Clinical trial NCT04377620
Conditions: COVID-19
Keywords: Cytokine storm COVID-19 ARDS SARS-CoV-2 ruxolitinib pneumonia
Sponsor: Incyte Corporation
Start date: 2020-05-24; Completion date: 2021-02-26
Enrollment: 211 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of ruxolitinib in the treatment of participants with COVID-19-associated Acute Respiratory Distress Syndrome (ARDS) who require mechanical ventilation.

Detailed description:

Arms: arm 1: Matching Placebo will be administered BID approximately 12 hours apart without regard to food/feeding via enteric feeding tube or oral. arm 2: Ruxolitinib 5mg will be administered BID approximately 12 hours apart without regard to food/feeding via enteric feeding tube or oral. arm 3: Ruxolitinib 15mg will be administered BID approximately 12 hours apart without regard to food/feeding via enteric feeding tube or oral.
Interventions: intervention 1: Placebo intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: Placebo administered BID approximately 12 hours apart intervention 2: Ruxolitinb administered BID approximately 12 hours apart

Protocol documents:
Prot_000.pdf: 
Incyte Co1poration 
Protocol INCB 18424-369 Am 1 
Version 2 
Clinical Study Protocol 
Page 1 of73 
02 JUN2020 
INCB 18424-369/NCT04377620
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Study to Assess the Efficacy and Safety of Ruxolitinib in Participants 
With COVID-19-Associated ARDS Who Require Mechanical 
Ventilation (RUXCOVID-DEVENT) 
Product: 
Ruxolitinib (INCB018424) 
IND Number: 
149,270 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
21 APR 2020 
Protocol Amendment 1: 
02 JUN 2020 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and countty-specific regulations in which the study is being conducted. 
The infonnation in this docwnent is confidential No part of this information may be duplicated, referenced, or 
trans1nitted in any fonn or by any means ( electt·onic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 
CONFIDENTIAL 


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Protocol INCB 18424-369 Am 1 
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CONFIDENTIAL 
INVESTIGATOR'S AGREEMENT 
I have read the INCB 18424-369 Protocol Amendment 1 (dated 02 JUN 2020) and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
(Printed Name of Investigator) 
(Signature of Investigator) 
(Date) 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1.
PROTOCOL SUMMARY ..........................................................................................10 
2.
INTRODUCTION ......................................................................................................17 
2.1. 
Background .................................................................................................................17 
2.1.1. 
Ruxolitinib ..................................................................................................................18 
2.1.2. 
Additional Evidence for Cytokine Release Syndrome and JAK-STAT 
Activation in COVID-19–Associated Acute Respiratory Distress Syndrome ...........18 
2.1.2.1. 
Laboratory Evidence ...................................................................................................18 
2.1.2.2. 
Animal Models ...........................................................................................................19 
2.1.2.3. 
Clinical Evidence ........................................................................................................19 
2.1.3. 
Background Summary ................................................................................................19 
2.2. 
Purpose .......................................................................................................................20 
3.
OBJECTIVES AND ENDPOINTS ............................................................................20 
3.1. 
Primary Estimates .......................................................................................................21 
4.
STUDY DESIGN .......................................................................................................22 
4.1. 
Overall Design ............................................................................................................22 
5.
RATIONALE .............................................................................................................23 
5.1. 
Rationale for Study Design .........................................................................................23 
5.1.1. 
Screening Period .........................................................................................................23 
5.1.2. 
Study/Treatment Period ..............................................................................................23 
5.2. 
Rationale for Choice of Background Therapy ............................................................24 
5.3. 
Rationale for Dose/Regimen and Duration of Treatment ...........................................24 
5.4. 
Rationale for Choice of Control Drugs (Comparator/Placebo) or 
Combination Drugs .....................................................................................................25 
5.5. 
Purpose and Timing of Interim Analyses/Design Adaptations ..................................25 
5.6. 
Risks and Benefits ......................................................................................................25 
6.
STUDY POPULATION .............................................................................................27 
6.1. 
Inclusion Criteria ........................................................................................................27 
6.2. 
Exclusion Criteria .......................................................................................................27 
7.
STUDY TREATMENT ..............................................................................................29 
7.1. 
Study Treatment Administered ...................................................................................29 
7.1.1. 
Supply of Study Treatment .........................................................................................30 


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7.1.2. 
Treatment Duration .....................................................................................................30 
7.2. 
Other Treatments ........................................................................................................30 
7.2.1. 
Concomitant Therapy .................................................................................................30 
7.2.1.1. 
Permitted Concomitant Therapy Requiring Caution and/or Action ...........................30 
7.2.1.2. 
Coadministration With Potent CYP3A4 Inhibitors ....................................................31 
7.2.1.3. 
CRRT and Intermittent Hemodialysis ........................................................................31 
7.2.2. 
Prohibited Medication ................................................................................................31 
7.3. 
Participant Numbering, Treatment Assignment, and Randomization ........................31 
7.3.1. 
Participant Numbering ................................................................................................31 
7.3.2. 
Treatment Assignment, and Randomization ...............................................................32 
7.4. 
Treatment Blinding .....................................................................................................32 
7.5. 
Dose Modification ......................................................................................................32 
7.5.1. 
Dose Modifications .....................................................................................................32 
7.5.1.1. 
Follow-Up on Potential Drug-Induced Liver Injury Cases ........................................32 
7.6. 
Additional Treatment Guidance .................................................................................33 
7.6.1. 
Treatment Compliance ................................................................................................33 
7.6.2. 
Recommended Treatment of Adverse Events ............................................................33 
7.6.2.1. 
Neutropenia .................................................................................................................33 
7.6.2.2. 
Thrombocytopenia ......................................................................................................33 
7.6.2.3. 
Other Adverse Events (Nonhematologic) Attributed to Ruxolitinib/Placebo ............34 
7.7. 
Preparation and Dispensation .....................................................................................34 
7.7.1. 
Handling of Study Treatment .....................................................................................34 
8.
INFORMED CONSENT PROCEDURES .................................................................35 
9.
VISIT SCHEDULE AND ASSESSMENTS ..............................................................36 
9.1. 
Screening ....................................................................................................................36 
9.1.1. 
Information to Be Collected on Screening Failures ...................................................36 
9.2. 
Participant Demographics/General Medical History ..................................................36 
9.3. 
Efficacy .......................................................................................................................37 
9.3.1. 
Clinical Status (9-Point Scale) ....................................................................................37 
9.3.2. 
Vital Signs ..................................................................................................................37 
9.3.3. 
Arterial Blood Gases, PaO2/FiO2, and Pulse Oximetry ..............................................38 
9.3.4. 
Sequential Organ Failure Assessment Score ..............................................................38 
9.3.5. 
In-Hospital Outcomes .................................................................................................38 


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9.3.6. 
Lung Imaging ..............................................................................................................38 
9.4. 
Safety ..........................................................................................................................38 
9.4.1. 
Adverse Events ...........................................................................................................38 
9.4.2. 
Presence SARS-CoV-2 Virus/Viral Load/Antibody Testing .....................................39 
9.4.3. 
Laboratory Evaluations ...............................................................................................39 
9.4.3.1. 
Hematology .................................................................................................................39 
9.4.3.2. 
Chemistry ....................................................................................................................39 
9.4.3.3. 
Inflammatory Markers ................................................................................................39 
9.4.3.4. 
Monitoring of Thromboembolic Risk .........................................................................40 
9.4.4. 
Height and Weight ......................................................................................................40 
9.4.5. 
Pregnancy and Assessments of Fertility .....................................................................40 
9.5. 
Correlative Studies ......................................................................................................40 
9.5.1. 
Sample Collection, Processing, and Shipment ...........................................................40 
9.5.2. 
Biomarker Analysis ....................................................................................................40 
10.
TREATMENT DISCONTINUATION AND STUDY WITHDRAWAL .................41 
10.1. 
Discontinuation and Completion ................................................................................41 
10.1.1. 
Study Treatment Discontinuation and Study Withdrawal ..........................................41 
10.1.2. 
Replacement Policy ....................................................................................................42 
10.1.3. 
Withdrawal of Informed Consent ...............................................................................42 
10.1.4. 
Lost to Follow-Up .......................................................................................................42 
10.1.5. 
Early Study Termination by the Sponsor ....................................................................43 
10.2. 
Study Completion and Post–Study Treatment ............................................................43 
11.
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................44 
11.1. 
Definition of Adverse Event .......................................................................................44 
11.2. 
Definition of Serious Adverse Event ..........................................................................45 
11.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........46 
11.4. 
Reporting of Serious Adverse Events .........................................................................48 
11.5. 
Emergency Unblinding of Treatment Assignment .....................................................49 
11.6. 
Pregnancy ...................................................................................................................49 
11.7. 
Warnings and Precautions ..........................................................................................50 
11.8. 
Product Complaints ....................................................................................................50 
11.9. 
Treatment of Overdose ...............................................................................................51 


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12.
STATISTICS ..............................................................................................................51 
12.1. 
Sample Size Determination ........................................................................................51 
12.2. 
Populations for Analysis .............................................................................................52 
12.3. 
Level of Significance ..................................................................................................53 
12.4. 
Statistical Analyses .....................................................................................................53 
12.4.1. 
Primary and Secondary Analysis ................................................................................53 
12.4.2. 
Safety Analyses ..........................................................................................................55 
12.4.3. 
Exploratory Efficacy Analyses ...................................................................................56 
12.5. 
Interim Analysis ..........................................................................................................56 
12.5.1. 
Efficacy Analysis ........................................................................................................56 
12.5.2. 
Futility Analysis for Overall Survival ........................................................................57 
13.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................58 
13.1. 
Investigator Responsibilities .......................................................................................58 
13.2. 
Data Management .......................................................................................................59 
13.3. 
Data Privacy and Confidentiality of Study Records ...................................................60 
13.4. 
Financial Disclosure ...................................................................................................61 
13.5. 
Publication Policy .......................................................................................................61 
13.6. 
Study and Site Closure ................................................................................................62 
14.
REFERENCES ...........................................................................................................63 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................66 
APPENDIX B. 9-POINT ORDINAL SCALE (SECONDARY ENDPOINT) ..........................67
APPENDIX C. SEQUENTIAL ORGAN FAILURE ASSESSMENT SCORE .........................68 
APPENDIX D. LIST OF CYP3A4 INHIBITORS AND INDUCERS .......................................70 
APPENDIX E. CORRELATIVE SERUM COLLECTION, PROCESSING, AND 
SHIPPING INFORMATION .....................................................................................71 
APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................72 


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LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................10 
Table 2: 
Key Study Design Elements .......................................................................................11 
Table 3: 
Schedule of Activities .................................................................................................15 
Table 4: 
Objectives and Endpoints ...........................................................................................20 
Table 5: 
Study Treatment Information .....................................................................................29 
Table 6: 
Ruxolitinib Dose Levels .............................................................................................32 
Table 7: 
COVID-19 9-Point Ordinal Clinical Status ................................................................37 
Table 8: 
Simulation Estimates for Power and Type 1 Error for Various Mortality 
Rates ...........................................................................................................................52 
Table 9: 
Populations for Analysis .............................................................................................52 
Table 10: Analyses of Primary and Secondary Endpoints ..........................................................53 
Table 11: In-Hospital Outcome Event-Free Days Variable Definition ......................................55 
Table 12: Interim Analysis for Day 29 Mortality With HSD(–4) ..............................................56 
Table 13: Type 1 Error Allocated to 5 mg BID to 15 mg BID Comparison Based on 
Timing for Rejection of Each Null Hypothesis ..........................................................57 
Table 14: Projected Futility Analysis Rules for Example Enrollment Profile ............................57 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................14 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AE 
adverse event 
aGVHD 
acute graft versus host disease 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
BAL 
bronchoalveolar lavage 
BID 
bis in die/twice a day 
BMI 
body mass index 
CAR 
chimeric antigen receptor 
CK 
creatine kinase 
CK-MB 
creatine kinase myocardial band 
CoV 
coronavirus 
COVID-19 
coronavirus disease 2019 
CRP 
C-reactive protein
CRRT 
continuous renal replacement therapy 
CRS 
cytokine release syndrome 
CT 
computerized tomography 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HLH 
hemophagocytic lymphohistiocytosis 
HSD 
Hwang-Shih-DeCani 
HU 
hydroxyurea 


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Abbreviations and 
Special Terms 
Definition 
ICU 
intensive care unit 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IL 
interleukin 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
JAK 
Janus kinase 
LPS 
lipopolysaccharide 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
PD 
pharmacodynamic(s) 
PET-MF 
post–essential thrombocythemia myelofibrosis 
PMF 
primary myelofibrosis 
PML 
progressive multifocal leukoencephalopathy 
POM 
proportional odds model 
PP 
per protocol 
PPV-MF 
post–polycythemia vera myelofibrosis 
PV 
polycythemia vera 
QD 
once a day 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RRT 
renal replacement therapy 
SAE 
serious adverse event 
SARS-CoV 
severe acute respiratory syndrome coronavirus 
sHLH 
secondary hemophagocytic lymphohistiocytosis 
SoC 
standard-of-care 
SOFA 
sequential organ failure assessment 
STAT 
signal transducer and activator of transcription 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 


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Protocol INCB 18424-369 Am 1 
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CONFIDENTIAL 
1.
PROTOCOL SUMMARY
Protocol Title:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study 
to Assess the Efficacy and Safety of Ruxolitinib in Participants With COVID-19–Associated 
ARDS Who Require Mechanical Ventilation (RUXCOVID-DEVENT) 
Protocol Number:  INCB 18424-369 
Objectives and Endpoints: 
Table 1 presents the primary and major/key secondary objectives and endpoints. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the 28-day mortality rate of ruxolitinib 
5 mg BID + SoC therapy and ruxolitinib 15 mg BID + 
SoC compared with placebo + SoC therapy, in 
participants with COVID-19–associated ARDS who 
require mechanical ventilation. 
Proportion of participants who have died due to any 
cause through Study Day 29. 
Secondary 
To evaluate the efficacy of ruxolitinib 5 mg BID + SoC 
therapy and ruxolitinib 15 mg BID + SoC therapy 
compared with placebo + SoC therapy on in-hospital 
outcomes, in participants with COVID-19–associated 
ARDS who require mechanical ventilation. 
At Day 29, the number of ventilator-free days, 
ICU-free days, oxygen-free days, vasopressor-free 
days, and hospital-free days will be summarized by 
treatment group. 
To evaluate the efficacy of ruxolitinib 5 mg BID + SoC 
therapy and ruxolitinib 15 mg BID + SoC therapy 
compared with placebo + SoC therapy using a 9-point 
ordinal scale at Study Days 15 and 29, in participants 
with COVID-19–associated ARDS who require 
mechanical ventilation. 
Ordinal scale: 
•
Percentage of participants with at least 2-point
improvement in clinical status at Day 15 and at
Day 29.
•
Percentage of participants with at least 1-point
improvement in clinical status at Day 15 and at
Day 29.
•
Time to improvement from baseline category to
earliest 1-point improvement in the ordinal scale.
•
Percentage of participants in each 9-point ordinal
scale category Day 29.
•
Mean change in the 9-point ordinal scale from
baseline to Days 15 and 29.
To evaluate the efficacy of ruxolitinib 5 mg BID + SoC 
therapy and ruxolitinib 15 mg BID + SoC therapy 
compared with placebo + SoC therapy on change from 
baseline SOFA score, in participants with 
COVID-19–associated ARDS who require mechanical 
ventilation. 
Change from baseline to Days 3, 5, 8, 11, 15, and 29 in 
SOFA score. 
To evaluate the safety of ruxolitinib 5 mg BID + SoC 
therapy and ruxolitinib 15 mg BID + SoC therapy 
compared with placebo + SoC therapy, in the treatment 
of participants with COVID-19–associated ARDS who 
require mechanical ventilation. 
Number and proportion of participants with 
treatment-related side effects (as assessed by CTCAE 
v5.0) and SAEs; includes clinically significant changes 
in laboratory measures and vital signs. 


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Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 
Table 2: 
Key Study Design Elements 
Sponsor and clinical phase 
Incyte/Phase 3 
Investigation type 
Drug (ruxolitinib/INCB018424) 
Study type 
Interventional 
Purpose and rationale 
There are no approved treatments for COVID-19–associated ARDS.  
The purpose of this study is to evaluate the efficacy and safety of 
ruxolitinib in the treatment of participants with COVID-19–associated 
ARDS who require mechanical ventilation. 
Study design 
This is a randomized (2:2:1, ruxolitinib 5 mg BID to ruxolitinib 15 mg 
BID to placebo [placebo randomized 1:1 to 5 mg or 15 mg]), 
double-blind, placebo-controlled, 29-day, multicenter study to assess 
the efficacy and safety of 2 doses of ruxolitinib (5 mg and 15 mg BID) 
+ SoC therapy, compared with placebo + SoC therapy, in participants
aged ≥ 12 years with COVID-19–associated ARDS who require
mechanical ventilation.
Study population 
Approximately 500 participants ages 12 and older with COVID-19–
associated ARDS who require mechanical ventilation at study 
enrollment. 
Key inclusion criteria 
• Participant or guardian/health proxy must provide informed consent
(and assent, if applicable) before any study assessment is
performed.
• Male or female participants aged ≥ 12 years.
• Participants with coronavirus (SARS-CoV-2) infection confirmed
≤ 3 weeks prior to randomization by any test with local regulatory
approval.
• Participants who are intubated and receiving mechanical ventilation
due to COVID-19–associated ARDS and have a PaO2/FiO2 of
≤ 300 mmHg within 6 hours of randomization.
• Participants with lung imaging showing bilateral or diffuse
pulmonary infiltrates on chest x-ray or CT scan.


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Protocol INCB 18424-369 Am 1 
Key exclusion criteria 
Study treatment 
Version 2 
Page 12 of73 
02 JUN2020 
• Known history of hypersensitivity to any dmgs or metabolites of
similar chemical classes as mxolitinib.
• Presence of severely impaired renal function defined by estimated
creatinine clearance < 15 mL/min measured or calculated by
Cockcroft-Gault equation or calculated by the updated bedside
Schwartz equation. Pa1ticipants must not be receiving CRRT or
intermittent hemodialysis at screening.
• In the opinion of the investigator, unlikely to smvive for > 24 hours
from randomization.
• Suspected active uncontrolled bacterial, fungal, viral, or other
infection (besides COVID-19).
• CmTently receiving ECMO.
• Participant may not be sharing a ventilator, or co-ventilating, with
any other patient.
• Treatment with anti-IL-6, IL-6R, IL-IRA, IL-I, or GM-CSF
antagonists, or a BTK inhibitor, within 7 days of randomization.
• Treatment with a JAK inhibitor within 30 days of randomization. 
• Participants who are on long-term use of antirejection or
immunomodulatory drugs.
• Pregnant or nursing (lactating) women.
Ruxolitinib 5 mg BID, mxolitinib 15 mg BID, or matching-image 
placebo (placebo randomized I : I to match mxolitinib 5 mg or 15 mg) 
for 14 days with possible extension of treatment to 28 days 
Treatment of interest 
Ruxolitinib 5 mg tablets 
-----------+ 
----------------------1 
Principal coordinating 
investigator 
Efficacy assessments 
Key safety assessments 
Other assessments 
• Overall smvival through Study Day 29
• In-hospital outcomes
• Clinical status using a 9-point ordinal scale
• Vital signs, oxygenation and ventilator par·ameters
• SOFA score
• Adverse event monitoring through safety follow-up period
• Laboratory mar·kers
• SARS-CoV-2 viral load
Inflammatory markers including fenitin, CRP, D-dimer, procakitonin, 
IL-6 at sites where feasible 
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Data analysis 
Individual comparisons between placebo and ruxolitinib treatment 
groups will be performed in a pairwise fashion (placebo vs 5 mg BID 
and placebo vs 15 mg BID). 
The primary endpoint of the Day 28 mortality rate will be analyzed 
using the ITT population using a logistic regression model including 
treatment group, ARDS severity  mild/moderate (PaO2/FiO2 > 100 to 
≤ 300 mmHg) vs severe (PaO2/FiO2 ≤ 100 mmHg), and gender as fixed 
effects and investigational site as a random effect.  The statistical test 
will test the null hypothesis that the odds-ratio between ruxolitinib and 
placebo treatment is 1 with a 1-sided test. 
Overall familywise Type I error control of 2.5% (1-sided) will be 
accomplished using a Dunnett's procedure, where the nominal alpha 
level for the individual comparisons will be adjusted to 0.01436968.  
An interim analysis for efficacy is intended when the first 40% of the 
planned randomized participants have died or have reached their 
Day 29 assessment, and additional futility analyses for the primary 
endpoint based on a Cox regression model are planned weekly for the 
study. 
If both ruxolitinib groups are found to be superior to placebo, then a 
statistical comparison will be performed between the 2 ruxolitinib 
groups in an alpha-controlled fashion.  The approach will account for 
Type I error expended at the interim analysis. 
The distribution of 9-point ordinal scale will be summarized by 
treatment arm as percentages.  The odds of observing a better category 
on the ordinal scale (lower number) will be analyzed with a POM 
separately at Days 15 and 29.   
Each model will include treatment group, ARDS severity category 
(mild or moderate vs  severe), and gender as fixed covariates and 
investigational site as a random effect.  The estimated odds ratios, 
p-values, and 95% confidence intervals will be presented.
The study will be considered positive if ruxolitinib demonstrates a
statistically significant greater reduction Day 28 mortality rate.
DMC 
An DMC will be formed.  The DMC will consist of qualified 
individuals who are not involved with the conduct of the study.  The 
establishment, composition, roles, duties, and responsibilities of the 
DMC are addressed in the approved DMC charter. 
Key words 
Cytokine storm, COVID-19, ARDS, SARS-CoV-2, ruxolitinib 
The study design is presented in Figure 1.  Adherence to the study design requirements, 
including those specified in the SoA (see Table 3), is essential and required for study conduct. 


