Status 
The clinical status at Day 8 (+/- 1 day), Day 15 (+/- 1 day), Day 22 (+/- 1 day), and Day 28 
(+/- 2 day) will be summarized by treatment arm using counts and percentages. 
Clinical status assessments will be listed by patient.   


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7.4.2.4 
Time to Improvement in Clinical Status 
Time to improvement in clinical status is defined as the first ordinal scale assessment with 2 
points reduction from the baseline clinical status assessment. Patients not known to have 
improved by Day 28 will be censored at the date of their last clinical status assessment. Patients 
who have died will be censored at Day 28. Table 7 provides the rules for improvement in 
clinical status and censoring for the time to event analysis 
Table 7  Event and Censoring Rules for Improvement in Clinical Status 
 
Situation 
Date of Event or Censoring 
2-point reduction 
from baseline in 
the clinical status 
form (event) 
2-point reduction from 
baseline documented in 
the clinical status form 
Earliest date when a 2-point reduction from 
baseline in the clinical status form is observed 
Censor 
Death 
Day 28  
No post-baseline 
clinical status 
assessments 
Randomization Date 
No 2-point reduction 
from baseline 
Date of last clinical status assessment  
Lost to follow-up 
Date of last clinical status assessment  
The rules apply to dates up to study Day 28 +2 day window (Day 30). 
 
Kaplan-Meier methods will be used to estimate time to improvement by treatment arm. 
Summary statistics, including median time to improvement and corresponding 95% confidence 
intervals, will be presented by treatment arm.  The time to improvement will be analyzed using 
the log-rank test stratified by age (< 60 
 60 years) and baseline 7-point clinical 
status scale (baseline 3 or 4 versus 5).   
The hazard ratio (HR) for time to improvement by treatment arm will be estimated using a 
stratified Cox proportional hazards model stratified by age (< 60 
 60 years) and 
baseline 7-point clinical status scale (baseline 3 or 4 versus 5).  
Kaplan-Meier plots of the time to improvement in clinical status will be generated by treatment 
arm.  
7.4.2.5 
Use of Immunomodulatory Agents 
The rate of use of immunomodulatory agents as treatment for COVID-19 will be compared 
between treatment arms using the CMH test stratified by age (< 60 years versus 
 60 years) 
and baseline 7-point clinical status scale (baseline 3 or 4 versus 5). The point estimates and 
95% confidence intervals of the rates of immunomodulatory agents use will be presented by 
treatment arm. The CMH odds ratio, difference in rates of immunomodulatory agent use, and 
associated 95% confidence intervals will be presented.  


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In addition, the number of immunomodulatory agents will be summarized using descriptive 
statistics (e.g. number of immunomodulatory agents used per patient). Additional summaries 
presenting the percentage of patients using immunomodulatory agents in each defined category 
in Appendix 1 and the immunomodulatory agents summarized by preferred term may be 
generated.  
Immunomodulatory agents used will be listed by patient.  
7.4.3 
Tertiary Analyses 
7.4.3.1 
Markers of Disease Severity 
Markers of disease severity will be summarized with descriptive statistics. The summary will 
include both recorded values and change from baseline for each scheduled assessment and 
maximum and minimum post-baseline assessment. Both scheduled and unscheduled visits will 
be considered in derivations of the maximum and minimum post-baseline assessments.  
Markers of disease severity data will be listed by patient.  
7.5 
Safety Analyses 
Safety will be assessed through 30 days of follow-up after the last dose of study treatment 
andassessed by the cumulative incidence, severity and seriousness of TEAEs, drug 
discontinuations, laboratory values, and clinical assessments.    
Summaries will be tabulated by treatment arm and in total for the Safety Population.  
7.5.1 
Adverse Events 
Summaries of adverse events will be presented by treatment arm and in total for the Safety 
Population.  
An overview of treatment-emergent adverse events will be provided which summarizes the 
patient incidence of the following for the Safety Population. This overview will include the 
number and percentage of patients with: 
Any TEAEs, 
TEAEs related to study treatment, 
Serious TEAEs (TESAEs),  
CTCAE Grade 3+ TEAEs, 
TEAEs with outcome of death, 
TEAEs leading to study drug discontinuation, interruption, or dose reduction, 
Cardiac TEAEs (defined by MedDRA SMQ List), 