Incyte Co1poration 
Protocol INCB 18424-369 Am 1 
Figure 1: 
Study Design Schema 
... 
<:'! 
Screening (Day -1) 
Eligibility': 
N 
QJ 
N 
----·E 
0 
"O 
C 
(0 
a: 
;;, 12 years 
Confirmed SARS-CoV-2 infection confirmed 
s 3 weeks prior to randomization 
•
Patients with COVID-19-associated ARDS 
who require mechanical ventilation 
Lung imaging demonstrating bilateral or 
diffuse pulmonary infiltrates
' Not induslve; see Section 6 for complete eligibility criteria. 
Day 1 
Version 2 
Study Period 
Initial Treatment Period
- -
Optional Continued -
Days 1-14
Day 
15 
Treatment 
Day 29 
Days 15-28 
Ruxolltlnlb 15 mg BID+ SoC Therapy 
Ruxolitinib 5 mg BID + SoC Therapy 
Placebo BID + SoC Therapy0 
• Placebo arm will be randomized between a 5 mg BID (I tablet/dosel and 15 mg BID (3 tablets/dose). 
CONFIDENTIAL 
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AE Follow-Up 
(28 ± 3 days 
after last dose) 


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Table 3: 
Schedule of Activities 
Study Day 
Screening 
Study Period 
AE 
Follow-Up 
Day −1 
(Screening) Day 1a 
Day 2-14 
(every day unless otherwise 
specified below) 
Day 15b,c 
Day 16-28 
(every day unless 
otherwise specified below) Day 29c 
28 ± 3 
days after 
last dosed 
Informed consent (assent, if applicable)e 
X 
Inclusion/exclusion criteria 
X 
X 
Contact IRT 
X 
X 
X 
X 
X 
Demographics/medical history 
X 
SARS-CoV-2 virus/viral load/antibody testingf 
X 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
Height (if feasible) and weight 
X 
ABGs, PaO2/FiO2, and pulse oximetryh 
X 
X 
X 
X 
X 
X 
Ventilator/oxygen supporti 
X 
X 
X 
X 
X 
X 
Clinical status evaluation with 9-point ordinal 
scalej 
X 
X 
X 
X 
X 
X 
Drug dispensation and administrationk 
X 
Days 2 through14 
Days 15 through 28 (if applicable) 
Hematology (local laboratory assessments)l 
X 
X 
Days 3, 5, 7, 9, 11, 13 
(while in hospital) 
X 
Days 17, 19, 21, 23, 25, 27 
(while in hospital) 
X 
Clinical chemistry (local laboratory 
assessments)l 
X 
X 
Days 3, 5, 7, 9, 11, 13 
(while in hospital) 
X 
Days 17, 19, 21, 23, 25, 27 
(while in hospital) 
X 
Inflammatory markers (ferritin, CRP, D-dimer, 
procalcitonin, IL-6 [if feasible]; local laboratory 
assessments)l 
X 
X 
Days 3, 5, 7, 9, 11, 13 
(while in hospital) 
X 
Days 17, 19, 21, 23, 25, 27 
(while in hospital) 
X 
Correlative serum collection (optional)m 
X 
Day 7 only 
X 
Pregnancy test (local laboratory assessments)n 
X 
X 
Lung imaging (chest x-ray or CT scan)o 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medicationsp 
X 
X 
X 
X 
X 
X 
Surgeries and proceduresp 
X 
X 
X 
X 
X 
X 
SOFA scoreq 
X 
X 
X 
X 
X 
X 
In-hospital outcomesr 
X 
X 
X 
X 
X 
X 
X 
a The Day 1 visit may occur on the same day as the screening visit.  If this occurs, non-laboratory assessments that occur at both visits do not have to be repeated. 
b If treatment is approved to continue beyond the initial 14-day period (ie, Day 15 through 28), if needed, contact IRT to dispense additional study drug. 
c If participant is discharged from the hospital, the scheduled assessments may be performed remotely, via telephone. 


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d A follow-up assessment for patient-reported AEs and in-hospital outcomes (if applicable) will be conducted 28 ± 3 days after the last dose of study treatment.  If participant has 
been discharged, the assessment may be performed remotely, via telephone. 
e Participant must provide informed consent (and assent, if applicable) before any study assessment is performed;  informed consent may be obtained from a health care proxy 
where appropriate. 
f Confirmation of  SARS-CoV-2 infection ≤ 3 weeks prior to randomization by any test with local regulatory approval.  Confirmation prior to informed consent (and assent, if 
applicable) is acceptable.  Viral load and antibody testing may be performed by any approved method and is only required if local capabilities allow; a consistent method and 
specimen source should be used at all timepoints. 
g Vital signs will be collected once daily while hospitalized between 7:00 AM and 12:00 PM local time and include heart rate, respiratory rate, systolic and diastolic blood 
pressure, and body temperature.  Not required after discharge. 
h Arterial blood gases will be collected during screening, within 6 hours of planned randomization, to assess PaO2/FiO2.  Thereafter, ABGs will be performed daily while 1) the 
participant is receiving mechanical ventilation, OR 2) the participant has an arterial line.  Parameters including pH, PaO2, PaCO2, and SaO2 will be collected for each ABG.  
SpO2 (pulse oximetry) will be recorded in the eCRF once daily while hospitalized.  ABGs and SpO2 not required after discharge. 
i Ventilator settings (as applicable) will be collected once daily between 7:00 AM and 12:00 PM local time.  Settings to be collected include mode, FiO2, PEEP, VT, and 
respiratory rate.  Dates of intubation and extubation (if applicable) will be recorded.  Supplemental oxygen support post-extubation will be collected daily through Day 29, until 
hospital discharge.  
j If participant is discharged, a telephone call may be used to perform assessment.  See Appendix B for scale. 
k Beginning at Day 15, the participant may continue treatment up to Day 28 at the discretion of the investigator and after approval by the sponsor medical monitor. 
l Hematology, clinical chemistry, and markers of inflammation should be measured by the local laboratory.  See Section 9.4.3 for required analytes.  If participant is discharged,
local laboratory assessments may be performed on Day 15 and/or Day 29 if feasible.
m An optional serum sample will be collected at Day 1 (predose) and Day 7 and 15 for cytokine analysis.  See Section 9.5.1 for collection, processing, storage and shipment 
instructions. 
n Pregnancy test:  only for females of childbearing potential, serum pregnancy test (serum hCG) will be performed at screening assessment.  Serum or urine test is acceptable at 
subsequent assessment(s). 
o Screening chest imaging may be ≤ 2 days prior to Day 1.
p All medications, procedures, and significant non-drug therapies administered from randomization through Day 29 must be recorded on the appropriate eCRF.  Additionally,
antivirals and therapeutic agents administered for SaRS-CoV-2 infection/COVID-19 infection and treatments for COVID-19 pneumonia/ARDS administered within 14 days of 
randomization must also be recorded.  If participant is discharged from the hospital, the scheduled assessments may be performed via telephone. 
q The SOFA score is to be determined per Appendix C.  Not required after discharge from the ICU.  SpO2 method for calculating respiratory score may be used if arterial blood 
gases were not performed on corresponding assessment day. 
r In-hospital outcomes will be collected on eCRFs as outlined in Section 9.3.5. 


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2.
INTRODUCTION
2.1. 
Background
In DEC 2019, the Wuhan Municipal Health Committee identified an outbreak of viral 
pneumonia cases of an unknown cause.  This outbreak of viral pneumonia was reported to the 
WHO Country Office in China on 31 DEC 2019.  Subsequently, CoV RNA was identified in 
some of the patients with viral pneumonia. 
Coronaviruses are positive-stranded RNA viruses with a crown-like appearance under an 
electron microscope due to the presence of spike glycoproteins on the envelope.  They are a large 
family of viruses that cause illness ranging from the common cold to more severe diseases such 
as Middle East respiratory syndrome and SARS-CoV. 
The novel coronavirus detected in late 2019 has been designated SARS-CoV-2, and the disease 
caused by this virus has been designated COVID-19.  This new coronavirus strain was not 
previously identified in humans and was newly named on 11 FEB 2020 by the WHO.  Genetic 
sequencing of the virus suggests that SARS-CoV-2 is a beta-coronavirus closely linked to 
SARS-CoV. 
On 11 MAR 2020, the WHO declared a pandemic for COVID-19.  According to the WHO, as of 
24 MAR 2020 over 409,000 cases of COVID-19 were reported in over 100 countries worldwide, 
with over 18,000 deaths.  To date, there is no vaccine and no specific antiviral medicine shown 
to be effective in preventing or treating COVID-19. 
While most people with COVID-19 develop mild or uncomplicated illness, approximately 14% 
develop severe disease requiring hospitalization and oxygen support, and 5% require admission 
to an ICU (China CDC Weekly 2020).  In severe cases, COVID-19 can be complicated by 
ARDS, sepsis and septic shock, and/or multiorgan failure, including acute kidney injury and 
cardiac injury (Yang et al 2020).  Of those cases that develop ARDS, there is an approximate 
50% to 80% mortality rate (Grasselli et al 2020, Zhou et al 2020).  Additionally, many patients 
with severe respiratory disease due to COVID-19 have features consistent with CRS, also 
referred to as cytokine storm, and increased activation of the JAK-STAT pathway (Hermans 
et al 2018, Wang et al 2020). 
According to the WHO interim guidance of 13 MAR 2020 on the clinical management of severe 
acute respiratory infection when COVID-19 is suspected, "older age and comorbid disease have 
been reported as risk factors for death, and recent multivariable analysis confirmed older age, 
higher SOFA score and d-dimer > 1 µg/L on admission were associated with higher mortality" 
(WHO 2020b).  The same study quoted by the WHO also noted that the median duration of viral 
RNA detection was 20.0 days (interquartile range 17.0–24.0) in survivors, but SARS-CoV-2 was 
detectable until death in nonsurvivors.  The longest observed duration of viral shedding in 
survivors was 37 days (Huang et al 2020, Zhou et al 2020). 
There are sparse data on the clinical presentation of COVID-19 in specific populations, such as 
children and pregnant women.  In children with COVID-19, the symptoms are usually less 
severe than in adults and present mainly with cough and fever, and coinfection has been 


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observed (Cai et al 2020, Xia et al 2020).  Relatively few cases have been reported of infants 
with confirmed COVID-19, and they experienced mild illness (Wei et al 2020). 
2.1.1. 
Ruxolitinib 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) is a well-established, 
potent and selective inhibitor of JAK1 and JAK2, with modest to marked selectivity against 
tyrosine kinase 2 and JAK3, respectively.  Ruxolitinib interferes with the signaling of a number 
of cytokines and growth factors that are important for hematopoiesis and immune function as 
noted in the ruxolitinib IB. 
Janus kinase signaling involves recruitment of STATs to cytokine receptors, activation, and 
subsequent localization of STATs to the nucleus leading to modulation of gene expression.  
Dysregulation of the JAK-STAT pathway has been associated with several types of cancers and 
increased proliferation as well as survival of malignant cells.  In particular, this pathway may be 
dysregulated in the majority of patients with Philadelphia chromosome-negative 
myeloproliferative neoplasms, including MF and PV, demonstrating that JAK inhibition may be 
efficacious in these diseases. 
Ruxolitinib (JAKAVI®) is currently approved in the EU for the treatment of disease-related 
splenomegaly or symptoms in adult patients with PMF (also known as chronic idiopathic MF), 
PPV-MF, or PET-MF and for the treatment of adult patients with PV who are resistant to or 
intolerant of HU. 
In the US, ruxolitinib (JAKAFI®) is approved for the treatment of intermediate or high-risk MF, 
including PMF, PPV-MF, and PET-MF in adults; for the treatment of adult patients with PV who 
have had an inadequate response to or are intolerant of HU; and for patients 12 years and older 
with steroid refractory aGVHD. 
Ruxolitinib is currently under further development for the treatment of MF, PV, essential 
thrombocytopenia, and other hematologic malignancies. 
2.1.2. 
Additional Evidence for Cytokine Release Syndrome and JAK-STAT Activation 
in COVID-19–Associated Acute Respiratory Distress Syndrome 
There is preclinical evidence from both laboratory and animal models that blockade/inhibition of 
the JAK-STAT pathway could have a beneficial effect of the cytokine driven ARDS in patients 
with COVID-19. 
2.1.2.1. 
Laboratory Evidence 
Hermans et al (2018) studied human mast cell lines and demonstrated that ruxolitinib can inhibit 
mast cell activity, possibly through prevention of STAT5 activation.  They postulated that the 
JAK-STAT pathway is a potential target for therapy to release symptom burden in mastocytosis 
and many other mast cell mediator-related diseases such as CRS. 
Hoffmann et al (2016) demonstrated that viral and bacterial coinfection in a macrophage model 
modulates the JAK-STAT signaling pathway and leads to exacerbated IP-10 expression, which 
could play a major role in the pathogenesis of pneumonia, suggesting that targeting this pathway 
could have a beneficial effect. 
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2.1.2.2. 
Animal Models 
Zhao et al (2016) looked at LPS-induced lung injury in mice, which models some of the ARDS 
manifestations (eg, cytokine increases and cell influx) as well as an increase in STAT3 
expression.  STAT3 is downstream of JAK and the authors show that STAT3 inhibition with a 
tool compound partly inhibits cytokine and cell increases after LPS challenge.  A caveat is that a 
positive control (eg, dexamethasone) is absent from the in vivo studies.  Using conditional 
knockouts of SOCS3 (an antinflammatory protein that negatively regulates JAK activity), they 
provide further evidence that the effects are STAT3 pathway–dependent.  They also show 
increased STAT3 expression in peripheral blood mononuclear cells from ARDS patients could 
be blocked with the same tool compound. 
Coon et al (2015) identified a new ubiquitinylating ligase, HECTD2, which degrades PIAS-1, an 
antinflammatory protein that negatively regulates the JAK-STAT pathway.  They show 
degradation of PIAS by HECTD2 induces lung inflammation (cytokine increases and cell 
counts) in a mouse pneumonia challenge model.  An HECTD2 inhibitor reduces lung 
inflammation in the same model (no positive control).  They also identify a polymorphism (loss 
of function) in the HECTD2 gene that appears to be protective against ARDS. 
Kenderian et al (2017) described for the first time a clinically relevant animal model of human 
CRS and demonstrated that the JAK-STAT inhibitor ruxolitinib can prevent the development of 
severe CRS without impairing the anti-tumor effect of CAR-T cells.  These findings provide a 
useful platform for the future study of CRS prevention and treatment modalities.  These 
experiments indicate that ruxolitinib could also be combined with CAR–T-cell therapy for the 
prevention of CRS in patients identified to be at high risk for the development of CRS. 
Calbet et al (2019) studied a novel pan-JAK inhibitor and showed that it reduced 
allergen-induced airway inflammation, late asthmatic response, and pSTAT activation in rats. 
In a mouse model of HLH (model of CRS), Maschalidi et al (2016) found that administration of 
ruxolitinib suppressed the harmful consequences of macrophage activation with improvement in 
vital signs and hematologic parameters. 
2.1.2.3. 
Clinical Evidence 
There is clinical evidence of efficacy with ruxolitinib in another recognized disease with CRS, 
secondary HLH.  Two pilot studies of ruxolitinib led to resolution of symptoms and associated 
laboratory abnormalities in the patients studied, alleviating the need for more toxic therapies 
(Ahmed et al 2019, Goldsmith et al 2019). 
2.1.3. 
Background Summary 
It is reasonable to consider the use of ruxolitinib in the treatment of COVID-19 patients with 
severe respiratory disease/ARDS because these patients have clinical features consistent with 
CRS/cytokine storm and increased activation of the JAK-STAT pathway (Hermans et al 2018, 
Wang et al 2020).  Moreover, recent literature specifically suggests consideration of molecules 
that block inflammatory pathways, including inhibition of the JAK-STAT pathway, where a 
number of cytokines converge, for the treatment of COVID-19 (Mehta et al 2020, Zumla 
et al 2020). 


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In summary, the above-mentioned data provide scientific justification for the study of a 
JAK-STAT inhibitor, such as ruxolitinib, in a controlled clinical study setting. 
2.2. 
Purpose 
There are no approved treatments for COVID-19–associated ARDS.  The purpose of this study is 
to evaluate the efficacy and safety of ruxolitinib in the treatment of participants with COVID-19–
associated ARDS who require mechanical ventilation. 
3.
OBJECTIVES AND ENDPOINTS
Table 4 presents the objectives and endpoints. 
Table 4: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the 28-day mortality rate of 
ruxolitinib 5 mg BID + SoC therapy and 
ruxolitinib 15 mg BID + SoC therapy compared 
with placebo + SoC therapy, in participants with 
COVID-19–associated ARDS who require 
mechanical ventilation. 
Proportion of participants who have died due to 
any cause through Study Day 29. 
Secondary 
To evaluate the efficacy of ruxolitinib 5 mg BID + 
SoC therapy and ruxolitinib 15 mg BID + SoC 
therapy compared with placebo + SoC therapy on 
in-hospital outcomes, in participants with 
COVID-19–associated ARDS who require 
mechanical ventilation. 
At Day 29, the number of ventilator-free days, 
ICU-free days, oxygen-free days, vasopressor-free 
days, and hospital-free days will be summarized 
by treatment group. 
To evaluate the efficacy of ruxolitinib 5 mg BID + 
SoC therapy and ruxolitinib 15 mg BID + SoC 
therapy compared with placebo + SoC therapy 
using a 9-point ordinal scale at Study Days 15 and 
29, in participants with COVID-19–associated 
ARDS who require mechanical ventilation. 
Ordinal scale: 
• Percentage of participants with at least
2-point improvement in clinical status at
Day 15 and at Day 29.
• Percentage of participants with at least
1-point improvement in clinical status at
Day 15 and at Day 29.
• Time to improvement from baseline category
to earliest 1-point improvement in the ordinal
scale.
• Percentage of participants in each 9-point
ordinal scale category Day 29.
• Mean change in the 9-point ordinal scale
from baseline to Days 15 and 29.


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Table 4: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Secondary (continued) 
To evaluate the efficacy of ruxolitinib 5 mg BID + 
SoC therapy and ruxolitinib 15 mg BID + SoC 
therapy compared with placebo + SoC therapy on 
change from baseline SOFA score, in participants 
with COVID-19–associated ARDS who require 
mechanical ventilation. 
Change from baseline to Days 3, 5, 8, 11, 15, and 
29 in SOFA score. 
To evaluate the safety of ruxolitinib 5 mg BID + 
SoC therapy and ruxolitinib 15 mg BID + SoC 
therapy compared with placebo + SoC therapy, in 
the treatment of participants with 
COVID-19–associated ARDS who require 
mechanical ventilation. 
Number and proportion of participants with 
treatment-related side effects (as assessed by 
CTCAE v5.0) and SAEs; includes clinically 
significant changes in laboratory measures and 
vital signs. 
Exploratory 
To evaluate the efficacy of ruxolitinib + SoC  
therapy compared with placebo + SoC therapy in 
proportion of participants requiring IL-6, IL-1, 
GM-CSF, or JAK-directed therapies. 
Proportion of participants requiring treatments 
with IL-6, IL-6R, IL-1RA, IL-1β, GM-CSF, BTK, 
or JAK-directed therapies by Day 15 and by 
Day 29 
To evaluate ruxolitinib + SoC therapy compared 
with placebo + SoC therapy on change in 
inflammatory markers (when available). 
Change from baseline to Day 15 and to Day 29 in 
the following clinical chemistry measurements: 
• Serum ferritin
• CRP
• D-dimer
• Procalcitonin
• IL-6
To evaluate ruxolitinib + SoC therapy compared 
with placebo + SoC therapy on change in 
COVID-19 virologic and serologic parameters. 
Change from baseline to Day 15 and to Day 29 in 
viral load and anti-SARS-CoV2-antibody titer.  
3.1. 
Primary Estimates 
•
Treatment – ruxolitinib added to SoC therapy.
•
Population – Participants with SARS-CoV-2 infection confirmed ≤ 3 weeks before
randomization and with COVID-19–associated ARDS requiring mechanical
ventilation.
•
Endpoint – Primary efficacy endpoint is the proportion of participants who have died
due to any cause through Study Day 29.


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•
Population-level summary – Odds-ratio comparing each of 2 doses of ruxolitinib
(5 mg BID and 15 mg BID) + SoC therapy with SoC therapy alone.  Odds-ratio
comparing 5 mg BID ruxolitinib + SoC therapy with 15 mg BID ruxolitinib + SoC
therapy, tested only if both odds-ratios for pairwise comparisons are statistically
significant.
•
Intercurrent event(s) – Discontinuation from study for reasons other than death.
4.
STUDY DESIGN
4.1. 
Overall Design
This is a randomized, double-blind, placebo-controlled, 29-day, multicenter study to assess the 
efficacy and safety of ruxolitinib 5 mg BID + SoC therapy and 15 mg BID + SoC therapy 
compared with placebo + SoC therapy, in participants aged ≥ 12 years with COVID-19–
associated ARDS who require mechanical ventilation (see Figure 1). 
Participants aged ≥ 12 years with SARS-CoV-2 virus infection confirmed ≤ 3 weeks before 
randomization by any test with local regulatory approval, hospitalized with COVID-19–
associated ARDS (demonstrated by chest x-ray or chest CT and PaO2/FiO2 ≤ 300 mmHg) who 
have been intubated and are receiving mechanical ventilation.  Participants who are unlikely to 
survive for > 24 hours after randomization (in the opinion of the treating investigator); who have 
active tuberculosis or active and uncontrolled bacterial, fungal, viral, or other infection (besides 
SARS-CoV-2 virus); or who are currently receiving ECMO support will be excluded from the 
study. 
Informed consent (written or verbal) and assent (if applicable) will be obtained from the 
participant or health care proxy before any study-related assessments or procedures are 
performed.  Thereafter, medications and eligibility criteria will be reviewed by study personnel.  
All participants signing informed consent (or by health care proxy) and assent (if applicable) 
must be registered in the IRT. 
The study will include the following: 
•
Screening period of 1 day.
•
Study period of 29 days.  Treatment with ruxolitinib 5 mg BID/placebo or ruxolitinib
15 mg BID/placebo will initially be administered for 14 days.  If in the opinion of the
treating investigator the benefit/risk is appropriate for the participant, then continued
treatment up to 28 days is permitted with approval from the sponsor medical monitor.
Approval must be requested ≥ 24 hours before initiation of dosing on Day 15.
•
AE follow-up assessment 28 (± 3) days following the last dose of study treatment.
Eligible participants will be randomized after completing the screening period (Day −1) and 
having been confirmed eligible.  Screening and randomization may occur on the same day.  
Participants will be assigned in a 2:2:1 ratio to receive ruxolitinib 5 mg BID, 15 mg BID, or  
matching-image placebo for an initial period of 14 days (see Section 7.1); participants 
randomized to placebo will be randomized 1:1 to either receive matching placebo for 5 mg BID 
(1 tablet BID) or matching placebo for 15 mg BID (3 tablets BID).  On Day 15, if in the opinion 


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of the investigator the benefit/risk is appropriate, then continued treatment up to 28 days is 
permitted with medical monitor approval.  There is no crossover between treatment groups.  
Study treatment will be given in combination with SoC therapy according to the investigator's 
clinical judgment.  Study treatment will be administered via an enteric feeding tube (see 
Section 7.1 for directions) while the participant is intubated.  Randomization will be stratified by 
ARDS severity (mild/moderate [PaO2/FiO2 > 100 and ≤ 300 mmHg] vs severe [PaO2/FiO2 
≤ 100 mmHg]; ARDS Definition Task Force et al 2012) and investigative site. 
Participants who do not meet the criteria for participation in this study (screen failures) may not 
be rescreened. 
Assessments during the 29-day study period will occur per the SoA.  See Section 9 and Table 3 
for specific assessments and timing for these assessments.  The primary endpoint of the study is 
the 28-day mortality rate.  Should a participant be discharged from the hospital during the 29-day 
study period, assessments will be performed remotely (eg, telephone call, video call) as per 
Table 3. 
A follow-up assessment (in person or remote telephone contact) for AE and clinical status will 
occur approximately 28 (± 3) days following the last dose of study treatment to complete safety 
assessments. 
This study will include a DMC, which will function independently of all other individuals 
associated with the conduct of this clinical study, including the site investigators participating in 
the study. 
5.
RATIONALE
5.1. 
Rationale for Study Design 
This randomized, double-blind, parallel-group, placebo-controlled design supports the rigorous 
assessment of efficacy as well as safety of 2 doses of ruxolitinib (5 mg BID and 15 mg BID) as 
an add-on to SoC therapy for participants with COVID-19–associated ARDS requiring 
mechanical ventilation. 
5.1.1. 
Screening Period 
The screening period allows for the assessment of participant entry criteria to ensure suitable 
participants are entered into the study. 
5.1.2. 
Study/Treatment Period 
During the treatment period, ruxolitinib 5 mg BID, 15 mg BID, or matching-image placebo BID 
(treatment arms will be randomized 2:2:1; participants randomized to placebo will be 
randomized 1:1 to either receive matching placebo for 5 mg BID [1 tablet BID] or matching 
placebo for 15 mg BID [3 tablets BID]).  Study treatment will initially be administered for 
14 days; if on Day 15, the benefit/risk is appropriate in the opinion of the investigator, continued 
treatment up to 28 days is permitted with approval from the sponsor's medical monitor.  The 
endpoints included in this study measure overall mortality, clinical, laboratory, and virologic 
status, and in-hospital outcomes during the 29-day study period.  These measurements are 


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consistent with endpoints and measurement times of the WHO COVID-19 adaptive design 
protocol (WHO 2020a, Cao et al 2020). 
The safety follow-up 28 days after last dose of study treatment will assess the long-term safety 
and tolerability profile after completion of ruxolitinib/placebo dosing. 
5.2. 
Rationale for Choice of Background Therapy 
Although there are no approved treatments for COVID-19, SoC therapy for participants with 
COVID-19 pneumonia generally includes supportive care, antiviral treatments, and when 
required, mechanical ventilation.  Thus, placebo + SoC therapy is appropriate as a control in this 
study. 
5.3. 
Rationale for Dose/Regimen and Duration of Treatment 
Ruxolitinib is currently approved in the US at doses up to 25 mg BID for the following 
indications (Jakafi 2019): 
•
Intermediate or high-risk MF, including primary MF, PV-MF and PET-MF (approved
2011; starting dose of 5, 15, or 20 mg BID)
•
Patients with PV who have had an inadequate response to or are intolerant of HU
(approved 2014; starting dose of 10 mg BID)
•
Steroid-refractory aGVHD in adult and pediatric patients 12 years and older
(approved 2019; starting dose of 5 mg BID)
In addition to the FDA-approved indications above, sHLH shares many of the same 
characteristics of COVID-19–associated cytokine storm, including being commonly virally 
induced; patients have persistent fevers, cytopenias, and hyperferritinemia and frequently 
progress to pneumonitis/ARDS.  In addition, the cytokine profile seen in COVID-19–associated 
cytokine storm demonstrates elevation in many of the same cytokines associated with sHLH, 
including IL-2, IL-7, G-CSF, IP-10, MIP-1a, MCP1, and TNF-alpha (Mehta et al 2020).  Further, 
there is evidence of macrophage activation in the BAL of patients with COVID-19.  The BAL 
from patients with severe disease shows that immunosuppressive alveolar macrophages are 
replaced with activated and highly cytokine/chemokine secretory FCN1+ macrophages (Liao 
et al 2020).  Such activated macrophages are hallmarks of the sHLH syndrome.  Ruxolitinib has 
demonstrated efficacy in the treatment of patients with sHLH (Ahmed et al 2019, Goldsmith 
et al 2019, Wang et al 2019).  In these studies, participants received ruxolitinib doses between 
5 and 20 mg BID with improvement in symptoms and inflammatory markers.  Thirty-four 
participants treated in the Wang study were treated at 0.3 mg/kg, which corresponds to a dose of 
approximately 10 mg BID.  The overall response rate was 73.5% with a complete response rate 
of 14.7%.  Seven participants in the Ahmed study were treated at 15 mg BID.  The overall 
response rate was 100% with a complete response rate of 42.8%.  In addition to clinical 
responses, hematologic parameters including platelet, RBC, and neutrophil counts improved 
while on ruxolitinib, likely as a result of decreased inflammation from treatment of the 
underlying sHLH.  At 15 mg BID, ruxolitinib was well-tolerated in this population with 
1 participant coming off study for pain in extremity.  All others remained on therapy at the time 
of publication. 


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This study will evaluate both a 5 mg BID dose of ruxolitinib, based on the approved and lowest 
effective dose for aGVHD, and a 15 mg BID dose of ruxolitinib, which demonstrated 
preliminary efficacy and a tolerable safety profile in the sHLH study (Ahmed et al 2019).  The 
initial 14-day duration of treatment should further reduce the risk of significant side effects in 
this setting.  Deaths and SAEs will be monitored in real time with routine pharmacovigilance and 
a DMC in order to detect any unexpected safety signal.  The DMC will function independently 
of all other individuals associated with the conduct of this clinical study. 
5.4. 
Rationale for Choice of Control Drugs (Comparator/Placebo) or 
Combination Drugs 
This study will compare the efficacy and safety of 2 doses (5 mg BID and 15 mg BID) of 
ruxolitinib + SoC therapy compared with matching-image placebo + SoC therapy.  Despite the 
lack of targeted treatments for COVID-19, SoC for participants with severe COVID-19 
respiratory disease generally includes supportive care and may include available antiviral agents 
and corticosteroids.  Therefore, SoC plus placebo treatment is appropriate as a control in this 
study. 
5.5. 
Purpose and Timing of Interim Analyses/Design Adaptations 
A DMC will be formed.  The DMC will consist of qualified individuals who are not involved 
with the conduct of the study.  The establishment, composition, roles, duties, and responsibilities 
of the DMC are addressed in the approved DMC charter.  Additional details regarding interim 
analyses may be found in Section 12.5. 
There will be 1 planned interim analysis conducted for efficacy based on the first 40% of 
participants enrolled in the study.  The efficacy interim analysis will be conducted when the first 
40% of the planned randomized participants (approximately 200 randomized participants) have 
died or have reached their Day 29 assessment.  Based on the results of this interim analysis, the 
DMC may choose to terminate the study for positive efficacy or continue the study with no 
changes to enrollment. 
5.6. 
Risks and Benefits 
There is preclinical evidence from both laboratory and animal models that blockade/inhibition of 
the JAK-STAT pathway could have a beneficial effect on cytokine storm and the course of 
ARDS in patients with COVID-19.  Additionally, there is clinical evidence of efficacy with 
ruxolitinib in pilot studies in another recognized disease associated with CRS/cytokine storm:  
sHLH (see Section 5.3).  However, ruxolitinib has not previously been studied in patients with 
COVID-19–associated ARDS.  Therefore, it is unknown as to whether there will be a benefit for 
patients being treated with ruxolitinib in this disease. 
The primary clinical risks with ruxolitinib treatment are the potential sequelae of decreased 
hematopoietic proliferation attributable to the inhibition of growth factor pathways associated 
with JAK inhibition.  In the Phase 3 clinical studies of ruxolitinib in participants with MF, which 
involved longer-term dosing and, in general, higher doses than those proposed in this Protocol, 
the most frequent TEAEs were dose-dependent, reversible thrombocytopenia, anemia, and 
neutropenia.  These events could increase the risk of infection, including pneumonia and 


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bronchitis, and the possibility of developing anemia, bleeding, fatigue, and/or shortness of 
breath.  In healthy volunteers, rheumatoid arthritis patients, and patients with pancreatic cancer 
or hormone-refractory prostate cancer, the effects on hematopoietic proliferation are less 
pronounced, presumably because of greater bone marrow reserve.  The most frequent 
nonhematologic AEs were mild, reversible increases in ALT and AST; bruising; 
hypercholesterolemia; dizziness; headache; and urinary tract infections.  Tuberculosis has been 
infrequently reported in patients receiving ruxolitinib to treat MF (< 1/100 patients).  The 
symptoms of tuberculosis include chronic cough with blood-tinged sputum, fever, night sweats, 
and weight loss.  There may be risks associated with rapid discontinuation of ruxolitinib. 
Patients with MF, particularly those who have stopped taking ruxolitinib suddenly after 
long-term administration, have reported return of MF symptoms such as fatigue, bone pain, 
fever, pruritus, night sweats, symptomatic splenomegaly, and weight loss.  In very few MF 
patients, respiratory distress, disseminated intravascular coagulation, and multiorgan failure have 
been reported. 
Hepatitis B viral load increases, with and without associated elevations in ALT and AST, have 
been reported in patients with chronic hepatitis B infections taking ruxolitinib.  The effect of 
ruxolitinib on viral replication in patients with chronic hepatitis B virus is unknown.  A rare 
disease called PML has been reported during treatment with ruxolitinib.  It is important to note 
that PML and infections are complications associated with MF that have been previously 
described in the absence of ruxolitinib.  Additionally, non–melanoma skin cancers, including 
basal cell, squamous cell, and a rare and aggressive type of skin cancer called Merkel cell 
carcinoma have been reported in patients who took ruxolitinib; it is unknown whether this was 
due to ruxolitinib treatment. 
In the presence of potent CYP3A4 inhibitors (see Appendix D), there is the possibility of 
increased exposure to ruxolitinib.  A dose adjustment for the 15 mg BID ruxolitinib/placebo 
group is required when coadministered with potent CYP3A4 inhibitors (see Section 7.2.1.2).  No 
dose adjustment of ruxolitinib is required for participants assigned to 5 mg BID 
ruxolitinib/placebo. 
To date, there have been multiple reports of increased thromboembolic events in COVID-19 
patients.  In addition, high prevalence of lupus anticoagulant has been noted in severe cases of 
COVID-19, which predisposes patients to thromboembolic sequelae.  Participants should be 
monitored as per SoC for elevated D-dimer, aPTT, and fibrinogen, as these may be associated 
with an increased risk of thromboembolic disease.  In addition, participants deemed at high risk 
for thromboembolic sequelae and eligible for prophylactic or therapeutic intervention per local 
evaluation should be considered for appropriate anticoagulation.  Anticoagulation with either 
prophylactic or therapeutic doses of warfarin, heparin, low-molecular-weight heparin, or 
anti-Factor Xa therapies are allowed per protocol. 
For a comprehensive assessment of the risks of ruxolitinib, refer to the IB. 


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6.
STUDY POPULATION
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant must provide informed consent (participant should provide assent if
12-17 years of age, if possible) before any study specific assessment is performed;
informed consent may be obtained from a health care proxy where appropriate and/or
institutionally approved method of consenting when applicable (verbal consent) as
defined in their local consent form.
2. Male or female participants aged ≥ 12 years.
3. Participants with coronavirus (SARS-CoV-2) infection confirmed ≤ 3 weeks prior to
randomization by any test with local regulatory approval.
4. Participants who are currently hospitalized, intubated (orotracheal or nasotracheal), and
receiving invasive mechanical ventilation due to COVID-19–associated ARDS.
Participants must have confirmed PaO2/FiO2 of ≤ 300 mmHg within 6 hours of
randomization.
5. Participants with lung imaging showing bilateral or diffuse pulmonary infiltrates on chest
x-ray or CT scan.
6.2. 
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply: 
1. Known history of hypersensitivity to any drugs or metabolites of similar chemical classes
as ruxolitinib.
2. Presence of severely impaired renal function defined by estimated creatinine clearance
< 15 mL/min measured or calculated by Cockroft-Gault equation or calculated by the
updated bedside Schwartz equation.  Participants must not be receiving CRRT or
intermittent hemodialysis at screening.
3. Suspected active uncontrolled bacterial, fungal, viral, or other infection (besides
COVID-19).
4. Known active TB infection.
5. In the opinion of the investigator, unlikely to survive for > 24 hours from randomization.
6. Currently receiving ECMO.
7. Participant may not be sharing a ventilator, or coventilating, with any other patient.


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8. Participants who are on long-term use of antirejection or immunomodulatory drugs
(eg, JAK inhibitors, IL-6/IL-6R/IL-1RA or IL-1β inhibitors).
Note:  Participants who are taking tacrolimus, cyclosporine, and mycophenolate mofetil
are eligible for study.
9. Treatment with anti–IL-6, IL-6R, IL-1RA, IL-1β, or GM-CSF antagonists, or a BTK
inhibitor, within 7 days of randomization.
10. Treatment  with a JAK inhibitor within 30 days of randomization.
11. Concurrent participation in any other interventional clinical study or experimental
treatment for COVID-19 or ARDS.
Note:  Participants on clinical studies evaluating investigational antivirals are allowed.
12. ALT or AST > 5 × ULN detected within 24 hours at screening (according to local
laboratory reference ranges).
13. Participants who have known evidence of liver cirrhosis (Child-Pugh A to C).
14. Active metastatic malignancy within 1 year of screening, unless with medical monitor
approval.
15. ANC < 1.0 × 109/L at screening (according to local laboratory).
16. Platelet count < 50 × 109/L at screening (according to local laboratory).
17. Pregnant or nursing (lactating) women.
18. Females of childbearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception as
defined below, throughout the study and for up to 30 days after stopping treatment.
Highly effective contraception methods (Appendix A) include the following:
a.
Total abstinence (when this is in line with the preferred and usual lifestyle of the
participant).  Periodic abstinence (eg, calendar, ovulation, symptothermal,
postovulation methods) and withdrawal are not acceptable methods of contraception.
b. Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking
study treatment.  In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment.
c.
Male sterilization (at least 6 months prior to screening).  The vasectomized male
partner should be the sole partner for that participant.
d. Use of oral, injected, or implanted hormonal methods of contraception.  Placement of
an IUD or IUS or other forms of hormonal contraception that have comparable
efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal
hormone contraception (in case of oral contraception, participants should have been
using the same pill on a stable dose for a minimum of 3 months before screening).
Women are considered postmenopausal and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(eg, age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 


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least 6 weeks before screening.  In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level 
assessment is she considered not of childbearing potential. 
7.
STUDY TREATMENT
7.1. 
Study Treatment Administered 
Ruxolitinib 5 mg tablets or matching placebo will be administered BID approximately 12 hours 
apart (morning and night) without regard to food/feeding.  One or 3 tablets will be administered 
per dose, depending on the assigned treatment arm (ie, 1 tablet per dose for 5 mg 
ruxolitinib/placebo and 3 tablets per dose for 15 mg ruxolitinib/placebo). 
Initially, ruxolitinib will be administered through an enteric feeding tube as follows: 
•
Suspend tablet(s) in approximately 40 mL of water with stirring for approximately
10 minutes.
−
For 5mg BID ruxolitinib/placebo treatment assignment:  one 5 mg tablet in 40 mL
water
−
For 15 mg BID ruxolitinib/placebo treatment assignment:  three 5 mg tablets in
40 mL water
Within 6 hours after the tablet has dispersed, the suspension can be administered 
through the enteric feeding tube using an appropriate syringe. 
•
The tube should be rinsed with approximately 75 mL of water.
Dosing of ruxolitinib during prone positioning is permitted if consistent with institutional policy.  
If enteric medication administration is not possible during prone positioning, administration of 
ruxolitinib should occur before or after proning sessions, adhering as closely to the BID dosing 
schedule as possible. 
If a participant is extubated during the study and is able to take oral medication, study drug may 
be administered orally with water, without regard to food.   
The recommended duration of treatment is up to 14 days.  Beginning on Day 15, treatment may 
be extended another 14 days (through Day 28) at the discretion of the investigator, if the benefits 
of treatment outweigh the risks, and with approval from the sponsor medical monitor. 
Dose reductions or interruptions for any toxicity attributed to ruxolitinib are permitted to allow 
the participant to continue on study treatment (see Section 7.6.2). 
Table 5 presents the study treatment information. 
Table 5: 
Study Treatment Information 
Investigational/Control 
Drug 
Pharmaceutical 
Dosage Form 
Route of Administration 
Supply Type 
Ruxolitinib 5 mg 
Tablet 
Enteric feeding tube or oral 
Double-blind supply; bottles 
Placebo for 5 mg ruxolitinib 
Tablet 
Enteric feeding tube or oral 
Double-blind supply; bottles 


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7.1.1. 
Supply of Study Treatment 
No additional treatment beyond ruxolitinib 5 mg tablets or matching image placebo tablets will 
be provided.  Ruxolitinib will packaged in 60-count high-density polyethylene bottles.  All tablet 
excipients comply with the requirements of the applicable compendial monographs. 
If the participant continues treatment beyond the initial 14-day treatment period, if needed, the 
IRT should be contacted to dispense additional study drug. 
7.1.2. 
Treatment Duration 
The planned initial duration of treatment is 14 days.  Treatment may be extended to an additional 
14 days (ie, Days 15-28) at the discretion of the investigator, if the benefits of treatment 
outweigh the risks, and with approval from the sponsor medical monitor.  Approval must be 
requested ≥ 24 hours before initiation of dosing on Day 15.  Participants may be discontinued 
from treatment earlier due to unacceptable toxicity, progression/worsening of COVID-19 ARDS, 
or resolution/improvement of COVID-19 symptoms and/or at the discretion of the investigator or 
the participant.  Treatment will not be provided upon completion of the study. 
7.2. 
Other Treatments 
7.2.1. 
Concomitant Therapy 
All medications, procedures, and significant nondrug therapies administered from randomization 
through Day 29 must be recorded on the appropriate eCRFs.  Additionally, antivirals and 
therapeutic agents administered for SaRS-CoV-2 infection/COVID-19 infection and treatments 
for COVID-19–associated ARDS administered within 14 days of randomization must also be 
recorded.   
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication.  If in doubt, the investigator should contact the Incyte medical monitor before 
randomizing a participant or allowing a new medication to be started.  If the participant is 
already enrolled, contact Incyte to determine if the participant should continue participation in 
the study. 
7.2.1.1. 
Permitted Concomitant Therapy Requiring Caution and/or Action 
Participants may receive the following (not inclusive):  antiemetics, calcineurin inhibitors, azole 
fungal prophylaxis, antibiotics, acyclovir prophylaxis, granulocyte-colony stimulating factor, 
corticosteroid premedications prior to RBC/platelet transfusions, narcotics, and sedatives; 
however, close monitoring of potential drug-drug interaction effects of these concurrent drugs is 
warranted. 
Use of oral, injected, or implanted hormonal methods of contraception are allowed while on 
ruxolitinib. 
In the presence of potent CYP3A4 inhibitors, there is the possibility of increased exposure to 
ruxolitinib.  Dose adjustment when coadministering ruxolitinib and a potent CYP3A4 inhibitor is 
only required for participants assigned to the 15 mg BID ruxolitinib/placebo arm; see 
Section 7.2.1.2 for additional details.  No dose adjustment is required for participants 


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randomized to the 5 mg BID ruxolitinib/placebo arm.  See Appendix D for a list of CYP3A4 
inhibitors and inducers. 
The participant and the treating investigator should be aware of potential signs of overdose of the 
concomitant medications; in the event of suspected study drug–related toxicity, administration of 
ruxolitinib should be dose reduced or held according to the treating investigator’s judgement. 
For additional information, please refer to the IB. 
7.2.1.2. 
Coadministration With Potent CYP3A4 Inhibitors 
Coadministration of ruxolitinib and potent CYP3A4 inhibitors may result in increased ruxolitinib 
exposure; in the setting of potent CYP3A4 inhibitors (see Appendix D for a list), participants 
assigned to the 15 mg BID ruxolitinib/placebo arm only should be reduced 1 dose level (see 
Table 6) with daily complete blood cell count monitoring during the period of coadministration. 
7.2.1.3. 
CRRT and Intermittent Hemodialysis 
If a participant requires CRRT during the study treatment period, the ruxolitinib/placebo dose 
frequency should be reduced from BID to QD.  If a participant requires intermittent hemodialysis 
during the study treatment period, the assigned ruxolitinib/placebo dose should only be given on 
hemodialysis days and following each hemodialysis session. 
7.2.2. 
Prohibited Medication 
The following medications are prohibited until treatment discontinuation: 
•
Concomitant use of another JAK inhibitor or IL-6/IL-6R, IL-1RA, IL-1β, or GM-CSF
antibodies.
•
Any investigational medication except antivirals being used to treat SARS-CoV-2
infection or ARDS.
•
Aspirin in doses exceeding 150 mg/day.
For additional information, refer to the IB. 
7.3. 
Participant Numbering, Treatment Assignment, and Randomization 
7.3.1. 
Participant Numbering 
Each participant is identified in the study by a participant number that is assigned by the IRT 
when the participant is enrolled for screening and is retained for the participant throughout 
participation in the study.  A new participant number will be assigned at every subsequent 
enrollment if the participant is rescreened.  The participant number consists of the center number 
(as assigned by Incyte to the investigative site) with a sequential participant number suffixed to it 
so that each participant's participation is numbered uniquely across the entire database.  Upon 
signing the ICF (or having the consent signed on their behalf by their legal guardian/health care 
proxy) and assent (if applicable), participants are assigned to the next sequential participant 
number available. 


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7.3.2. 
Treatment Assignment, and Randomization 
Block randomization with stratification for severity of ARDS (mild/moderate [PaO2/FiO2 > 100 
to ≤ 300 mmHg] vs severe [PaO2/FiO2 ≤ 100 mmHg]) and investigational site will be used.  
Participants will be randomly assigned to either ruxolitinib 5 mg BID, ruxolitinib 15 mg BID, or 
placebo.  All participants will be centrally assigned to study treatment using an IRT system.  The 
randomization schedule will be generated by a sponsor-independent statistician and sent directly 
to the IRT vendor without being provided to the Sponsor.  Before the study is initiated, the URL 
and contact information (if applicable) for the IRT and/or the log-in information and directions 
for the IRT will be provided to each site.  Full details will be provided in the IRT manual. 
7.4. 
Treatment Blinding 
Participants, investigator staff, persons performing the assessments, and the Incyte study team 
will remain blind to the identity of the treatment from the time of randomization until database 
lock using the following methods:  (a) randomization data will be kept strictly confidential until 
the time of unblinding and will not be accessible by anyone else involved in the study, and 
(b) the identity of the treatments will be concealed by the use of study treatments that are all
identical in packaging, schedule of administration, appearance, taste, and odor.
Unblinding will occur in the case of participant emergencies and at the conclusion of the study.  
If the investigator feels that unblinding prior to completion of the treatment period is clinically 
indicated, consult the Medical Monitor. 
7.5. 
Dose Modification 
7.5.1. 
Dose Modifications 
Dose reductions or interruptions for worsening cytopenias or nonhematologic toxicity attributed 
to ruxolitinib are permitted to allow the participant to continue on study treatment (see 
Section 7.6.2 for additional guidance).  For the purpose of dose modifications, Table 6 will be 
used to guide dose reductions based on treatment arm assignment. 
Table 6: 
Ruxolitinib Dose Levels 
Treatment Arm 
Dose Level 1 (Initial Dose) 
Dose Level −1 
Ruxolitinib/placebo:  5 mg BID 
5 mg BID 
5 mg QD 
Ruxolitinib/placebo:  15 mg BID 
15 mg BID 
5 mg BID 
Dose modifications must be reported in the appropriate eCRFs. 
7.5.1.1. 
Follow-Up on Potential Drug-Induced Liver Injury Cases 
Transaminase increase combined with total bilirubin increase may be indicative of potentially 
severe DILI, which should be considered a clinically important event and assessed appropriately 
to establish the diagnosis.  The required clinical information, as detailed in the following text, 
should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities. 