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Haemorrhage TEAEs (defined by MedDRA SMQ List), 
The number and percentage of patients with TEAEs will be tabulated by the highest CTCAE 
Grade, System Organ Class, and Preferred Term (PT).  
In addition, serious TEAEs (TESAEs), CTCAE grade 3 or more TEAEs, TEAEs leading to 
study drug discontinuation, interruption, or dose reduction, TEAEs with an outcome of death, 
and related TEAEs will be summarized by System Organ Class and PT.  
The PT of TEAEs of all grades and grade 3 or more TEAEs will also be presented for each 
treatment arm in order of decreasing frequency. 
Cardiac and haemorrhage TEAEs will also be summarized by System Organ Class and PT. 
For all above summaries, patients with multiple adverse events will be counted only once per 
System Organ Class and PT.  
Listings of all AEs (i.e. including those that are not treatment-emergent), SAEs, AEs leading to 
treatment discontinuation, AEs leading to treatment interruption or dose reduction, AEs with 
outcome of death, Cardiac TEAEs, and Haemorrhage TEAEs will be provided.  
7.5.2 
Laboratory Assessments 
Clinical laboratory evaluations will be summarized using descriptive statistics for all 
laboratory parameters including absolute measurements and changes from baseline by 
scheduled time of evaluation. Changes from baseline by scheduled time of evaluation will 
include last visit on-study, maximum post-treatment value, and minimum post-treatment value. 
Both scheduled and unscheduled post-treatment visits will be considered for the summaries of 
the maximum and minimum post-treatment values. Results will be presented in SI units.  
Laboratory results will be graded according to NCI-CTCAE version 4.03 as applicable. A shift 
table, presenting the frequency tabulation for baseline to each timepoint and the worst post-
treatment value according to the NCI-CTCAE grade, will be provided for selected clinical 
laboratory tests. For select parameters (e.g. glucose), separate shift tables indicating hyper  
and hypo-directionality of change may be produced. Both scheduled and unscheduled post-
treatment visits will be considered in tabulation of the worst post-treatment value. 
Clinical laboratory evaluations in SI units will be listed, including high and low flags, CTCAE 
grades where applicable, and the corresponding normal range. 
7.5.3 
Vital Signs 
A table summarizing clinically notable blood pressure and weight measurements which are 
aligned with CTCAE cut-offs, where available, will be displayed.  The proportion of subjects 
whose worst observed values while on study (on or after the first day of treatment) meet the 
following clinically notable criteria will be tabulated by treatment arm: 


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Systolic Blood Pressure 
< 85 mm Hg 
 140 - < 160 mm Hg 
 160 mm Hg 
Diastolic Blood Pressure 
< 50 mm Hg 
 90 - < 100 mm Hg 
 100 mm Hg 
Weight gain from baseline 
 5% - < 10% increase 
 10% - < 20% increase 
 20% increase 
Weight loss from baseline 
 5% - < 10% decrease 
 10% - < 20% decrease 
 20% decrease 
Vital signs will be listed by patient.  
7.5.4 
Electrocardiograms 
The frequency distribution of abnormal mean QTcF interval measurements on study (after the 
first study drug treatment through the last dose of study drug) will be summarized. That is, the 
proportion of subjects with the worst mean QTcF interval on study will be reported, and the 
following QTcF intervals will be tabulated by treatment arm: 
A measured value  
> 450 ms 
 > 480 ms 
 > 500 ms 
Change 
> 0 and 
 
> 10 and < 20 ms above baseline 
 


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> 30 ms above baseline 
> 60 ms above baseline 
Plots of the QTcF  across study day (Day8, Day 15, Day 22 and Day28 )will also be presented 
for each treatment arm. 
ECG assessments including clinical significance will be listed by patient.  
7.5.5 
Other Safety Assessments 
If applicable, other safety assessments will be listed by patient.  
8 
GENERAL INFORMATION 
8.1 
Statistical Software 
The generation of analysis datasets and analysis tables, figures, and listings (TFLs) will be 
done using SAS® version 9.4 or higher. The Medpace standard operating procedures (Medpace 
Standard Operating Procedures GL-DS-02-S4 and GL-DS-03-S3) will be followed for the 
validation of all SAS programs and outputs.   
8.2 
Format of Tables, Listings, and Figures 
The format of tables, listings, and figures will be described in a stand-alone programming 
specifications document that will be prepared before database lock.   
9 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSIS 
No changes from the protocol-specified analysis are planned.  
10 REFERENCES 
Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., ... & Li, X. (2020). A trial of lopinavir
ritonavir in adults hospitalized with severe Covid-19. New England Journal of Medicine  
Goyal, P., Choi, J. J., Pinheiro, L. C., Schenck, E. J., Chen, R., Jabri, A., ... & Hoffman, K. L. 
(2020). Clinical Characteristics of Covid-19 in New York City. New England Journal of 
Medicine. 
 
 


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11 APPENDIX 1: IMMUNOMODULATORY AGENTS 
Immunomdulatory agent usage will be identified based on concomitant medications that are 
classified according to the following WHODD preferred names. 
 Table 8  MedDRA Preferred Term List for Immunomodulatory Agents 
Immunomodulatory Agent Category 
Preferred Names(s)* 
Corticosteroids 
Decadron, Dexamethason, Hydrocortisone, 
Metholprednisiolne, Prednisone, Solumedrol 
IL-6 inhibitors 
Tocilizumab 
IL-1 inhibitors 
Anakinra  
Antiretrovirals 
Remdesivir 
*WHO-DDE B3, March, 2020.