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The threshold for potential DILI may depend on the participant's baseline AST/ALT and total 
bilirubin; participants meeting any of the following criteria will require further follow-up as 
outlined as follows: 
•
For participants with normal ALT and AST and total bilirubin at baseline:  AST or
ALT > 3.0 × ULN combined with total bilirubin > 2.0 × ULN.
•
For participants with elevated AST or ALT or total bilirubin value at baseline:  (AST
or ALT > 2 × baseline) OR (AST or ALT > 300 U/L), whichever occurs first,
combined with (total bilirubin > 2 × baseline AND > 2.0 × ULN).
Because DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should 
be considered and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, and history of any 
pre-existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, 
gamma-glutamyl transferase, glutamate dehydrogenase, prothrombin time/international 
normalized ratio, ALP, albumin, and CK. 
7.6. 
Additional Treatment Guidance 
7.6.1. 
Treatment Compliance 
Treatment will be recorded on the appropriate eCRF. 
7.6.2. 
Recommended Treatment of Adverse Events 
Dose reductions or interruptions for worsening cytopenias attributed to ruxolitinib/placebo are 
permitted to allow the participant to continue on study treatment.  Table 6 describes dose levels 
of ruxolitinib by treatment arm.  Dose adjustments for different ranges of cytopenias are 
described in the following text.  Use of transfusion support is allowed during the study. 
7.6.2.1. 
Neutropenia 
Grade 3 (ANC < 1.0 to 0.5× 109/L ):  Reduce by 1 dose level, monitor ANC daily until resolved 
to ≤ Grade 2, and then resume initial dose level.   
Grade 4 (ANC < 0.5× 109/L):  Hold dose, monitor ANC daily until resolved to ≤ Grade 3, and 
then resume at 1 dose level lower.  If resolves to ≤ Grade 2, can resume at initial dose level. 
7.6.2.2. 
Thrombocytopenia 
Transfusion support should be provided as clinically indicated. 
For platelet counts < 20 × 109/L:  hold dose until resolved to ≥ 20 × 109/L and then resume at 
1 dose level lower.  If counts are stable, dose may be cautiously re-escalated to initial dose level. 
Dose reductions or interruptions for nonhematologic toxicity are permitted to allow the 
participant to continue on study treatment.  Dose adjustments for different ranges of 
nonhematologic toxicity are described in the following text.  The objective of the dose 


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adjustment rules is to optimize treatment response for each individual participant while avoiding 
significant nonhematologic toxicities. 
7.6.2.3. 
Other Adverse Events (Nonhematologic) Attributed to Ruxolitinib/Placebo 
Recommendation for Grade 1 or 2:  maintain dose level. 
Recommendation for Grade 3:  reduce by 1 dose level until resolved to ≤ Grade 2. 
Recommendation for Grade 4:  discontinue from study treatment. 
Medication used to treat AEs must be recorded on the appropriate eCRF. 
7.7. 
Preparation and Dispensation 
Each study site will be supplied with study drug in packaging as described in Section 7.4. 
A unique medication number is printed on the study medication label. 
7.7.1. 
Handling of Study Treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access.  Upon receipt, all study treatment must be stored according to the 
instructions specified in the IB (or Pharmacy Manual).  Bottles of ruxolitinib tablets should be 
stored at room temperature (15°C-30°C [59°F-86°F]). 
Medication labels will be in the local language and comply with the legal requirements of each 
country.  They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log.  Monitoring of drug accountability will be performed by 
monitors during on-site visits or remotely and at the completion of the study (on-site or 
remotely).  Participants will be asked to return all unused study treatment and packaging at the 
end of the study or at the time of discontinuation of study treatment. 
The study site may destroy all unused study treatment, packaging, and drug labels locally per site 
policies and procedures, which are subject to review and prior approval by Incyte.  If local 
destruction or procedure is not available, the site may return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the address 
indicated in the Pharmacy Manual. 


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8.
INFORMED CONSENT PROCEDURES
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB-approved informed consent (and assent, as applicable); 
informed consent may be obtained from a health care proxy where appropriate and/or 
institutionally approved method of consenting when applicable (verbal consent) as defined in 
their local consent form. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding.  If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent (and assent, as applicable) must be obtained before conducting any 
study-specific procedures (eg, all of the procedures described in the Protocol).  The process of 
obtaining informed consent (and assent, as applicable) must be documented in the participant 
source documents.  The date when a participant's informed consent was actually obtained will be 
captured in their eCRFs. 
Incyte will provide to investigators in a separate document a proposed ICF that complies with the 
ICH GCP guidelines and regulatory requirements and is considered appropriate for this study.  
Any changes to the proposed consent/assent form suggested by the investigator must be agreed 
upon by Incyte before submission to the IRB. 
Information about common side effects already known about the investigational drug can be 
found in the IB.  This information will be included in the participant informed consent/assent and 
should be discussed with the participant during the study as needed.  Any new information 
regarding the safety profile of the investigational drug that is identified between IB updates will 
be communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding.  New information might require an update to the informed consent/assent and 
then must be discussed with the participant. 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order to 
participate in the study, they must adhere to the contraception requirements during treatment and 
after discharge from hospital. 
Male participants must be informed that if a female partner becomes pregnant during treatment 
or after discharge from the hospital and within 30 days of the last dose of study medication, 
contact with the female partner will be attempted to request her consent/assent to collect 
pregnancy outcome information. 
A copy of the approved version of all consent and assent forms must be provided to Incyte after 
IRB approval. 


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9.
VISIT SCHEDULE AND ASSESSMENTS
The SoA (see Table 3) lists all of the assessments and when they are performed.  All data 
obtained from these assessments must be supported in the participant's source documentation.  
Any assessments outlined in Table 3 otherwise performed per standard of care may be used to 
satisfy study requirements. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule (see 
Table 3) or as close to the designated day/time as possible.  Missed or omitted visits or 
assessments should not lead to automatic discontinuation.  Participants who prematurely 
discontinue the study (see Section 10.1.1) for any reason should be scheduled for a visit (in 
person or remote) as soon as possible, at which time all of the assessments listed for the final 
visit will be performed.  At this final visit, all dispensed investigational product should be 
reconciled, and the AE and concomitant medications should be recorded on the eCRF. 
If a participant is discharged from the hospital during the study period, the clinical status 
evaluation with 9-point ordinal scale will be performed via telephone call (7:00 AM-12:00 PM 
local time) daily, except for Day 15 and Day 29 when it will be performed in clinic, when 
possible (telephone contact is an acceptable alternative for clinic visits).  If the participant is 
unable to return to the clinic on Day 15 and Day 29, all scheduled assessments may be performed 
by telephone; local laboratory assessments may be performed on Day 15 and/or Day 29 if 
feasible. 
9.1. 
Screening 
The screening assessments should be performed within 1 day (defined as a 24-hour period, 
independent of calendar days) prior to randomization and Day 1 assessments.  If the screening 
and Day 1 visits are conducted on the same day, overlapping assessments do not need to be 
repeated.  Screening laboratory assessments may be repeated if considered spurious or invalid.  
No rescreening will be allowed. 
9.1.1. 
Information to Be Collected on Screening Failures 
Participants who give informed consent (directly or via legal guardian/health care proxy; with 
assent as applicable) and are subsequently found to be ineligible prior to randomization will be 
considered a screen failure.  The reason for screen failure should be recorded on the appropriate 
eCRF.  The demographic information, informed consent/assent (as applicable), and eligibility 
forms must also be completed for screen failure participants.  No other data will be entered into 
the clinical database for participants who are screen failures.  If the participant fails to be 
randomized, the IRT must be notified within 1 day of the screen failure that the participant was 
not randomized. 
Participants who are randomized and fail to start treatment (eg, participants randomized in error) 
will be considered an early terminator.  The reason for early termination should be recorded on 
the appropriate eCRF. 
9.2. 
Participant Demographics/General Medical History 
Country-specific regulations should be considered for the collection of demographic and baseline 
characteristics in alignment with eCRF. 


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Participant race and ethnicity are collected and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as required 
by Health Authorities. 
Medical history will include relevant medical or surgical treatment unrelated to SARS-CoV-2 
infection or COVID-19 within the past 6 months that are considered to be clinically significant 
by the investigator. 
9.3. 
Efficacy 
9.3.1. 
Clinical Status (9-Point Scale) 
Assessment of clinical status using a 9-point ordinal scale (WHO 2020b) will be recorded at 
baseline on Day 1 and then again once daily every morning (between 7:00 AM and 12:00 PM 
local time) through Day 29 of the study period.  If a participant is discharged from the hospital, 
the assessment will be made by phone (between 7:00 AM and 12:00 PM local time).  Each day, 
the worst score for the previous day will be recorded (ie, on Day 3, Day 2 score is obtained and 
recorded as Day 2).  The scale is shown in Table 7. 
Table 7: 
COVID-19 9-Point Ordinal Clinical Status 
Participant State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatorya 
No limitation of activities 
1 
Limitation of activities 
2 
Hospitalized 
Mild Disease 
Hospitalized, no oxygen therapy (defined as SpO2 ≥ 94% on 
room air) 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalized 
Severe Disease 
Non-invasive ventilation or high-flow oxygen 
5 
Intubation and mechanical ventilation 
6 
Ventilation + additional organ support – vasopressors, RRT, 
ECMO 
7 
Dead 
Death 
8 
a Defined as not in hospital or in hospital and ready for discharge. 
If the participant dies, the date of death will be collected in the eCRF. 
9.3.2. 
Vital Signs 
Vital sign measurement include respiratory rate, heart rate, systolic and diastolic blood pressure, 
and body temperature; one set of vital signs will be collected daily while hospitalized.  While the 
participant is in the ICU, the daily vital sign collection should be the same as that used for the 
cardiovascular component (mean arterial pressure) of the of the SOFA score. 


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9.3.3. 
Arterial Blood Gases, PaO2/FiO2, and Pulse Oximetry 
Arterial blood gases will be collected during screening, within 6 hours of planned randomization, 
to assess PaO2/FiO2 for eligibility, and daily thereafter while on a ventilator or if an arterial line 
is present.  The FiO2 being administered at the time of ABG collection should be recorded.  The 
following parameters will be collected for each ABG:  pH, PaO2, PaCO2, and SaO2.  Oxygen 
saturation (SpO2 via pulse oximetry) will be recorded once daily while hospitalized; SpO2 is not 
required after hospital discharge. 
9.3.4. 
Sequential Organ Failure Assessment Score 
The SOFA score (Appendix C) is a scoring system to determine the extent of a person's organ 
function or rate of failure.  The score is based on 6 different scores, 1 each for the respiratory, 
cardiovascular, hepatic, coagulation, renal, and neurological systems.  The screening/Day 1 
assessment should be based on data collected closest to (but also prior to) randomization.  Each 
subsequent day should use the worst value for each parameter in the preceding 24-hour period. 
At each required timepoint, the SOFA score will be calculated by the investigative site and 
recorded in the appropriate eCRF.  The SOFA score assessments are no longer required after 
discharge from the ICU. 
9.3.5. 
In-Hospital Outcomes 
In addition to endpoints mentioned above, the following in-hospital outcomes will be captured 
on eCRFs: 
•
Ventilator-free days
•
ICU-free days
•
Vasopressor-free days
•
Hospital-free days
•
Oxygen-free days
9.3.6. 
Lung Imaging
A chest x-ray or chest CT scan is required at the screening assessment.  If a chest x-ray or chest 
CT has been performed per standard of care within the 2 days prior to the screening visit, no 
additional chest imaging needs to be performed.  Chest x-ray/CT findings performed as standard 
of care during the study should be recorded on the appropriate eCRF. 
9.4. 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
9.4.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until the 28-day 
post-treatment AE assessment (28 ± 3 days after last dose of study treatment).  Adverse events 
that begin or worsen after informed consent should be recorded on the Adverse Events Form in 


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the eCRF regardless of the assumption of a causal relationship with ruxolitinib/placebo.  
Conditions that were already present at the time of informed consent should be recorded on the 
Medical History Form in the eCRF.  Adverse events (including laboratory abnormalities that 
constitute AEs) should be described using a diagnosis whenever possible rather than by 
individual underlying signs and symptoms. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 10.1.4). 
9.4.2. 
Presence SARS-CoV-2 Virus/Viral Load/Antibody Testing 
For the screening inclusion criterion, SARS-CoV-2 virus is to be measured by PCR or by other 
locally approved diagnostic methodology ≤ 3 weeks of randomization.  Documentation of the 
method used should be available in the source notes.  Viral load and antibody testing may be 
performed by any approved method and is only required if local capabilities allow; a consistent 
method and specimen source should be used at all timepoints. 
9.4.3. 
Laboratory Evaluations 
Laboratory evaluations will be performed by a local laboratory. 
9.4.3.1. 
Hematology 
Hemoglobin, hematocrit, RBC count, white blood cell count with differential, and platelet count 
will be measured according to the assessment schedule in Table 3. 
9.4.3.2. 
Chemistry 
Blood urea nitrogen/urea, creatinine, CK (total), CK-MB, total bilirubin, AST, ALT, ALP, 
sodium, potassium, chloride, calcium, bicarbonate, total protein, albumin, and glucose will be 
measured according to the assessment schedule in Table 3.  If a given test is not available 
locally, this should be documented on the eCRF. 
If the total bilirubin concentration is increased above 1.5 × ULN, the total bilirubin will 
differentiated into the direct and indirect reacting bilirubin. 
9.4.3.3. 
Inflammatory Markers 
•
Ferritin
•
CRP
•
D-dimer
•
Procalcitonin
•
IL-6 at sites where feasible


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Samples will be collected at the timepoints defined in Table 3.  If a given test is not available 
locally, this should be documented on the eCRF. 
9.4.3.4. 
Monitoring of Thromboembolic Risk 
Laboratory parameters to assess thromboembolic risk, including D-dimer, aPTT, and fibrinogen, 
should be monitored per SoC. 
Participants deemed at high risk for thromboembolic sequelae and eligible for prophylactic or 
therapeutic intervention per local evaluation should be considered for appropriate 
anticoagulation. 
9.4.4. 
Height and Weight 
If possible, height in centimeters will be measured at screening as specified in the SoA (see 
Table 3).  Otherwise, participant- or legal guardian/health proxy-reported height will be 
obtained. 
Body weight will be measured at the screening visit as specified in Table 3. 
9.4.5. 
Pregnancy and Assessments of Fertility 
A serum pregnancy test (serum hCG) will be performed at screening assessment in women of 
childbearing potential.  Serum or urine pregnancy testing is acceptable at subsequent 
assessment(s) (see Table 3). 
9.5. 
Correlative Studies 
9.5.1. 
Sample Collection, Processing, and Shipment 
An optional serum sample will be collected at Day 1 (predose) and Day 7 and 15 for cytokine 
analysis.  See Appendix E for instructions on sample collection, processing, storage and 
shipment. 
9.5.2. 
Biomarker Analysis 
Proteomic analysis will be conducted on serum samples to evaluate the levels of circulating 
inflammatory mediators including, but not limited to, GM-CSFα, TNF-α, IFN-γ, and IL-1a at 
Day 1 (predose) and on Days 7 and 15.  These assessments will improve our understanding of 
the role of JAK inhibition in resolving the cytokine storm associated with COVID-19–associated 
ARDS participants. 


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10.
TREATMENT DISCONTINUATION AND STUDY
WITHDRAWAL
10.1. 
Discontinuation and Completion 
10.1.1. 
Study Treatment Discontinuation and Study Withdrawal 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. 
The investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively affect the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
•
Participant/health care proxy decision.
•
Pregnancy.
•
Use of prohibited treatment as per recommendations in the prohibited treatment
section (see Section 7.2.2).
•
Any situation in which study participation might result in a safety risk to the
participant.
•
Following emergency unblinding.
•
Any laboratory abnormalities that in the judgment of the investigator, taking into
consideration the participant's overall status, prevent the participant from continuing
participation in the study.
If discontinuation of study treatment occurs, the investigator should make a reasonable effort to 
understand the primary reason for the participant's premature discontinuation of study treatment 
and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw their 
consent (see Section 10.1.3).  If they fail to return (either in person or remotely) for these 
assessments for unknown reasons, every effort (eg, telephone, e-mail, letter) should be made to 
contact the participant/predesignated contact as specified in Section 10.1.4.  This contact should 
preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant or with a person predesignated by the participant.  
This telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/e-mail contact: 
•
New/concomitant treatments.
•
AEs/SAEs.


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The investigator must also contact the IRT to register the participant's discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, see Section 11.5. 
10.1.2. 
Replacement Policy 
Participants discontinuing the study will not be replaced. 
10.1.3. 
Withdrawal of Informed Consent 
Participants (or health care proxy who provided consent on behalf of the participant) may 
voluntarily withdraw consent (or assent) to participate in the study for any reason at any time.  
Withdrawal of consent occurs only when a participant does not want the following: 
•
To participate in the study anymore.
•
Any further visits or assessments.
•
Any further study-related contacts.
In this situation, the investigator should make a reasonable effort (eg, telephone, e-mail, letter) to 
understand the primary reason for the participant's decision to withdraw consent and record this 
information. 
Where consent to the use of personal and coded data is not required, participants cannot 
withdraw consent.  They still retain the right to object to the further use of personal data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communication or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation.  A final 
evaluation at the time of the participant's study discontinuation should be made as detailed in the 
assessment table. 
Incyte will continue to retain and use all research results (data) that have already been collected 
for the study evaluation. 
10.1.4. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible and counsel the participant on the importance of maintaining the
assigned visit schedule and ascertain whether or not the participant wishes to and/or
should continue in the study.


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•
Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, 3 telephone
calls and, if necessary, a certified letter to the participant's last known mailing address
or local equivalent methods).  These contact attempts should be documented in the
participant's medical record.
•
Should the participant continue to be unreachable, he/she will be considered to have
withdrawn from the study.
10.1.5. 
Early Study Termination by the Sponsor 
The study can be terminated by Incyte at any time. 
Reasons for early termination include the following: 
•
Individual treatment arms or the entire study may be stopped based on review and
recommendation from the DMC, including futility as defined in Section 12.5.2.
•
Unexpected, significant, or unacceptable safety risk to participants enrolled in the
study.
•
Decision based on recommendations from applicable board(s) after review of safety
and efficacy data.
•
Discontinuation of study drug development.
In making the decision to terminate, Incyte will always consider participant welfare and safety.  
Should early termination be necessary, participants must be seen as soon as possible and treated 
as prematurely withdrawn participants.  The investigator may be informed of additional 
procedures to be followed to ensure that adequate consideration is given to the protection of the 
participants’ interests.  The investigator or sponsor, depending on local regulation, will be 
responsible for informing IRBs of the early termination of the study. 
10.2. 
Study Completion and Post–Study Treatment 
Study completion is defined as when the last participant finishes the final assessment and any 
procedures or assessments associated with this visit have been documented and followed up 
appropriately by the investigator or, in the event of an early study termination decision, the date 
of that decision (eg, each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to that participant). 
All randomized and/or treated participants should have a safety follow-up assessment conducted 
by telephone or video call 28 days (± 3 days) for AE review after last administration of study 
treatment.  The information collected is kept as source documentation.  All SAEs reported during 
this time period must be reported as described in Section 11.4.  Documentation of attempts to 
contact the participant should be recorded in the source documentation. 


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11.
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
11.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or
not considered drug-related.
• An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study
treatment.
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from
baseline, considered clinically significant in the medical and scientific judgment of the investigator
(ie, not related to worsening of underlying disease), should be reported as an AE.
• Abnormal laboratory test results constitute an AE if they are considered clinically meaningful, induce
clinical signs or symptoms, require concomitant therapy, or require changes in study drug.
Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in the eCRF
rather than the abnormal laboratory test result (eg, low hemoglobin, platelet count decreased).
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in
frequency and/or intensity of the condition constitute an AE.
• New conditions detected or diagnosed after study treatment administration even though they may
have been present before the start of the study, should be reported as an AE.
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction constitute an AE.
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an
intentional overdose taken with possible suicidal/self-harming intent.  Such overdoses should be
reported regardless of sequelae.
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an
AE or SAE (including disease progression).  Such instances will be captured in the efficacy
assessments.
• A condition that leads to a medical or surgical procedure (eg, endoscopy, appendectomy) is an AE if
it occurred after signing informed consent.  If present before entering the study, the condition should
be captured as medical history.
• Situations in which an untoward medical occurrence did not occur (social and/or convenience
admission to a hospital) need not be considered AEs.
• Anticipated day-to-day fluctuations of pre-existing disease(s), or condition(s) present, or detected at
the start of the study judged by the investigator to have worsened more than expected for the
participant's condition since study participation should be reported as an AE.


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11.2. 
Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death
b. Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an adverse drug experience that places 
the participant, in the opinion of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred.  This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
d. Results in persistent or significant disability/incapacity
• The term "disability" means a substantial disruption of a person's ability to conduct normal life
functions.
• This definition is not intended to include experiences of relatively minor medical significance, such
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma
(eg, sprained ankle), that may interfere with or prevent everyday life functions but do not constitute a
substantial disruption.
e. Is a congenital anomaly/birth defect
f. Other situations (Important Medical Event)
An event that may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event may jeopardize the 
participant and may require medical or surgical intervention to prevent 1 of the outcomes listed in the 
above definition.  Examples of such events include new invasive or malignant cancers, intensive 
treatment in an emergency department or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.   


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11.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed through safety follow-up should
be recorded on the Adverse Event Form in the eCRF.  Conditions that were present at the time
informed consent was given should be recorded on the Medical History Form in the eCRF.
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event.
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF.
• It is not acceptable for the investigator to send photocopies of the participant's medical records in
lieu of completing the AE eCRF page.
• There may be instances when copies of medical records for certain cases are requested.  In this case,
all participant identifiers, with the exception of the participant number, will be redacted on the copies
of the medical records before submission.
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms)
will be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or
symptom should be reported as a separate AE/SAE.
To the extent possible, each AE/SAE should be evaluated to determine: 
• The severity grade (CTCAE v5.0 Grade 1 to 5).  See below for further instructions on the assessment
of intensity.
• Whether there is at least a reasonable possibility that the AE is related to the study treatment
(including study drug):  suspected (yes) or not suspected (no).  See below for further instructions on
the assessment of causality.
• The start and end dates, unless unresolved at final follow-up.
• The action taken with regard to study drug as a result of the AE/SAE(s).
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving,
recovered/resolved with sequelae, fatal, unknown).
• The seriousness, as per the SAE definition provided in Section 11.2.
• The action taken with regard to the event.  Note:  If an AE is treated with a concomitant medication
or nondrug therapy, this action should be recorded on Adverse Event Form and the treatment should
be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and Non-Drug
Therapy).
Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to estimate the 
grade of severity. 
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories: 
• Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment
not indicated.
• Grade 2:  Moderate; minimal, local, or noninvasive treatment indicated; limiting age appropriate
activities of daily living.


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• Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.
• Grade 4:  Life-threatening consequences; urgent treatment indicated.
• Grade 5:  Fatal.
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and each occurrence
of each AE/SAE.  If reference therapy is used in combination with an Incyte study drug or multiple
Incyte study drugs are used, the relationship to each study drug must be assessed (ie, for the Incyte
product(s) and for the other product(s) that is used in combination with the Incyte product).  If
appropriate, the relationship to the combination may be assessed as well.
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or arguments
to suggest a causal relationship, rather than that a relationship cannot be ruled out.
• The investigator will use clinical judgment to determine the relationship.
• The investigator will also consult the Reference Safety Information in the IB and/or Product
Information, for marketed products, in his/her assessment.
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well
as the temporal relationship of the event to study treatment administration, will be considered and
investigated.
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the
AE/SAE and has provided an assessment of causality.
• With regard to assessing causality of SAEs:
−There may be situations in which an SAE has occurred and the investigator has minimal
information to include in the initial report.  However, the causality assessment is one of the criteria
used when determining regulatory reporting requirements.  Therefore, it is very important that
the investigator always make an assessment of causality for every event before the initial
transmission of the SAE.
−The investigator may change his/her opinion of causality in light of follow-up information and
send a follow-up SAE report with the updated causality assessment.
Follow-Up of Adverse Events and Serious Adverse Events 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature
and/or causality of the AE or SAE as fully as possible.  This may include additional laboratory tests
or investigations, histopathological examinations, or consultation with other health care
professionals.
• New or updated information will be recorded in the eCRF.
• Any updated SAE data will be submitted to the sponsor (or designee) within 24 hours of receipt of
the information.
• Once an AE is detected, it should be followed until it has resolved or until it is judged to be
permanent; assessment should be made at each visit (or more frequently if necessary) of any changes
in severity, the suspected relationship to the study drug, the interventions required to treat the event,
and the outcome.
• When the severity of an AE changes over time for a reporting period (eg, between visits), each
change in severity will be reported as a separate AE until the event resolves.


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11.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study drug or study procedures), all SAEs 
occurring after the participant has signed the ICF through AE/safety follow-up (28 ± 3 days after 
last dose of study treatment) must be reported to the sponsor (or designee) within 24 hours of 
learning of its occurrence, unless otherwise specified by the Protocol.  The investigator will 
submit any updated SAE data to the sponsor (or designee) within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of study 
participation.  However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the investigator must notify the sponsor (or 
designee) within 24 hours of becoming aware of the event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 10.1.4). 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification to inform all investigators involved in any study 
with the same drug that this SAE has been reported.  Suspected unexpected serious adverse 
reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB, if appropriate according to local requirements. 


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Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF.
• The investigator must report within 24 hours of learning of its occurrence any SAEs via the EDC
system (primary method) or by completing the Incyte Serious Adverse Event Report Form, in
English (only if EDC system is not available).
• Follow-up information is also recorded in the eCRF and transmitted to Incyte PhV via the EDC
system.  The follow-up report should include information that was not provided previously, such as
the outcome of the event (eg, resolved or ongoing), treatment provided, action taken with study drug
because of the SAE (eg, dose reduced, interrupted, or discontinued), or participant disposition (eg,
continued or withdrew from study participation).  Each recurrence, complication, or progression of
the original event should be reported as follow-up to that event, regardless of when it occurs.
• In circumstances where the EDC system would not work properly, initial and/or follow-up SAE
information shall be documented on new or amended Serious Adverse Event Report Form.  Refer to
the Incyte Reference Guide for Completing the Serious Adverse Event Report Form.
• Email transmission (or facsimile) of the Serious Adverse Event Report Form is the preferred method
to transmit this information to the PhV/designee.  The contact information of the sponsor's
study-specific representatives is listed in the Study Reference Manual provided to each site.  The
original copy of the Serious Adverse Event Report Form and the confirmation sheet must be kept at
the study site.
• Contacts for SAE reporting can be found in the Study Procedures Manual.
11.5. 
Emergency Unblinding of Treatment Assignment 
In a medical emergency, if knowledge of the treatment assignment is necessary to determine 
optimal medical management of the participant, the procedure for emergency unblinding is 
provided in the IRT Manual.  This option may be used only if the participant's well-being 
requires the investigator to be aware of the participant's treatment assignment.  If a participant's 
treatment assignment is unblinded, the sponsor or its designee must be notified immediately by 
telephone. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be withdrawn from the study treatment, unless there are ethical reasons to have 
the participant remain on the study treatment.  In these cases, the investigator must obtain 
specific approval from the sponsor's (or its designee's) medical monitor for the participant to 
continue in the study. 
11.6. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
•
The study drug must be discontinued immediately unless the investigator, with
approval from the medical monitor, agrees that the risks of continued treatment do not
outweigh the potential benefits of continuing, given the life-threatening nature of
COVID-19–associated ARDS (female participants only).


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•
The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form
to the sponsor or its designee within 24 hours of learning of the pregnancy.
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 11.4.  If an abnormal pregnancy outcome is reported in 
a study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
11.7. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB.  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications.  Any 
important new safety information should be discussed with the participant during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
11.8. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be recorded as described in Section 11.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 


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11.9. 
Treatment of Overdose 
For this study, any dose of study treatment greater than 30 mg ruxolitinib/placebo within a 
24-hour time period will be considered an overdose.
Incyte does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
•
Contact the medical monitor immediately.
•
Closely monitor the participant for any AE/SAE and laboratory abnormalities.
•
Document the quantity of the excess dose as well as the duration of the overdose in
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
12.
STATISTICS
12.1. 
Sample Size Determination
The primary endpoint of this study is the proportion of participants who die on or prior to 
Day 29.  Participants will be randomized at a 2:2:1 (5 mg BID ruxolitinib:15 mg BID 
ruxolitinib:placebo) ratio.  The primary endpoint will be tested using a logistic regression mixed 
model including treatment group, ARDS severity (mild/moderate [PaO2/FiO2 > 100 to ≤ 300] vs 
severe [PaO2/FiO2 ≤ 100]), and gender as covariates and investigational site as a random 
(intercept) effect.  The Wald test for the treatment regression coefficient will test the primary 
endpoint.  Individual comparisons between placebo and ruxolitinib treatment arms will be 
performed in a pairwise fashion (placebo vs 5 mg BID and placebo vs 15 mg BID), with 
alpha-control accomplished using a Dunnett's procedure.  Based on the expected correlation 
between the 2 statistical tests of 2/3, the adjusted nominal p-values for each treatment group is 
approximately 0.01436968. 
Assuming a 40% mortality rate for ruxolitinib vs 60%, a sample size for a pairwise comparison 
of 100 placebo and 200 ruxolitinib participants (with 500 participants total) will achieve 
approximately 83% power to detect a statistically significant difference with a nominal 1-sided 
Type I error of 1.436968%.  Estimated power for various scenarios, based on a simulation study 
of 1000 study replications, are provided in Table 8. 


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Table 8: 
Simulation Estimates for Power and Type 1 Error for Various Mortality 
Rates 
Mortality Rates 
Probability to Reject H0 for 
PLB 
5 mg BID 
15 mg BID 
5 mg BID 
15 mg BID 
Either RUX 
60% 
60% 
60% 
0.015 
0.016 
0.027 
60% 
60% 
40% 
0.012 
0.873 
0.873 
60% 
50% 
40% 
0.268 
0.865 
0.866 
60% 
40% 
40% 
0.868 
0.872 
0.940 
60% 
40% 
30% 
0.861 
0.998 
0.998 
Note:  For the simulation, investigational site was drawn from a integer uniform distribution (1, 2, …, 10) and 
probability (ARDS severe) = 0.5, fitting a mixed logistic regression model with no direct effects for the ARDS 
severity or site. 
12.2. 
Populations for Analysis 
The populations for analysis are provided in Table 9. 
Table 9: 
Populations for Analysis 
Population 
Description 
ITT 
All randomized participants.  The ITT population will be used for the summary of 
demographics, baseline characteristics, participant disposition, and analyses of all 
efficacy data.  Participants will be analyzed according to the treatment group to 
which they were randomized regardless of the treatment received during the 
study. 
PP population 
Participants in the ITT population who are considered to be sufficiently compliant 
with the Protocol compose the PP population.  Review of individual randomized 
participants will take place in a blinded fashion, and a list of excluded participants 
will be prepared and signed before unblinding and database freeze.  Data review 
for identification of excluded participants will include clinical review of major 
Protocol deviations, clinical review of concomitant medications, and clinical 
review of the dose administration and drug accountability listings. 
Safety 
The safety population includes all randomized participants who received at least 
1 dose of study drug.  Treatment groups for this population will be determined 
according to the actual treatment the participant received regardless of assigned 
study drug treatment.  All safety analyses will be conducted using the safety 
population. 
PD evaluable 
The PD evaluable population will include all participants who received at least 
1 dose of study drug and provided at least 1 post-treatment PD measurement. 


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12.3. 
Level of Significance 
The overall familywise error level for the primary endpoint is 1-sided 2.5%.  Familywise error 
control for the primary endpoint, comparing each ruxolitinib treatment group individually against 
placebo, will be accomplished using Dunnett's procedure by using a nominal significance level 
of 0.01436968 to control the overall 1-sided Type I error at 2.5%. 
One interim analysis for efficacy is planned for the study, which will use an alpha-spending 
function and is planned when the first 40% of participants have died or have reached their 
planned Day 29 visit.  The nominal overall significance level of 0.01436968 will be used for 
each alpha-spending function.  Details of the interim analysis plan are provided in Section 12.5. 
12.4. 
Statistical Analyses 
12.4.1. 
Primary and Secondary Analysis 
Unless otherwise noted, all statistical comparisons of each ruxolitinib treatment groups will be 
performed as pairwise comparisons against placebo.  See Table 10 for analyses of primary and 
secondary endpoints. 
Table 10: 
Analyses of Primary and Secondary Endpoints 
Endpoint 
Statistical Method 
Analysis 
Population 
Primary (P) or 
Supportive (S) 
Primary Endpoint 
Proportion of participants 
who have died due to any 
cause through Study Day 29. 
Logistic regression with treatment 
group, ARDS severity 
(mild/moderate vs severe), gender 
(male or female) as fixed covariates, 
and investigational site as a random 
effect.  Wald test for treatment group 
regression coefficient = 0. 
Estimation:  Odds-ratio for treatment 
effect and associated 95% CI. 
ITT 
P 
PP 
S 
Overall survival up to 
Day 29 determined from the 
date of randomization until 
death due to any cause 
Inference:  Cox proportional hazards 
model including treatment group, 
ARDS severity (mild/moderate vs 
severe), and gender (male or female) 
as fixed covariates, and 
investigational site as a random 
effect. 
Estimation:  Kaplan-Meier. 
ITT 
S 


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Table 10: 
Analyses of Primary and Secondary Endpoints (Continued) 
Endpoint 
Statistical Method 
Analysis 
Population 
Primary (P) or 
Supportive (S) 
Secondary Endpoint 
Improvement in the 
COVID-19 ordinal scale at 
Day 15 and 29 
Proportional odds model including 
treatment group, ARDS severity 
(mild/moderate vs severe), and 
gender (male or female) as fixed 
covariates, and investigational site as 
a random effect. 
ITT 
P 
PP 
S 
All other secondary endpoints will be tabulated by summary statistics. 
The primary endpoint will also be compared between the treatment groups within each of the 
following subgroups.  In the event that any subgroup category has fewer than 10 participants, the 
subgroup in question may be excluded. 
•
ARDS severity:  mild/moderate versus  severe
•
Gender:  male or female
•
Age group:  < 18 years, 18-64 years, or ≥ 65 years
•
Baseline CRP:  ≤ 100 mg/L or > 100 mg/L
•
D-dimer at baseline:  ≤ 1000 ng/mL or > 1000 ng/mL
•
Ferritin at baseline:  ≤ 300 ng/mL or > 300 ng/mL
•
Race:  White/Caucasian, Black/African-American, Asian, American-Indian/Alaska
Native, Native Hawaiian/Pacific Islander, or Other
•
Ethnicity:  Hispanic/Latino, Not Hispanic/Latino, or Other
•
Hours of mechanical ventilation at baseline:  ≤ 48 hours or > 48 hours
•
BMI at baseline:  ≥ 30 or < 30
In addition, the 28-day mortality rates and participants lost to follow-up in the placebo group will 
be compared by the placebo image assigned (5 mg BID and 15 mg BID) to determine if the rate 
is consistent across the 2 treatment images.  Additional endpoints may also be compared within 
placebo-assigned participants by treatment image. 
The 9-point ordinal scale will be tabulated by visit.  The odds of observing an improvement in 
the 9-point ordinal scale on Days 15 and 29 will be analyzed using a POM, which will include 
treatment group, ARDS severity (mild/moderate vs severe), and gender (male or female) as fixed 
covariates and investigational site as a random effect.  The odds ratio for treatment group 
(ruxolitinib vs placebo) estimated from the POM can be interpreted as a summary of the odds 
ratios obtained from separate binary logistic regressions using all possible cutoff points of the 
ordinal outcome (eg, the cutoff of level 5, "Hospitalized, on non-invasive ventilation or high 
flow oxygen device" will combine levels 0, 1, 2, 3, and 4 versus combined levels 5, 6, 7, and 8).  


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The assumption of POM is that the effect of treatment is identical across all possible cutoff 
points of the ordinal outcome. 
The number and percentage of participants with a 1-point improvement at Days 15 and 29 will 
be tabulated and summarized by treatment group.  A logistic regression model will be used to 
model the probability of such an improvement that includes treatment group, ARDS 
severity (mild/moderate vs severe), and gender (male or female) as fixed covariates and 
investigational site as a random effect.  A similar summary will be used for two-point 
improvements at Days 15 and 29. 
The time from randomization to first improvement in the COVID-19 9-point ordinal scale will be 
derived.  Participants who never improve on-study will be censored at their last assessment or 
Study Day 29, whichever is earlier.  A Kaplan-Meier analysis will be used to describe the time to 
first improvement. 
Endpoints related to clinical outcomes are defined in Table 11.  Outcome-free days between 
Days 2 and 29 will be summarized descriptively (mean, mean, standard deviation) with 
treatment-group statistical comparisons using a Kruskal-Wallis test. 
Table 11: 
In-Hospital Outcome Event-Free Days Variable Definition 
Endpoint 
The Number of Study Days That a Participant Was Alive and… 
Ventilator-free days 
did not require mechanical ventilation.a 
ICU-free days 
is out of the ICU.a 
Vasopressor-free days 
without use of vasopressor therapy.a 
Hospital-free days 
is out of the hospital.a 
Oxygen-free days 
did not receive supplemental oxygen.a 
a Participants who do not survive through Day 29 will have 0 assigned days. 
12.4.2. 
Safety Analyses 
Safety analyses will be conducted for the safety population.  Adverse events will be coded by the 
MedDRA dictionary, and TEAEs (ie, AEs reported for the first time or worsening of a 
pre-existing event after first dose of study drug/treatment) will be tabulated by preferred term 
and system organ class for all events, related events, SAEs, and events of Grade 3 or higher.  
Quantitative safety variables and their changes from baseline (eg, laboratory, vital signs) will be 
summarized with descriptive statistics. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned.  In addition, distributions of key laboratory parameters (eg, IL-6, 
ferritin, platelets) may be plotted over time; these values will also be classified into CTCAE 
toxicity grades, and tabulated.  Descriptive statistics and mean change from baseline will be 
determined for vital signs at each assessment time.   
Measures of exposure (eg, days of exposure, duration of treatment, and average daily dose) of 
study drug and/or reference therapy will be summarized by means of summary statistics. 


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12.4.3. 
Exploratory Efficacy Analyses 
Change from baseline to Day 15 and Day 29 in serum ferritin, C-reactive protein (CRP), 
D-dimer, IL-6, and viral load will be summarized by treatment arm.  Additional details will be
provided in the Statistical Analysis Plan.
Exploratory endpoints will be summarized descriptively using ITT population. 
12.5. 
Interim Analysis 
12.5.1. 
Efficacy Analysis 
There will be 1 planned interim analyses conducted for efficacy for this study, based on the first 
40% of participants enrolled in the study.  The efficacy interim analysis will be conducted when 
the first 40% of the planned randomized participants (approximately 200 randomized 
participants) have died or have reached their Day 29 assessment.  Based on the results of this 
interim analysis, the DMC may choose to terminate the study for positive efficacy or continue 
the study with no changes to enrollment.   
At the efficacy interim analysis, Day 28 mortality will be tested using an overall nominal Type I 
error of 0.01436968 within each ruxolitinib treatment arm in comparison versus placebo.  An 
HSD (Hwang et al 1990) alpha-spending function with γ = −4 will be used to determine the 
efficacy boundary for the primary endpoint.  The study will reject the null hypothesis for a given 
ruxolitinib treatment group if the Day 29 mortality endpoint crosses the efficacy boundary.  
Table 12 provides the projected stopping rules if the interim analysis is conducted at the 
projected number of participants. 
Table 12: 
Interim Analysis for Day 29 Mortality With HSD(–4) 
Interim Analysis 
Final Analysis 
Number of Participants 
200 
500 
Decision Outcome 
Continue 
Stop for Early 
Efficacy 
Do Not Reject 
Null Hypothesis 
Reject Null 
Hypothesis 
Z-statistic
≤ 3.07 
> 3.07
≤ 2.20 
> 2.20
One-sided p-value 
≥ 0.001 
< 0.001 
≥ 0.013 
< 0.013 
Ruxolitinib mortality at 
Day 29a 
≥ 30.0% 
< 30.0% 
≥ 46.0% 
< 46.0% 
a Assumes overall mortality rate at Day 29 is 60% for placebo. 
In the event that the null hypothesis regarding 28-day mortality is rejected for a given ruxolitinib 
treatment group when compared with placebo at the interim analysis, but not the other ruxolitinib 
treatment group, the DMC may provide guidance to the sponsor to terminate the study or allow 
the study to continue in order to better characterize the treatment effects within the other 
ruxolitinib treatment group.  For treatment groups continued beyond rejection of their specific 
null hypothesis, final reported p-values will be based on the highest level of significance 
achieved, either at the interim or final analysis. 


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If the null hypotheses are rejected for both ruxolitinib treatment groups when compared with 
placebo for the primary endpoint, then a statistical comparison will be performed between the 
2 ruxolitinib groups in an alpha-controlled fashion.  The 1-sided for the comparison will be based 
on the timing of the rejection (interim or final analysis) for the individual ruxolitinib 
comparisons versus placebo, while accounting for the Type I error expended at the interim 
analysis as appropriate (Table 13). 
Table 13: 
Type 1 Error Allocated to 5 mg BID to 15 mg BID Comparison Based on 
Timing for Rejection of Each Null Hypothesis 
Timing of Rejection of 
Null Hypothesis 
Alpha Expended 
2-Sided Alpha for Comparison
if IA Occurs at 40% of Data
Both at interim analysis 
0 
5.00% 
One at interim analysis, one 
at final analysis 
Alpha spent for single comparison at IA: 
HSD(–4) × 0.01436968 
4.79% 
Both at final analysis 
Alpha spent in both comparisons at IA: 
~HSD(–4) × 0.025 
4.63% 
12.5.2. 
Futility Analysis for Overall Survival 
A weekly futility analysis, starting 14 days after first randomized participant, is planned for this 
study.  The futility analyses, upon agreement of the DMC, may not be performed if rapid study 
enrollment does not permit operationalizing the analysis. 
The analysis will use a Cox regression model, for each ruxolitinib treatment arm individually 
when compared with placebo, including treatment, ARDS severity, and gender as  fixed 
covariates and investigational site as a random effect.  The planned nonbinding futility rule for 
the analysis will use a beta-spending approach with an HSD(–1) spending function assuming an 
overall power of 94.5% to detect a hazard ratio of 0.55.  As the exact number of events for the 
final analysis is unknown, the interim analysis will be a function of the number of participant 
days after randomization (up to and including Day 28) for randomized participants.  Assuming 
enrollment day for participant i follows the function 
f (i) = 28 • (i / n)0.7, 
the resulting spending function will have the boundaries for futility shown in Table 14. 
Table 14: 
Projected Futility Analysis Rules for Example Enrollment Profile 
Interim 
Analysis No 
Proportion of 
Monitoring 
Days 
Number of Participants 
Enrolled in Placebo & 
Ruxolitinib Comparison 
Number of 
Participants 
Completed Day 28 
Stop for Futility 
if Z < 
1 
0.058 
111 
0 
–1.98
2 
0.151 
198 
0 
–1.21
3 
0.300 
300 
0 
–0.37
4 
0.475 
300 
41 
0.35 
5 
0.650 
300 
111 
0.94 
6 
0.825 
300 
198 
1.47 


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13.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
13.1. 
Investigator Responsibilities 
•
The Protocol, Protocol amendments, ICF, IB, and other relevant documents
(eg, advertisements) must be submitted to an IRB by the investigator and reviewed
and approved by the IRB before the study is initiated. 
•
The investigator is responsible for ensuring that the safety reports provided by the
sponsor are reviewed and processed in accordance with regulatory requirements, the
policies and procedures established by the IRB, and institutional requirements.
•
Any amendments to the Protocol will require approval from both Health Authorities
and IRB before implementation of changes made to the study design, except for
changes necessary to eliminate an immediate hazard to study participants.
•
The investigator will be responsible for the following:
−
Providing written summaries of the status of the study to the IRB annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB.
−
Notifying the IRB of SAEs or other significant safety findings as required by IRB
procedures.
−
Providing oversight of the conduct of the study at the site and adherence to GCP,
IRB requirements, institutional requirements, and applicable laws and
country-specific regulations.
•
Adhering to the Protocol as described in this document and agreeing that changes to
the Protocol procedures, with the exception of medical emergencies, must be
discussed and approved, first, by the sponsor or its designee and, second, by the IRB.
Each investigator is responsible for enrolling participants who have met the specified
eligibility criteria.
•
Decentralized assessments, which are study assessments performed at a facility other
than the primary site, are acceptable as indicated in the SoA.  The investigator is
responsible to provide oversight of all study assessments.
•
Retaining records in accordance with all local, national, and regulatory laws but for a
minimum period of at least 2 years after the last marketing application approval in an
ICH region and until there are no pending or contemplated marketing applications in
an ICH region, or if not approved, 2 years after the termination of the test article for
investigation to ensure the availability of study documentation should it become
necessary for the sponsor or a regulatory authority to review.


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−
The investigator must not destroy any records associated with the study without
receiving approval from the sponsor.  The investigator must notify the sponsor or
its designee in the event of accidental loss or destruction of any study records.  If
the investigator leaves the institution where the study was conducted, the sponsor
or its designee must be contacted to arrange alternative record storage options.
−
All eCRF data entered by the site (including audit trail), as well as computer
hardware and software (for accessing the data), will be maintained or made
available at the site in compliance with applicable record retention regulations.
The sponsor will retain the original eCRF data and audit trail. 
13.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in the 
eCRF.  The study monitor will reference the Monitoring Plan in order to ensure that each issue 
identified is appropriately documented, reported, and resolved in a timely manner in accordance 
with the plan's requirements.  Other data outside the EDC system required in the study conduct 
of the Protocol such as documents or results transmitted to the sponsor via a central laboratory or 
specialized technical vendors and, as designated by the sponsor, will have their own data flow 
management plans, study charters, or biomarker plans, as applicable. 
The sponsor (or designee) will be responsible for: 
•
Managing the integrity of the data and the quality of the conduct of the study, such as
ensuring that study monitors perform ongoing source data verification to confirm that
data entered into the eCRF by authorized site personnel are accurate, complete, and
verifiable from source documents; that the safety and rights of participants are being
protected; and that the study is being conducted in accordance with the currently
approved Protocol and any other study agreements, ICH GCP, and all applicable
regulatory requirements.  Remote monitoring and remote source data review will be
performed as defined in the monitoring plan.
•
Managing and reconciling the data generated, and/or collected including documents
and results such as laboratory or imaging data analyzed centrally by a designated
vendor of the sponsor.
The investigator will be responsible for: 
•
Recording, or ensuring the recording of, all relevant data relating to the study in the
eCRF.
•
Delivering, or ensuring the delivery of, all other results, documents, data, know-how,
or formulas relating to the study to the sponsor or designee electronically or as
otherwise specified in the Protocol.
•
Verifying that data entries are accurate and correct by physically or electronically
signing the eCRF.


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•
Maintaining accurate documentation (source data) that supports the information
entered in the eCRF, or sent to a central vendor designated by the sponsor, or as
described in other study and data flow manuals.
−
Source documents provide evidence for the existence of the participant and
substantiate the integrity of the data collected.  Source documents are filed at the
investigator's site.
−
Data entered in the eCRF that are transcribed from source documents must be
consistent with the source documents or the discrepancies must be explained.  The
investigator may need to request previous medical records or transfer records,
depending on the study.  Current applicable medical records must be available.
•
May have responsibility for sending participants' data, either as unique samples, or
copies, or photographs, to be evaluated centrally or analyzed centrally, or both, by a
qualified vendor designated by the sponsor.
•
Permitting study-related monitoring, sponsor audits, IRB review, and regulatory
inspections by providing direct access to source data and other relevant clinical study
documents.
−
Monitoring:  Qualified representatives of the sponsor or its designee, study
monitors, will monitor the study according to a predetermined plan.  The
investigator must allow the study monitors to review any study materials and
participant records at each monitoring visit.
−
Auditing:  Qualified representatives of the sponsor or its designee may audit the
clinical study site and study data to evaluate compliance with the Protocol,
applicable local clinical study regulations, and overall study conduct.  The
investigator must allow the auditors to review original source records and study
documentation for all participants.
−
Regulatory inspection:  Regulatory authorities may conduct an inspection of the
study and the site at any time during the development of an investigational
product.  The investigator and staff are expected to cooperate with the inspectors
and allow access to all source documents supporting the eCRFs and other
study-related documents.  The investigator must immediately notify the sponsor
when contacted by any regulatory authority for the purposes of conducting an
inspection.
13.3. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations.  The investigator and the sponsor or its designee are responsible for ensuring 
that sensitive personal information is handled in accordance with local requirements 
(eg, HIPAA).  Appropriate consent and authorizations for use and disclosure and/or transfer (if 
applicable) of personal information must be obtained. 
Participant names will not be supplied to the sponsor or its designee.  Only the participant 
number will be recorded in the eCRF, where permitted; if the participant's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 


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supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with appropriate technical and organizational measures as required by local data 
protection laws. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 2 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor.  No records may be transferred to 
another location or party without written notification to the sponsor. 
13.4. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research participants, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
13.5. 
Publication Policy 
By signing the study Protocol, the investigator and his/her institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation, for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 


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Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
13.6. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
•
Failure of the investigator to comply with the Protocol, the requirements of the IRB
or local health authorities, the sponsor's procedures, or GCP guidelines.
•
Inadequate recruitment of participants by the investigator.
•
Discontinuation of further study treatment development.


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14.
REFERENCES
Ahmed A, Merrill SA, Alsawah F, et al. Ruxolitinib in adult patients with secondary 
haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. Lancet Haematol 
2019;6:e630-e637. 
ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress 
syndrome: the Berlin Definition. JAMA 2012;307:2526-2533. 
Cai J, Xu J, Lin D, et al. A case series of children with 2019 novel coronavirus infection: clinical 
and epidemiological features [published online ahead of print February 28, 2020]. Clin Infect 
Dis. doi:10.1093/cid/ciaa198. 
Calbet M, Ramis I, Calama E, et al. Novel inhaled pan-JAK inhibitor, LAS194046, reduces 
allergen-induced airway inflammation, late asthmatic response, and pSTAT activation in Brown 
Norway rats. J Pharmacol Exp Ther 2019;370:137-147.  
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 March 18, 2020]. N Engl J Med. 
doi:10.1056/NEJMoa2001282. 
Clinical Trial Facilitation and Coordination Group. Recommendations related to contraception 
and pregnancy testing in clinical trials. 2014. 
Coon TA, McKelvey AC, Lear T, et al. The proinflammatory role of HECTD2 in innate 
immunity and experimental lung injury. Sci Transl Med 2015;7:295ra109. 
Food and Drug Administration. Guidance for Industry: Drug Interaction Studies - Study Design, 
Data Analysis, Implications for Dosing, and Labeling Recommendations (Draft Guidance). 2012. 
Goldsmith SR, Saif Ur Rehman S, Shirai CL, Vij K, DiPersio JF. Resolution of secondary 
hemophagocytic lymphohistiocytosis after treatment with the JAK1/2 inhibitor ruxolitinib. Blood 
Adv 2019;3:4131-4135. 
Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients 
infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy [published online 
ahead of print April 6, 2020]. JAMA. doi:10.1001/jama.2020.5394. 
Hermans MAW, Schrijver B, van Holten-Neelen CCPA, et al. The JAK1/JAK2- inhibitor 
ruxolitinib inhibits mast cell degranulation and cytokine release. Clin Exp Allergy 
2018;48:1412-1420. 
Hoffmann J, Machado D, Terrier O, et al. Viral and bacterial co-infection in severe pneumonia 
triggers innate immune responses and specifically enhances IP-10: a translational study. Sci Rep 
2016;6:38532. 
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 January 30, 2020]. Lancet 
2020;395:497-506. 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of Type I error 
probability spending functions. Stat Med 1990;9:1439-1445. 


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Indiana University School of Medicine. Cytochrome P450 Drug Interaction Table: Abbreviated 
"Clinically Relevant" Table. 2007. 
Jakafi (ruxolitinimb) [package insert]. Incyte Corporation; 2019. 
Kenderian SS, Ruella M, Shestova O, et al. Ruxolitinib prevents cytokine release syndrome after 
car T-cell therapy without impairing the anti-tumor effect in a xenograft model. Biol Blood 
Marrow Transpl 2017;23(suppl):S19-S20 [abstr]. 
Liao M, Liu Y, Yuan J, et al. The landscape of lung bronchoalveolar immune cells in COVID-19 
revealed by single-cell RNA sequencing [published online ahead of print February 23, 2020]. 
medRxiv. doi: https://doi.org/10.1101/2020.02.23.20026690. 
Maschalidi S, Sepulveda FE, Garrigue A, Fischer A, de Saint Basile G. Therapeutic effect of 
JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood 
2016;128:60-71. 
Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and 
immunosuppression. Lancet 2020;395:1033-1034. 
The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. Vital 
surveillances: the epidemiological characteristics of an outbreak of 2019 novel coronavirus 
diseases (COVID-19)–China, 2020. China CDC Weekly 2020;2:113-122. 
Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of Spo2/Fio2 
ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure 
Assessment score. Crit Care Med 2009;37:1317-1321. 
Ruxolitinib Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
University of Washington School of Pharmacy. Drug Interaction Database Program. 2002. 
Vincent JL, de Mendonça A, Cantraine F, et al. Use of the SOFA score to assess the incidence of 
organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. 
Working group on "sepsis-related problems" of the European Society of Intensive Care 
Medicine. Crit Care Med 1998;26:1793-1800. 
Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) 
score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related 
Problems of the European Society of Intensive Care Medicine. Intensive Care Med 
1996;22:707-710. 
Wang J, Wang Y, Wu L, et al. Ruxolitinib for refractory/relapsed hemophagocytic 
lymphohistiocytosis [published online ahead of print September 12, 2019]. Haematologica. 
doi:10.3324/haematol.2019.222471. 
Wang W Jr, He J, Lie P, et al. The definition and risks of cytokine release syndrome-like in 
11 COVID-19-infected pneumonia critically ill participants: disease characteristics and 
retrospective analysis. medRxiv. doi: https://doi.org/10.1101/2020.02.26.20026989.  
Wei M, Yuan J, Liu Y, Fu T, Yu X, Zhang ZJ. Novel coronavirus infection in hospitalized 
infants under 1 year of age in China. JAMA 2020;323:1313-1314.  


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World Health Organization. WHO R&D Blueprint. Novel Coronavirus. COVID-19 Therapeutic 
Trial Synopsis, 18 February (draft guidance). Geneva, Switzerland: World Health Organization; 
2020a. 
World Health Organization. Clinical management of severe acute respiratory infection when 
novel coronavirus (2019-nCoV) infection is suspected: interim guidance v. 1.2, 13 March. 
Geneva, Switzerland: World Health Organization; 2020b. 
Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and CT features in pediatric patients with 
COVID-19 infection: Different points from adults. Pediatr Pulmonol 2020;55:1169-1174. 
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with 
SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study 
[published online ahead of print February 24, 2020] [published correction appears in Lancet 
Respir Med 2020;8:e26]. Lancet Respir Med. doi:10.1016/S2213-2600(20)30079-5. 
Zhao J, Yu H, Liu Y, et al. Protective effect of suppressing STAT3 activity in LPS-induced acute 
lung injury. Am J Physiol Lung Cell Mol Physiol 2016;311:L868-L880. 
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;395:1038]. Lancet 2020;395:1054-1062. 
Zumla A, Hui DS, Azhar EI, Memish ZA, Maeurer M. Reducing mortality from 2019-nCoV: 
host-directed therapies should be an option. Lancet 2020;395:e35-e36. 


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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For female participants in the study: 
The following methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods: 
•
Combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulationa 
−
oral
−
intravaginal
−
transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulationa
−
oral
−
injectable
−
implantableb
•
Intrauterine deviceb
•
Intrauterine hormone-releasing systemb
•
Bilateral tubal occlusionb
•
Vasectomized partnerbc
•
Sexual abstinenced
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary
mode of action
•
Male or female condom with or without spermicidee
•
Cap, diaphragm, or sponge with spermicidee
•
Tubal ligation
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method. 
b Contraception methods that in the context of this guidance are considered to have low user dependency. 
c Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
d In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. 
e A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
Source:  Clinical Trials Facilitation and Coordination Group 2014. 


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APPENDIX B. 9-POINT ORDINAL SCALE (SECONDARY ENDPOINT) 
Clinical status of participant at Day 15 and 29 (9-point ordinal scale): 
Participant State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatorya 
No limitation of activities 
1 
Limitation of activities 
2 
Hospitalized 
Mild Disease 
Hospitalized, no oxygen therapy (defined as SpO2 ≥ 94% on room air) 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalized 
Severe Disease 
Noninvasive ventilation or high-flow oxygen 
5 
Intubation and mechanical ventilation 
6 
Ventilation + additional organ support – vasopressors, RRT, ECMO 
7 
Dead 
Death 
8 
a Defined as not in hospital or in hospital and ready for discharge. 
Source:  WHO 2020a. 


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APPENDIX C. SEQUENTIAL ORGAN FAILURE ASSESSMENT SCORE 
The SOFA score is a scoring system to determine the extent of a person's organ function or rate 
of failure (Vincent et al 1996, Vincent et al 1998).  The score is based on six different scores, one 
each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems.  
Baseline assessment should be based on data collected closest to (but also prior to) 
randomization.  Each subsequent day should use the worst value for each parameter in the 
preceding 24-hour period. 
Respiratory System 
When using PaO2: 
PaO2/FiO2 (mmHg) 
0 = PaO2/FiO2 ≥ 400 
1 = PaO2/FiO2 < 400 
2 = PaO2/FiO2 < 300 
3 = PaO2/FiO2 < 200 and mechanically ventilated 
4 = PaO2/FiO2 < 100 and mechanically ventilated 
PaO2 should be used if available.  However, if PaO2 is not available, the following table can be 
used to generate the SOFA score with SpO2 (Pandharipande et al 2009): 
Use of SpO2/FiO2 in SOFA Score 
SOFA Respiratory 
System Points 
(Using SpO2) 
SpO2/FiO2 Ratio 
PEEP < 8 or 
Not Intubated 
PEEP 8-12 
PEEP > 12 
0 
≥ 457 
≥ 515 
≥ 425 
1 
< 457 
< 515 
< 425 
2 
< 370 
< 387 
< 332 
3 
< 240 
< 259 
< 234 
4 
< 115 
< 130 
< 129 
Note:  The original SpO2/FiO2 Ratio as published would require a SpO2 > 110% to achieve a SOFA score of 0. 
Therefore, this score has been modified to accept a SpO2 of 96% or greater on room air as normal (ie, an 
SpO2/FiO2 ratio of ≥ 457 would be a SOFA score = 0). 
Nervous System 
Glasgow coma score 
0 = GCS score of 15 
1 = GCS score of 13-14 
2 = GCS score of 10-12 
3 = GCS score of 6-9 
4 = GCS score of < 6  


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Cardiovascular System 
Mean arterial pressure (MAP) OR administration of vasopressors required (vasopressor drug 
doses are in mcg/kg/min) 
0 = No hypotension 
1 = MAP < 70 mmHg 
2 = dopamine ≤ 5 or dobutamine (any dose) 
3 = dopamine > 5 OR epinephrine ≤ 0.1 OR norepinephrine ≤ 0.1 
4 = dopamine > 15 OR epinephrine > 0.1 OR norepinephrine > 0.1 
Liver 
Total bilirubin (mg/dL) 
0 = Total Bilirubin < 1.2 
1 = Total Bilirubin 1.2 - 1.9 
2 = Total Bilirubin 2.0 - 5.9 
3 = Total Bilirubin 6.0 - 11.9 
4 = Total Bilirubin ≥ 12.0  
Coagulation 
Platelets×103/µL 
0 = Platelets ≥ 150 ×103/µL 
1 = Platelets < 150 ×103/µL 
2 = Platelets < 100 ×103/µL 
3 = Platelets < 50 ×103/µL 
4 = Platelets < 20 ×103/µL 
Renal System 
Creatinine (mg/dL) (or urine output) 
0 = Creatinine < 1.2 mg/dL 
1 = Creatinine 1.2 - 1.9 mg/dL 
2 = Creatinine 2.0 - 3.4 mg/dL 
3 = Creatinine 3.5 - 4.9 mg/dL, or urine output < 500 mL/d 
4 = Creatinine ≥ 5.0 mg/dL, or urine output < 200 mL/d, or dialysis requirement 
Source:  Pandharipande et al 2009, Vincent et al 1996, Vincent et al 1998. 


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APPENDIX D. LIST OF CYP3A4 INHIBITORS AND INDUCERS 
Dual CYP2C9/CYP3A4 inhibitor: 
Fluconazole:  Avoid the concomitant use of ruxolitinib with fluconazole doses ≥ 200 mg daily; if 
clinically necessary to use doses ≥ 200 mg daily consultation with sponsor is required (see 
Section 7.2). 
Table D1: 
CYP3A4 Inhibitors and Inducers 
Category 
Drug Names 
Strong inhibitorsa of CYP3A 
boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, eltegravir/ritonavir, grapefruit juiceb, idelalisib, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, LCL161, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, sequinavir/ritonavir, telaprevir, telithromycin, 
voriconazole, indinavir/ritonavir, tipranoavir/ritonavir, 
troleandomycin 
Moderate inhibitorsc of CYP3A 
amprenavir, aprepitant, atazanavir, atazanavir/ritonavir, casopitant, 
cimetidine, ciprofloxacin, crizotinib, cyclosporin, duranavir, 
darunavir/ritonavir, diltiazem, dronedarone, erythromycin, 
faldaprevir, fluconazoled, fosamprenavir, grapefruit juiceb, imatinib, 
lomitapide, netupitant, nilotinib, schisandra, sphenantherae, 
tofisopam, verapamil 
Strong inducersf of CYP3A 
avasimibe, carbamazepine, enzalutamide, mitotane,phenytoin, 
rifampin, St John's worte, rifabutin, phenobarbital 
Moderate inducersg of CYP3A 
bosentan, efavirenz, etravirine, genisteine, lersivirine, lopinavir, 
modafinil, nafcillin, ritonavir, semagacestath, talviralineh,
thioridazine, tipranavir 
Note:  This may not be an exhaustive list.  For a complete and most updated drug list, check the website 
https://www.crediblemeds.org/healthcareproviders/drug-list. 
a A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by equal or more than 5-fold. 
b Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. 
c A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold 
d Fluconazole is a dual CYP3A4 and CYP2C9 inhibitor.  Fluconazole is a strong CYP2C9 inhibitor based on the 
AUC ratio of omeprazole, which is also metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor. 
e Herbal product. 
f A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate for 
that CYP by equal or more than 80%. 
g A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that CYP 
by 50-80%. 
h Drugs not available in the US market. 
Source:  FDA 2012, Indiana University School of Medicine 2007, University of Washington School of Pharmacy 
2002. 


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APPENDIX E. CORRELATIVE SERUM COLLECTION, PROCESSING, 
AND SHIPPING INFORMATION 
Day 1, Day 7, and Day 15 Serum Collection 
1. Collect blood sample in 4 to 6 mL SST collection tube.
2. After obtaining sample, immediately invert collection tube 5 times gently to mix clot
activator with blood. 
3. Allow blood to clot for 30 minutes in a vertical position.
4. Process the collection tubes by centrifugation between 1100 and 1300 × g for 10 minutes
for swing-head units or 15 minutes for fixed angle units.  Barrier will form, separating
serum specimen from clot.
5. Transfer serum into labeled tube/cryovial with the Incyte study INCB 18424-369,
participant ID, and date/time of collection.
6. Freeze and store aliquots immediately in a freezer set to maintain a temperature of –70°C
or colder until ready for shipment.  Samples must be maintained in the frozen state until
assayed.  Short-term storage (< 7 days) at –20°C is acceptable when –70°C freezer is not
available.
7. Ship samples weekly to Incyte with a 2-day supply of dry ice following instruction
below.
8. When sending the sample shipment, if possible, please send an electronic sample listing
in Microsoft Excel format and sample shipment tracking information before sending to
. 
9. The shipping address is as follows:
Incyte Research Institute 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Email:  
Lab Phone Number:  


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APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1: 
02 JUN 2020 
Amendment 1 (02 JUN 2020) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to incorporate Health Authority comments. 
1. Section 1, Protocol Summary (Figure 1:  Study Design Schema; Table 2:  Key Study
Design Elements; Table 3:  Schedule of Activities); Section 3.1, Primary Estimates;
Section 4.1, Overall Design; Section 6.1, Inclusion Criteria; Section 9.4.2, Presence
SARS-CoV-2 Virus/Viral Load/Antibody Testing
Description of change:  The requirement for confirmation of SARS-CoV-2 infection
prior to randomization was changed from 2 weeks to 3 weeks.
Rationale for the change:  To include participants who may have had initial SARS-
CoV-2 diagnosis within 3 weeks and who have not had repeat testing.
2. Section 1, Protocol Summary (Figure 1:  Study Design Schema; Table 2:  Key Study
Design Elements; Table 3:  Schedule of Activities); Section 4.1, Overall Design;
Section 6.1, Inclusion Criteria; Section 7.3.1, Participant Numbering; Section 8,
Informed Consent Procedures; Section 9.1.1, Information to Be Collected on
Screening Failures; Section 10.1.3, Withdrawal of Informed Consent; Section 12.4.1,
Primary and Secondary Analysis
Description of change:  The eligibility criteria were updated to allow participants who
are ≥ 12 years of age to enroll, requirements to obtain assent when applicable were
added, and subgroup analysis for age was updated accordingly.
Rationale for the change:  To incorporate Health Authority comments.
3. Section 1, Protocol Summary (Table 3:  Schedule of Activities); Section 4.1, Overall
Design; Section 6.2, Exclusion Criteria
Description of change:  Exclusion criterion 6 was updated to allow participants who are
receiving nitric oxide and/or high frequency oscillatory ventilation.
Rationale for the change:  Nitric oxide and high frequency oscillatory ventilation are
treatment modalities that are occasionally used as standard therapy in the study
population.
4. Section 1, Protocol Summary (Table 3:  Schedule of Activities); Section 9.1,
Screening
Description of change:  The requirement that laboratory assessments performed for
screening be repeated if not done within 6 hours of randomization was deleted.
Rationale for the change:  As all screening assessments are performed within 24 hours
of randomization, the initial screening laboratory assessments are sufficient for study
baseline.


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5. Section 5.6, Risks and Benefits; Section 9.4.3.4, Monitoring of Thromboembolic
Risk
Description of change:  Guidance for monitoring and prophylaxis of thrombosis was
added.
Rationale for the change:  To incorporate Health Authority comments.
6. Section 7.1, Study Treatment Administered
Description of change:  Guidance for dosing during prone positioning was added.
Rationale for the change:  Given the frequent use of prone positioning in the study
population, it is appropriate to provide dosing guidance in this scenario.
7. Section 10.1.5, Early Study Termination by the Sponsor
Description of change:  The study stopping criteria were clarified to indicate that
individual treatment arms or the entire study may stop upon recommendation of the
DMC.
Rationale for the change:  To incorporate Health Authority comments.
8. Section 12.4.1, Primary and Secondary Analysis
Description of change:  Added analyses comparing participants by assigned placebo
image to determine if the rate is consistent across the 2 treatment images.
Rationale for the change:  To incorporate Health Authority comments.
9. Incorporation of administrative changes.  Other minor, administrative changes have
been incorporated throughout the Protocol and are noted in the redline version of the
amendment.


Signature Manifest 
Document Number: IC-DEV-PROT-AMEND-0587
Title: 18424-369 Protocol Amendment 1 
All dates and times are in Eastern Standard Time. 
Approval: 18424-369 Protocol AM1 
Approval and Release 
Date 
02 Jun 2020, 09 32 05 AM 
02 Jun 2020, 0948 54 AM 
02 Jun 2020, 09 51 32 AM 
02 Jun 2020, 10 32 02 AM 
02 Jun 2020, 0414:39 PM 
Meaning/Reason 
Approved 
Approved 
Approved 
Approved 
Approved 
Revision: 0

SAP_001.pdf: 
Incyte Co1poration 
INCB 18424-369 Statistical Analysis Plan Am 3 
Statistical Analysis Plan 
Page 1 of38 
22 FEB 2021 
INCB 18424-369/ NCT04377620
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Study to Assess the Efficacy and Safety of Ruxolitinib in Participants 
With COVID-19-Associated ARDS Who Require Mechanical 
Ventilation (RUXCOVID-DEVENT) 
IND Number: 
149,270 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Amendment 1 dated 02 JUN 2020 
CRF Approval Date: 
30 SEP 2020 
SAP Version: 
Amendment 3 
SAP Author: 
Date of Plan: 
22 FEB 2021 
This study is being conducted in compliance with Good Clinical Practice, 
including the archiving of essential documents. 
VV-CLIN-010351
CONFIDENTIAL 


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VV-CLIN-010351
CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1.
INTRODUCTION ........................................................................................................7
2.
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................8 
2.1. 
Protocol and Case Report Form Version ......................................................................8 
2.2. 
Study Objectives and Endpoints ...................................................................................8 
3.
STUDY DESIGN .......................................................................................................10 
3.1. 
Randomization ............................................................................................................11 
3.2. 
Control of Type I Error ...............................................................................................11 
3.3. 
Sample Size Considerations .......................................................................................11 
3.4. 
Schedule of Assessments ............................................................................................12 
4.
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................12 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................12 
4.1.1. 
Day 1 ...........................................................................................................................12 
4.1.2. 
Study Day ...................................................................................................................12 
4.1.3. 
Baseline Value ............................................................................................................13 
4.1.4. 
Last Available Value ..................................................................................................13 
4.1.5. 
Handling of Missing and Incomplete Dates and Times ..............................................13 
4.2. 
Variable Definitions ....................................................................................................14 
4.2.1. 
Body Mass Index ........................................................................................................14 
4.2.2. 
Prior and Concomitant Medication .............................................................................14 
4.2.3. 
Mean Arterial Pressure ...............................................................................................14 
5.
STATISTICAL METHODOLOGY ...........................................................................14 
5.1. 
General Methodology .................................................................................................14 
5.2. 
Treatment Groups .......................................................................................................14 
5.3. 
Analysis Populations ..................................................................................................15 
5.3.1. 
All-Screened Population .............................................................................................15 
5.3.2. 
Intent-to-Treat Population ..........................................................................................15 
5.3.3. 
Per-Protocol Population ..............................................................................................15 
5.3.4. 
Safety Population ........................................................................................................15 
6.
BASELINE, EXPOSURE, AND DISPOSITION ......................................................16 
6.1. 
Demographics, Baseline Characteristics, and Disease History ..................................16 


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6.1.1. 
Demographics and Baseline Characteristics ...............................................................16 
6.1.2. 
Baseline Disease Characteristics and Disease History ...............................................16 
6.1.3. 
Medical History ..........................................................................................................16 
6.2. 
Disposition of Participant ...........................................................................................17 
6.3. 
Protocol Deviations ....................................................................................................17 
6.4. 
Exposure .....................................................................................................................17 
6.5. 
Study Drug Compliance .............................................................................................17 
6.6. 
Prior and Concomitant Medication .............................................................................17 
7.
EFFICACY .................................................................................................................18
7.1. 
General Considerations ...............................................................................................18 
7.2. 
Efficacy Hypotheses ...................................................................................................18 
7.3. 
Analysis of the Primary Efficacy Parameter ..............................................................18 
7.3.1. 
Primary Efficacy Analysis ..........................................................................................18 
7.3.2. 
Subgroup Analyses for Primary Endpoint ..................................................................19 
7.3.3. 
Sensitivity and Supportive Analyses for Primary Endpoint .......................................20 
7.4. 
Analysis of the Secondary Efficacy Parameters .........................................................21 
7.4.1. 
In-Hospital Outcomes .................................................................................................21 
7.4.2. 
COVID-19 9-Point Ordinal Scale ...............................................................................21 
7.4.2.1. 
Proportional Odds Model for COVID-19 9-Point Ordinal Scale ...............................21 
7.4.2.2. 
Improvements and Changes in COVID-19 9-Point Ordinal Scale .............................22 
7.4.3. 
Sequential Organ Failure Assessment Score ..............................................................22 
7.4.3.1. 
Summary and Analysis of SOFA Score .....................................................................22 
7.4.3.2. 
Summary and Analysis of SOFA Score Components ................................................22 
7.5. 
Analysis of Exploratory Efficacy Variables ...............................................................22 
7.5.1. 
Participants Receiving IL-6, IL-6R, IL-1RA, IL-1β, GM-CSF, BTK, or 
JAK-Directed Therapies .............................................................................................22 
7.5.2. 
Inflammatory Markers ................................................................................................23 
7.5.3. 
SARS-CoV2 Virologic and Serologic Parameters .....................................................23 
8.
PHARMACODYNAMICS ........................................................................................23 
9.
SAFETY AND TOLERABILITY ..............................................................................23 
9.1. 
General Considerations ...............................................................................................23 
9.2. 
Adverse Events ...........................................................................................................23 
9.2.1. 
Adverse Event Definitions ..........................................................................................23 


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9.2.2. 
Adverse Event Summaries ..........................................................................................24 
9.3. 
Clinical Laboratory Tests ...........................................................................................25 
9.3.1. 
Laboratory Value Definitions .....................................................................................25 
9.3.2. 
Laboratory Value Summaries .....................................................................................25 
9.3.3. 
Potential Drug-Induced Liver Injury Events ..............................................................26 
9.4. 
Vital Signs ..................................................................................................................26 
10.
INTERIM ANALYSES ..............................................................................................26 
11.
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................27 
11.1. 
Changes to Protocol-Defined Analyses ......................................................................27 
11.1.1. 
Original to Amendment 1 ...........................................................................................27 
11.1.2. 
Amendment 1 to Amendment 2 ..................................................................................27 
11.1.3. 
Amendment 2 to Amendment 3 ..................................................................................27 
11.2. 
Changes to the Statistical Analysis Plan .....................................................................28 
11.2.1. 
Original to Amendment 1 ...........................................................................................28 
11.2.2. 
Amendment 1 to Amendment 2 ..................................................................................29 
11.2.3. 
Amendment 2 to Amendment 3 ..................................................................................29 
12.
REFERENCES ...........................................................................................................30 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................31 
APPENDIX B. COVID-19 9-POINT ORDINAL SCALE .........................................................36 
APPENDIX C. SEQUENTIAL ORGAN FAILURE ASSESSMENT .......................................37 


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LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................8 
Table 2: 
Simulation Estimates for Power and Type 1 Error for Various Mortality 
Rates ...........................................................................................................................12 
Table 3: 
Primary and Sensitivity Analyses of Primary Endpoints ...........................................20 
Table 4: 
In-Hospital Outcome Event-Free Days Variable Definition ......................................21 
Table 5: 
Identification of Records for Postbaseline By-Visit Summaries ................................25 
Table 6: 
Normal Ranges for Vital Sign Values ........................................................................26 
Table 7: 
Statistical Analysis Plan Versions ..............................................................................27 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................10 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical Classification System 
BID 
twice daily 
BMI 
body mass index 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
FiO2 
percentage of inspired oxygen 
ICU 
intensive care unit 
ITT 
intent to treat 
LDA 
longitudinal data analysis 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
PaO2 
partial pressure of arterial oxygen 
PLB 
placebo 
PP 
per protocol 
PT 
preferred term 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SOC 
system organ class 
SoC 
standard of care 
SOFA 
sequential organ failure assessment 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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1.
INTRODUCTION
This is a randomized, double-blind, placebo-controlled, 29-day, multicenter study to assess the 
efficacy and safety of ruxolitinib 5 mg BID + SoC therapy and 15 mg BID + SoC therapy 
compared with placebo + SoC therapy in participants aged ≥ 12 years with COVID-19–
associated ARDS who require mechanical ventilation.  Participants will be assigned in a 
2:2:1 ratio to receive ruxolitinib 5 mg BID, 15 mg BID, or matching-image placebo for an initial 
period of 14 days; participants randomized to placebo will be randomized 1:1 to either receive 
matching placebo for 5 mg BID (1 tablet BID) or matching placebo for 15 mg BID (3 tablets 
BID).  On Day 15, if in the opinion of the investigator the benefit/risk is appropriate, then 
continued treatment up to 28 days is permitted with medical monitor approval.  Study treatment 
will be given in combination with SoC therapy according to the investigator's clinical judgment.  
Study treatment will be administered via an enteric feeding tube while the participant is 
intubated.  Randomization will be stratified by ARDS severity (severe [PaO2/FiO2 ≤ 100] vs 
mild/moderate [PaO2/FiO2 > 100 and ≤ 300]) and investigative site.  Sections 2 and 5 of the 
Protocol provide a detailed description of the investigational product, target patient population, 
rationale for doses to be examined, and potential risks and benefits of treatment with 
ruxolitinib/placebo. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 18424-369 Protocol. 
The details of the analysis methodology of biomarkers and pharmacodynamics and results will 
appear in a separate report. 


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2.
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 18424-369 Protocol Amendment 1 dated 02 JUN 2020 and CRFs 
approved on 30 SEP 2020.  Unless superseded by an amendment, this SAP will be effective for 
all subsequent Protocol amendments and eCRF versions. 
2.2. 
Study Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the 28-day mortality rate of 
ruxolitinib 5 mg BID + SoC therapy and 
ruxolitinib 15 mg BID + SoC therapy compared 
with placebo + SoC therapy in participants with 
COVID-19–associated ARDS who require 
mechanical ventilation. 
Proportion of participants who have died due to 
any cause through Study Day 29. 
Secondary 
To evaluate the efficacy of ruxolitinib 5 mg BID + 
SoC therapy and ruxolitinib 15 mg BID + SoC 
therapy compared with placebo + SoC therapy on 
in-hospital outcomes in participants with 
COVID-19–associated ARDS who require 
mechanical ventilation. 
At Day 29, the number of ventilator-free days, 
ICU-free days, oxygen-free days, vasopressor-free 
days, and hospital-free days will be summarized  
by treatment group. 
To evaluate the efficacy of ruxolitinib 5 mg BID + 
SoC therapy and ruxolitinib 15 mg BID + SoC 
therapy compared with placebo + SoC therapy 
using a 9-point ordinal scale at Study Days 15 and 
29 in participants with COVID-19–associated 
ARDS who require mechanical ventilation. 
Ordinal scale: 
• Percentage of participants with at least 2-point
improvement in clinical status at Day 15 and
at Day 29.
• Percentage of participants with at least 1-point
improvement in clinical status at Day 15 and
at Day 29.
• Time to improvement from baseline category
to earliest 1-point improvement in the ordinal
scale.
• Percentage of participants in each 9-point
ordinal scale category at Day 29.
• Mean change in the 9-point ordinal scale from
baseline to Days 15 and 29.


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
To evaluate the efficacy of ruxolitinib 5 mg BID + 
SoC therapy and ruxolitinib 15 mg BID + SoC 
therapy compared with placebo + SoC therapy on 
change from baseline SOFA score in participants 
with COVID-19–associated ARDS who require 
mechanical ventilation. 
Change from baseline to Day 3, 5, 8, 11, 15, and 
29 in SOFA score. 
To evaluate the safety of ruxolitinib 5 mg BID + 
SoC therapy and ruxolitinib 15 mg BID + SoC 
therapy compared with placebo + SoC therapy in 
the treatment of participants with COVID-19–
associated ARDS who require mechanical 
ventilation. 
Number and proportion of participants with 
treatment-related side effects (as assessed by 
CTCAE v5.0) and SAEs; includes clinically 
significant changes in laboratory measures and 
vital signs. 
Exploratory 
To evaluate the efficacy of ruxolitinib + SoC 
therapy compared with placebo + SoC therapy in 
proportion of participants requiring IL-6, IL-1, 
GM-CSF, or JAK-directed therapies. 
Proportion of participants requiring treatments 
with IL-6, IL-6RA, IL-1RA, IL-1 beta, GM-CSF, 
BTK, or JAK directed therapies by Day 15 and by 
Day 29. 
To evaluate ruxolitinib + SoC therapy compared 
with placebo + SoC therapy on change in 
inflammatory markers (when available). 
Change from baseline to Day 15 and to Day 29 in 
the following clinical chemistry measurements: 
• Serum ferritin
• CRP
• D-dimer
• Procalcitonin
• IL-6
To evaluate ruxolitinib + SoC therapy compared 
with placebo + SoC therapy on change in 
COVID-19 virologic and serologic parameters. 
Change from baseline to Day 15 and Day 29 in 
viral load and anti–SARS-CoV-2-antibody titer. 


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3.
STUDY DESIGN
This is a randomized, double-blind, placebo-controlled, 29-day, multicenter study to assess the 
efficacy and safety of ruxolitinib 5 mg BID + SoC therapy and 15 mg BID + SoC therapy 
compared with placebo + SoC therapy in participants aged ≥ 12 years with COVID-19–
associated ARDS who require mechanical ventilation (see Figure 1). 
Participants aged ≥ 12 years with SARS-CoV-2 infection confirmed ≤ 3 weeks before 
randomization by any test with local regulatory approval, hospitalized with COVID-19–
associated ARDS (demonstrated by chest x-ray or chest computerized tomography and 
PaO2/FiO2 ≤ 300 mmHg) who have been intubated and are receiving mechanical ventilation.  
Participants who are unlikely to survive for > 24 hours after randomization (in the opinion of the 
treating investigator); who have active tuberculosis or active and uncontrolled bacterial, fungal, 
viral, or other infection (besides SARS-CoV-2); or who are currently receiving ECMO support 
will be excluded from the study. 
The study will include the following: 
•
Screening period of 1 day.
•
Study period of 29 days.  Treatment with ruxolitinib 5 mg BID/placebo or ruxolitinib
15 mg BID/placebo will initially be administered for 14 days.  If in the opinion of the
treating investigator the benefit/risk is appropriate for the participant, then continued
treatment up to 28 days permitted with approval from the sponsor medical monitor.
Approval must be requested ≥ 24 hours before initiation of dosing on Day 15.
•
AE follow-up assessment 28 (± 3) days following the last dose of study treatment.
Figure 1: 
Study Design 
Eligible participants will be randomized after completing the screening period (Day -1) and 
having been confirmed eligible.  Screening and randomization may occur on the same day.  
Participants will be assigned in a 2:2:1 ratio to receive ruxolitinib 5 mg BID, 15 mg BID, or 
matching-image placebo for an initial period of 14 days (refer to Protocol Section 7.1); 


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participants randomized to placebo will be randomized 1:1 to receive either matching placebo for 
5 mg BID (1 tablet BID) or matching placebo for 15 mg BID (3 tablets BID).  On Day 15, if in 
the opinion of the investigator the benefit/risk is appropriate, then continued treatment up to 
28 days permitted with medical monitor approval.  There is no crossover between treatment 
groups.  Study treatment will be given in combination with SoC therapy according to the 
investigator's clinical judgment.  Study treatment will be administered via an enteric feeding tube 
(refer to Protocol Section 7.1) while the participant is intubated.  Randomization will be stratified 
by ARDS severity (severe [PaO2/FiO2 ≤ 100] vs mild/moderate [PaO2/FiO2 > 100 and ≤ 300]) 
and investigative site. 
3.1. 
Randomization 
Participants will be randomized 2:2:1 to receive ruxolitinib 5 mg BID, 15 mg BID, or 
matching-image placebo for an initial period of 14 days.  Placebo participants will be 
randomized 1:1 to receive either the 5 mg BID image or the 15 mg BID image.  Block 
randomization with stratification for ARDS severity (severe [PaO2/FiO2 ≤ 100] vs mild/moderate 
[PaO2/FiO2 > 100 and ≤ 300]) and investigational site will be used. 
3.2. 
Control of Type I Error 
The Type 1 error level for the primary endpoint is 1-sided 2.5%.  A fixed sequence testing 
procedure will be used to test the 15 mg BID group against placebo first, and if that is 
significant, then the 5 mg BID group will be tested against placebo.  If the test for the 15 mg BID 
group is not significant, the 5 mg BID group will not be tested. 
If the null hypotheses are rejected for both ruxolitinib treatment groups when compared with 
placebo for the primary endpoint, then a statistical comparison will be performed between the 
2 ruxolitinib groups. 
No multiplicity adjustments will be applied to other endpoints.  Secondary efficacy variables will 
be tested at a 0.05 level and will use a 2-sided test.  All exploratory variables will use a 2-sided, 
5% alpha with no adjustment for multiplicity. 
3.3. 
Sample Size Considerations 
The primary endpoint of this study is the proportion of participants who die due to any cause 
through Study Day 29.  The primary endpoint will be tested for each ruxolitinib treatment group 
using a logistic regression model including treatment (ruxolitinib vs placebo) and ARDS severity 
(severe [PaO2/FiO2 ≤ 100] vs mild/moderate [PaO2/FiO2 > 100 and ≤ 300] as fixed covariates 
and investigational site as a random (intercept) effect.  For placebo randomized 2:2:1 (ruxolitinib 
5 mg BID:ruxolitinib 15 mg BID:placebo) assuming a 40% mortality rate for ruxolitinib versus 
60% for placebo, a sample size for a pairwise comparison of 100 placebo and 200 ruxolitinib 
participants (with 500 participants total) will achieve approximately 83% power to detect a 
statistically significant difference with a nominal 1-sided Type I error of 1.436968%. 
Estimated power and Type I error for various scenarios, based on a simulation study of 
1000 study replications, are provided in Table 2. 


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Table 2: 
Simulation Estimates for Power and Type 1 Error for Various Mortality 
Rates 
Mortality Rates 
Probability to Reject H0 for 
PLB 
5 mg BID 
15 mg BID 
5 mg BID 
15 mg BID 
Either RUX 
60% 
60% 
60% 
0.015 
0.016 
0.027 
60% 
60% 
40% 
0.012 
0.873 
0.873 
60% 
50% 
40% 
0.268 
0.865 
0.866 
60% 
40% 
40% 
0.868 
0.872 
0.940 
60% 
40% 
30% 
0.861 
0.998 
0.998 
Note:  For the simulation, investigational site was drawn from an integer uniform distribution (1, 2, …, 10) and 
probability (ARDS severe) = 0.5, fitting a mixed logistic regression model with no direct effects for the ARDS 
severity or site. 
Enrollment was halted and SAP Amendment 3 removed the interim analysis.  The final analysis 
will be performed using all randomized participants enrolled at the time of SAP Amendment 3, 
which is 211 participants. 
3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 1 dated 02 JUN 2020 for a full description of all study procedures 
and assessment schedules for this study. 
4.
DATA HANDLING DEFINITIONS AND CONVENTIONS
4.1. 
Scheduled Study Evaluations and Study Periods
4.1.1. 
Day 1
Day 1 is the date that the first dose of study drug (ruxolitinib/placebo) is administered to the 
participants. 
For randomized participants not treated with any study drug, Day 1 is defined as the date of 
randomization. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date). 
A study day of –1 indicates 1 day before Day 1. 


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4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of 
ruxolitinib/placebo, unless otherwise defined. 
For randomized participants not treated with any study drug, baseline is defined as the last 
nonmissing assessment before randomization for all parameters. 
When scheduled assessments and unscheduled assessments occur on the same day and the time 
of the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
•
If both a scheduled and an unscheduled visit are available on the day of the first dose
and the time is missing, use the scheduled assessment as baseline.
•
If all scheduled assessments are missing on the day of the first dose and an
unscheduled assessment is available, use the unscheduled assessment as baseline.
4.1.4. 
Last Available Value
The last available value is the last nonmissing measurement obtained after starting 
ruxolitinib/placebo and within 31 days after the last dose of ruxolitinib/placebo. 
4.1.5. 
Handling of Missing and Incomplete Dates and Times 
In general, values for missing dates will not be handled unless methods for handling missing 
dates are specified in this section or relevant sections.  The original reported dates collected on 
the eCRF should be used in all relevant listings.  The following rules will be used for handling 
partial dates for analyses requiring dates. 
When calculating the time since diagnosis, a partial date will be treated as missing and a time 
will not be calculated.  When calculating the time since intubation, a partial date and/or 24-hour 
time will be treated as missing and a time will not be calculated. 
When the date of the last dose is used in deriving variables such as duration of treatment or 
TEAE flag, a missing or partial date of the last dose will be handled as follows: 
•
If only the day is missing, then the earlier date of the last day of the month or the date
that the participant discontinued treatment will be used.
•
Otherwise, the date that the participant discontinued treatment will be used as the date
of the last dose.
For relevant efficacy endpoints, a partial date of the death date will be handled as follows in the 
calculation: 
•
If mmyyyy for the last known alive date = mmyyyy for the death date, then the death
date will be set to the day after the last known alive date.
•
If mmyyyy for the last known alive date < mmyyyy for the death date, then the death
date will be set to the first day of the death month.
•
Otherwise, the partial death date will not be imputed.


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4.2. 
Variable Definitions 
4.2.1. 
Body Mass Index 
Body mass index will be calculated as follows: 
Body mass index (kg/m2) = [weight (kg)] / [height (m)]2. 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
ruxolitinib/placebo. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
•
Before the date of first administration of ruxolitinib/placebo and is ongoing
throughout the study or ends on/after the date of first study drug administration.
•
On/after the date of first administration of ruxolitinib/placebo and is ongoing or ends
during the course of study.
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after the first dose of ruxolitinib/placebo.  In the listing, it will be indicated whether 
a medication is only prior, only concomitant, or both prior and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 
4.2.3. 
Mean Arterial Pressure 
The mean arterial pressure will be calculated as follows: 
Mean arterial pressure (mmHg) = [systolic blood pressure (mmHg) + 2 × diastolic blood 
pressure (mmHg)] / 3. 
5.
STATISTICAL METHODOLOGY
5.1. 
General Methodology
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9 or later) will be used 
for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries for 
continuous variables will include but not be limited to the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of participants in each category. 
5.2. 
Treatment Groups 
This is a randomized, double-blind, parallel treatment group design.  Participants will be 
summarized by treatment groups. 


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5.3. 
Analysis Populations 
5.3.1. 
All-Screened Population 
The all-screened population will include all participants who provided informed consent (written 
or verbal). 
5.3.2. 
Intent-to-Treat Population 
All participants who are randomized will constitute the ITT population.  Treatment groups for 
this population will be defined according to the treatment assignment at the time of 
randomization regardless of the actual study drug the participant might take during his/her 
participation in the study. 
The ITT population will be used for the summary of demographics, baseline characteristics, 
participant disposition, and analyses of all efficacy data. 
5.3.3. 
Per-Protocol Population 
The PP population comprises the subset of subjects in the ITT population who are compliant 
with requirements of the clinical study Protocol, including the following: 
•
Continued to meet all eligibility criteria on Study Day 1.
•
Initiated correct randomized therapy within the Protocol-specified window.
•
Did not significantly deviate from the Protocol in terms of missed study assessments,
noncompliance with randomized therapy, or prohibited concomitant medications.
The PP population will be used in a supportive sensitivity analysis for the primary efficacy 
endpoint. 
5.3.4. 
Safety Population 
The safety population will include all participants who received at least 1 dose of 
ruxolitinib/placebo.  Treatment groups for this population will be determined according to the 
actual treatment the participant received regardless of assigned study drug treatment. 
All safety analyses will be conducted using the safety population. 


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6.
BASELINE, EXPOSURE, AND DISPOSITION
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
6.1. 
Demographics, Baseline Characteristics, and Disease History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized for the ITT 
population:  age, gender, race, ethnicity, weight, height, and BMI. 
6.1.2. 
Baseline Disease Characteristics and Disease History 
The following baseline disease characteristics will be summarized for the ITT population:  
predefined coexisting disorders, baseline SOFA score, baseline COVID-19 9-point ordinal scale 
clinical status, baseline ARDS severity (severe [PaO2/FiO2 ≤ 100] vs mild/moderate 
[PaO2/FiO2 > 100 and ≤ 300 mmHg]), ARDS severity at randomization, time (in hours) from 
start of mechanical ventilation to randomization, time (in days) from initial diagnosis to 
randomization, time (in days) from hospital admission to randomization, baseline CRP 
(≤ 100 mg/L or > 100 mg/L), baseline D-dimer (≤ 1000 ng/mL or > 1000 ng/mL), baseline 
ferritin (≤ 300 ng/mL or > 300 ng/mL), BMI at baseline (≥ 30 or < 30), prior or concomitant 
remdesivir, prior or concomitant convalescent plasma, prior or concomitant corticosteroid, 
concomitant anti-coagulant, prior biologic, prior or concomitant neutralizing antibodies, and 
prior or concomitant corticosteroid with prior or concomitant remdesivir. 
Time from initial diagnosis will be calculated as follows: 
Time since diagnosis (days) = (date of randomization – date of diagnosis + 1). 
Time from start of mechanical ventilation will be calculated as follows: 
Time from start of mechanical ventilation (hours) = (date and time of randomization – date 
and time of intubation). 
Time from hospital admission to randomization will be calculated as follows: 
Time from hospital admission (days) = (date of randomization – date of hospital admission + 1). 
6.1.3. 
Medical History 
For participants in the ITT population, medical history will be summarized by assigned treatment 
group.  This summation will include the number and percentage of participants with significant 
medical history for each body system/organ class as documented on the eCRF. 


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6.2. 
Disposition of Participant 
The number and percentage of participants, who were treated, who were ongoing with study 
treatment, who completed study treatment, who discontinued study treatment with a primary 
reason for discontinuation, who were still in the study, who completed the study, and who 
withdrew from the study with a primary reason for withdrawal will be summarized for the ITT 
population.  The number of participants randomized by country and/or site will also be provided 
by treatment group. 
6.3. 
Protocol Deviations 
Protocol deviations recorded on the eCRF will be summarized and listed. 
6.4. 
Exposure 
For participants in the safety population, exposure to ruxolitinib/placebo will be summarized 
descriptively as the following: 
•
Duration of treatment with ruxolitinib/placebo (days):  date of last dose of
ruxolitinib/placebo – date of first dose of ruxolitinib/placebo + 1.
•
Average daily dose of ruxolitinib/placebo (mg/day):  total actual
ruxolitinib/placebo dose taken (mg) / duration of treatment with ruxolitinib/placebo
(days).
•
Ruxolitinib/placebo dose modifications:  number of participants who had
ruxolitinib/placebo dose reduction, escalation, and interruption.
In addition, total daily dose of ruxolitinib/placebo dosing will be summarized by day. 
6.5. 
Study Drug Compliance 
As ruxolitinib/placebo dosing will be captured on the appropriate exposure eCRF, overall 
compliance (%) will be calculated for all participants as follows: 
Compliance (%) = 100  [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications. 
6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary.  
The number and percentage of participants in the ITT for each prior and concomitant medication 
will be summarized by WHO drug class and WHO drug PT. 


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7.
EFFICACY
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
7.1. 
General Considerations 
Unless otherwise stated, the strata identified in the randomization process will be used in all 
efficacy analyses.  For statistical analyses of the primary and secondary endpoints, separate 
models will be fit for the ruxolitinib 5 mg BID versus placebo and ruxolitinib 15 mg BID versus 
placebo comparisons. 
7.2. 
Efficacy Hypotheses 
The primary hypothesis is that ruxolitinib in combination with SoC will reduce 28-day mortality, 
as measured by odds ratio, compared with placebo in combination with SoC in participants with 
COVID-19–associated ARDS who require mechanical ventilation.  The hypothesis of the study 
are as follows: 
•
H0 (null hypothesis):  θRUX05 = θRUX15 = θPLB
•
HA(alternative hypothesis):  θRUX15 < θPLB or (θRUX05 < θPLB and θRUX15 < θPLB)
The 5 mg BID hypothesis will only be tested if the 15 mg BID hypothesis is significant.  In the 
event that both individual null hypotheses are rejected, then a test for a difference between the 
5 mg BID and 15 mg BID treatment groups will be performed for the 28-day mortality endpoint.  
The hypothesis for this test is: 
•
H0 (null hypothesis):  θRUX05 = θRUX15
•
HA(alternative hypothesis):  θRUX15 ≠ θRUX05
7.3. 
Analysis of the Primary Efficacy Parameter
7.3.1. 
Primary Efficacy Analysis
The primary endpoint, 28-day mortality, will be tested using a logistic regression mixed model 
including treatment group (specific ruxolitinib treatment group vs placebo) and ARDS severity 
(severe vs mild/moderate) as fixed covariates and investigational site as a random (intercept) 
effect.  The estimation technique for the model fit will use the residual pseudo-likelihood with a 
subject-specific expansion (SAS Institute 2013) approach and will be implemented in the SAS 
GLIMMIX procedure.  If the model is not estimable due to convergence issues, a fixed effects 
logistic regression will be performed instead, excluding investigational site from the model.  The 
Wald test for the treatment regression coefficient will test the primary endpoint. 
An estimate and 95% CI for the difference in proportions for 28-day mortality for the 2 treatment 
groups will be provided.  The estimate will be based on the logistic regression model 
(Ge et al 2011) using an average of the difference between the 2 levels of the fixed factor 
(ARDS severity) weighted for the proportion of the study population within each of the 2 levels 


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of the fixed factor.  The delta method will be used to derive the variance estimate, based on the 
functional form of the estimate Tg(b) using  = (1, 2) where 
•
1 is the proportion of participants in the b2 = 0
•
2 is the proportion of participants in the b2 = 1
b is the vector of the logistic regression coefficients, and 
. 
Point estimates and 95% CIs will also be provided for the model-based mortality rates using the 
delta method. 
Participants who are lost to follow-up before Day 29 will not be evaluable for this endpoint.  As 
the participants begin the study intubated, those who remain hospitalized are unlikely to be lost 
to follow-up, but reasonable efforts will be made to track down missing participants. 
7.3.2. 
Subgroup Analyses for Primary Endpoint 
Subgroups will be formed based on the following participant characteristics and baseline 
variables for those participants whose data are available: 
•
ARDS severity:  severe (PaO2/FiO2 ≤ 100 mmHg) versus mild/moderate (PaO2/FiO2
> 100 and ≤ 300 mmHg)
•
Gender:  male or female
•
Age group:  < 18 years, 18-64 years, or ≥ 65 years
•
Baseline CRP:  ≤ 100 mg/L or > 100 mg/L
•
D-dimer at baseline:  ≤ 1000 ng/mL or > 1000 ng/mL
•
Ferritin at baseline:  ≤ 300 ng/mL or > 300 ng/mL
•
Race:  White/Caucasian, Black/African-American, Asian, American-Indian/Alaska
Native, Native Hawaiian/Pacific Islander, or Other
•
Ethnicity:  Hispanic/Latino, Not Hispanic/Latino, or Other
•
Hours of mechanical ventilation at baseline:  ≤ 48 hours or > 48 hours
•
BMI at baseline:  ≥ 30 or < 30
•
Prior or concomitant remdesivir:  yes or no
•
Prior or concomitant convalescent plasma:  yes or no
•
Concomitant anticoagulant use:  yes or no
•
Concomitant corticosteroid use:  yes or no
•
Prior biologic use:  yes or no
𝑔 𝑏 =
1 1 + exp⁡(−𝑏0 −𝑏1)
 
−1 1 + exp⁡(−𝑏0)
 
1 1 + exp⁡(−𝑏0 −𝑏1 −𝑏2)
 
−1 1 + exp⁡(−𝑏0 −𝑏2)
 


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7.3.3. 
Sensitivity and Supportive Analyses for Primary Endpoint 
A sensitivity analysis will be conducted in the ITT population, in which nonevaluable 
participants will be treated as deaths.  The primary endpoint will be analyzed using the 
PP population as a sensitivity analysis to the ITT analysis.  In addition, a tipping point analysis 
will be performed to measure the robustness of the treatment effect under assumptions for 
participant dropout.  The tipping point analysis will use an unstratified 2-sample test of 
proportion, modifying dropouts within the compared ruxolitinib treatment group as having died 
and placebo participants as having lived to determine if and at what point in this imputation a 
statistically significant treatment effect under the base assumptions will lose statistical 
significance. 
Analyses related to the primary endpoints are delineated in Table 3. 
Table 3: 
Primary and Sensitivity Analyses of Primary Endpoints 
Endpoint 
Statistical Method 
Analysis 
Population 
Primary (P) or 
Supportive (S) 
Proportion of 
participants who have 
died due to any cause 
through Study Day 29. 
Logistic regression with treatment group 
and ARDS severity (severe vs 
mild/moderate) as fixed covariates, and 
investigational site as a random effect.  
Wald test for treatment group regression 
coefficient = 0. 
Estimation:  Odds-ratio for treatment 
effect and associated 95% CI. 
ITT 
P 
PP 
S 
Logistic regression with treatment group 
and ARDS severity (severe vs 
mild/moderate) as fixed covariates, and 
investigational site as a random effect, 
treating participants who are lost to 
follow-up before Day 29 as deaths. 
ITT 
S 
Logistic regression with treatment group 
and ARDS severity (severe vs 
mild/moderate) as fixed covariates, and 
investigational site as a random effect 
using actual PaO2/FiO2 at Day 1 (as 
entered into eCRF). 
ITT 
S 
Logistic regression with treatment group, 
ARDS severity (severe vs mild/moderate), 
and gender (male or female) as fixed 
covariates, and investigational site as a 
random effect.  Wald test for treatment 
group regression coefficient = 0. 
ITT 
S 
The 28-day mortality rates and participants lost to follow-up in the placebo group will be 
compared by the placebo image assigned (5 mg BID and 15 mg BID) to determine if the rate is 
consistent across the 2 treatment images.  Statistical comparisons between the 2 images will be 
performed using a Fisher's exact test in all placebo-assigned participants and within ARDS 


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severity subgroup.  Additional endpoints may also be compared within placebo-assigned 
participants by treatment image. 
7.4. 
Analysis of the Secondary Efficacy Parameters 
7.4.1. 
In-Hospital Outcomes 
The number of ventilator-free, ICU-free, oxygen-free, vasopressor-free, and hospital-free 
calendar days between Study Days 2 and 29 (inclusive) will be derived using the rules as 
outlined in Table 4.  Note that qualifying vasopressor medications (ie, ATC Class 
C01CA - adrenergic and dopaminergic agents) will be determined through blinded review of 
concomitant medications, with the list of medications qualifying as vasopressors included as a 
note to file prior to final database lock. 
Outcome-free days between Days 2 and 29 will be summarized descriptively (mean, mean, 
standard deviation) with treatment-group statistical comparisons performed using a 
Kruskal-Wallis test.  Participants with missing data that do not permit evaluation for all 28 days, 
but are known to be alive at Day 29, will have each such day treated as not event-free.  
Participants who die prior to or on Day 29 will have 0 assigned days for each event-free 
endpoint.  Participants for whom Day 29 survival status cannot be ascertained will be missing 
from the analysis. 
Table 4: 
In-Hospital Outcome Event-Free Days Variable Definition 
Endpoint 
The Number of Study Days That a Participant Was Alive and… 
Ventilator-free days 
did not require mechanical ventilation.a 
ICU-free days 
is out of the ICU.a 
Vasopressor-free days 
without use of vasopressor therapy.a 
Hospital-free days 
is out of the hospital.a 
Oxygen-free days 
did not receive supplemental oxygen.a 
a Participants who do not survive through Day 29 will have 0 assigned days. 
7.4.2. 
COVID-19 9-Point Ordinal Scale 
The COVID-19 9-Point Ordinal Scale (see Appendix B) will be tabulated by study day, ordinal 
category, and treatment group.  Participants with missing values due to death will be imputed to 
have Category 8 (death).  Participants released from the hospital that are lost to follow-up will be 
considered missing with regards to this endpoint.  Missing intermediate days between 
observations will be imputed to the worst (highest) category from the 2 nonmissing observations. 
7.4.2.1. 
Proportional Odds Model for COVID-19 9-Point Ordinal Scale 
The odds of observing an improvement in the 9-point ordinal scale on Days 15 and 29 will be 
analyzed using a proportional odds model for the ITT and PP populations.  The odds of 
observing a better category on the ordinal scale (lower number) will be analyzed separately at 
Days 15 and 29.  The model will include treatment group and ARDS severity (severe vs 
mild/moderate) as fixed covariates and investigational site as a random effect. 


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As a sensitivity analysis to the proportional odds model, a Cochran-Mantel-Haenszel test for 
differences in treatment groups for the 9-point ordinal scale at Days 15 and 29, stratifying for 
ARDS severity, will also be provided. 
7.4.2.2. 
Improvements and Changes in COVID-19 9-Point Ordinal Scale 
The number and percentage of participants with a 1-point improvement at Days 15 and 29 will 
be tabulated and summarized by treatment group.  A logistic regression model will be used to 
model the probability of such an improvement that includes treatment group and ARDS severity 
(severe vs mild/moderate) as fixed covariates and investigational site as a random effect.  A 
similar summary will be used for 2-point improvements at Days 15 and 29. 
The time from randomization to first 1- (or more) point improvement in the COVID-19 9-point 
ordinal scale will be derived.  Participants who never improve on-study will be censored at their 
last assessment or Study Day 29, whichever is earlier.  A Kaplan-Meier analysis will be used to 
describe the time to first improvement. 
The mean change in the 9-point scale at Days 15 and 29 will be summarized descriptively by 
treatment group. 
7.4.3. 
Sequential Organ Failure Assessment Score 
7.4.3.1. 
Summary and Analysis of SOFA Score 
The change from baseline to Day 3, 5, 8, 11, 15, and 29 in SOFA score (see Appendix C) will be 
summarized descriptively by treatment group.   
Participants released from the hospital who are lost to follow-up will be considered missing with 
regards to numeric summaries of this endpoint.  Missing intermediate days between observations 
will be imputed to the worst (highest) score from the 2 nonmissing observations. 
7.4.3.2. 
Summary and Analysis of SOFA Score Components 
Individual scoring of organ systems (respiratory, nervous system, cardiovascular, liver, 
coagulation, and kidneys) will be tabulated.  Individual organ system scores by scheduled Study 
Days 3, 5, 8, 11, 15, and 29 will be compared using the Cochran-Mantel-Haenszel test stratified 
by baseline organ system score (0, 1, 2, 3, or 4).  Participants who have died will be imputed to 
the worst value (4) of the component.  Such comparisons will be for exploratory purposes to 
determine if the response is being driven by a subset of the components of the SOFA score. 
7.5. 
Analysis of Exploratory Efficacy Variables 
7.5.1. 
Participants Receiving IL-6, IL-6R, IL-1RA, IL-1β, GM-CSF, BTK, or 
JAK-Directed Therapies 
The number of participants receiving IL-6, IL-6R, IL-1RA, IL-1β, GM-CSF, BTK, or 
JAK-directed therapies by Day 15 and by Day 29 will be summarized for the safety population.  
The list of such therapies will include, but is not limited to, the following:  tocilizumab, 
canakinumab, anakinra, or sarilumab.  A blinded review of concomitant medications will be 
performed to identify any agents meeting this criteria prior to unblinding of the clinical team. 


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7.5.2. 
Inflammatory Markers 
Baseline and postbaseline levels of inflammatory markers will be summarized for the safety 
population.  These markers include serum ferritin, CRP, D-dimer, procalcitonin, and IL-6.  
Changes and percentage changes in each marker will be summarized at Day 15 and Day 29. 
7.5.3. 
SARS-CoV2 Virologic and Serologic Parameters 
Baseline and postbaseline levels of viral load and anti-SARS-CoV-2 antibodies will be 
summarized for the safety population at Study Days 1, 15, and 29.  The proportion of 
participants negative for SARS-CoV2 will be summarized at Day 15 and Day 29. 
8.
PHARMACODYNAMICS
See Section 7.5 for details regarding pharmacodynamic endpoints. 
9.
SAFETY AND TOLERABILITY
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
9.1. 
General Considerations 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique PTs reported on relatively 
few participants. 
9.2. 
Adverse Events 
9.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first dose of study drug until 31 days after the last dose of study drug.  Analysis of AEs (as 
discussed below) will be limited to TEAEs, but data listings will include all AEs regardless of 
their timing in relation to study drug administration.  For purposes of analysis, all AEs will be 
considered TEAEs unless the AE can unequivocally be defined as not treatment-emergent. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE v5.  The CTCAE reporting guidelines and grading details are available on 
the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs.  If the investigator does not specify the relationship of the AE to study 
drug, the AE will be considered to be treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  In addition, serious TEAEs will also be tabulated. 


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9.2.2. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include the following: 
•
Number (%) of participants who had any TEAEs
•
Number (%) of participants who had any serious TEAEs
•
Number (%) of participants who had any Grade 3 or higher TEAEs
•
Number (%) of participants who had any TEAEs related to ruxolitinib/placebo
•
Number (%) of participants who temporarily interrupted ruxolitinib/placebo because
of TEAEs
•
Number (%) of participants who permanently discontinued ruxolitinib/placebo
because of TEAEs
•
Number (%) of participants who had ruxolitinib/placebo dose reductions because of
TEAEs
•
Number (%) of participants who had any fatal TEAEs
The following summaries will be produced: 
•
Summary of TEAEs by MedDRA SOC and PT
•
Summary of TEAEs by MedDRA PT in decreasing order of frequency
•
Summary of TEAEs by MedDRA SOC, PT, and maximum severity category
•
Summary of Grade 3 or higher TEAEs by MedDRA SOC and PT
•
Summary of Grade 3 or higher TEAEs by MedDRA PT in decreasing order of
frequency
•
Summary of serious TEAEs by MedDRA SOC and PT
•
Summary of serious TEAEs by MedDRA PT in decreasing order of frequency
•
Summary of ruxolitinib/placebo treatment-related TEAEs by MedDRA SOC and PT
•
Summary of ruxolitinib/placebo treatment-related TEAEs by MedDRA PT in
decreasing order of frequency
•
Summary of ruxolitinib/placebo treatment-related TEAEs by MedDRA SOC, PT, and
CTCAE grade category
•
Summary of Grade 3 or higher ruxolitinib/placebo treatment-related TEAEs by
MedDRA SOC and PT
•
Summary of ruxolitinib/placebo treatment-related serious TEAEs by MedDRA SOC
and PT
•
Summary of TEAEs with a fatal outcome by MedDRA SOC and PT
•
Summary of TEAEs leading to ruxolitinib/placebo dose reduction by MedDRA SOC
and PT


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•
Summary of TEAEs leading to ruxolitinib/placebo dose interruption by MedDRA
SOC and PT
•
Summary of TEAEs leading to discontinuation of ruxolitinib/placebo by MedDRA
SOC and PT
•
Summary of TEAEs requiring concomitant medications by MedDRA SOC and PT
9.3. 
Clinical Laboratory Tests
9.3.1. 
Laboratory Value Definitions
Laboratory values and change from baseline values will be summarized descriptively by visit.  
Baseline will be determined according to Section 4.1.3.  If there are multiple values that meet the 
criteria for baseline, additional rules may be provided after consultation with the medical monitor 
to delineate which value will be defined as baseline. 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
The baseline value will be determined using the nonmissing values collected before the first 
dose, prioritizing scheduled assessments for baseline identification over unscheduled visits.  The 
last record before administration in the highest priority will be considered the baseline record.  
For baseline laboratory candidates with the same date and time in the same priority category, 
additional rules may be provided after consultation with the medical monitor to delineate which 
value will be defined as baseline. 
Laboratory test values will be assessed for severity based on the numerical component of 
CTCAE v5. 
9.3.2. 
Laboratory Value Summaries 
Any laboratory test results and associated normal ranges from local laboratories will be 
converted to SI units.  Scheduled laboratory tests for hematology and clinical chemistry will be 
summarized by scheduled study days (eg, Days 3, 5, 7) through Day 29.  Windows for 
postbaseline by-visit summaries will be ± 1 study day (eg, Day 3 will be Days 2-4).   
When there are multiple nonmissing laboratory values for a participant's particular test within a 
visit window, the convention described in Table 5 will be used to determine the record used for 
by-visit tabulations and summaries.  A record may only be used for 1 scheduled visit.  If a record 
qualifies for more than 1 by-visit summary, then the earlier study day will take precedence. 
Table 5: 
Identification of Records for Postbaseline By-Visit Summaries 
Priority 
Laboratory Visit 
Proximity to Visit 
Window 
Tiebreaker 
1 
Scheduled 
In-window 
Use smallest laboratory 
sequence number 
2 
Unscheduled 
In-window 
3 
Scheduled 
Out-of-window 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary.  In addition, line graphs and box-and-whisker plots will 


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be provided for hemoglobin, platelet counts, leukocytes, lymphocytes, neutrophils, creatinine, 
ALT, and AST. 
Severity grades will be assigned to laboratory test values based on the numerical component of 
CTCAE v5.  Shift tables will be presented showing change in CTCAE grade from baseline to 
worst grade postbaseline.  Separate summaries for abnormally high and abnormally low 
laboratory values will be provided when the laboratory parameter has both high and low grading 
criteria.  The denominator for the percentage calculation will be the number of participants in the 
baseline category.  Shift tables will also be presented showing change in CTCAE grade from 
baseline to the last value using the same methods explained above.  The number of participants 
who experienced worsening of laboratory abnormalities will be summarized by maximum 
severity. 
9.3.3. 
Potential Drug-Induced Liver Injury Events 
Participants with potential drug-induced liver injuries will be listed.  Potential drug-induced liver 
injuries will be defined in participants with normal ALT and AST and total bilirubin at baseline 
as having elevated ALT or AST > 3 × ULN accompanied by total bilirubin > 2 × ULN at the 
same visit.  Potential drug-induced liver injuries will be defined in participants with elevated 
ALT or AST or total bilirubin at baseline as having elevated ALT or AST > 2 × baseline or ALT 
or AST > 300 U/L, whichever occurs first, accompanied by total bilirubin > 2 × baseline and 
total bilirubin > 2 × ULN at the same visit. 
9.4. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, temperature, respiratory rate, 
pulse oximetry, and body weight will be summarized descriptively.  Normal ranges for vital 
signs are provided in Table 6. 
Table 6: 
Normal Ranges for Vital Sign Values 
Parameter 
12 ‒ < 16 yearsa 
≥ 16 years 
High 
Low 
High 
Low 
Systolic blood pressure (mmHg) 
≤ 131.0 
≥ 90.0 
≤ 155.0 
≥ 85.0 
Diastolic blood pressure (mmHg) 
≤ 83.0 
≥ 64.0 
≤ 100.0 
≥ 40.0 
Pulse (beats per minute) 
≤ 100.0 
≥ 60.0 
≤ 100.0 
≥ 45.0 
Body temperature (°C) 
≤ 38.0 
≥ 35.5 
≤ 38.0 
≥ 35.5 
Respiratory rate (breaths per minute) 
≤ 20.0 
≥ 12.0 
≤ 24.0 
≥ 8.0 
a Novak and Gill 2020. 
10.
INTERIM ANALYSES
Per SAP Amendment 3, no interim analysis will be performed. 


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11.
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN
All versions of the SAP are listed in Table 7. 
Table 7: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
21 APR 2020 
Amendment 1 
11 AUG 2020 
Amendment 2 
22 SEP 2020 
Amendment 3 
22 FEB 2020 
11.1. 
Changes to Protocol-Defined Analyses 
11.1.1. 
Original to Amendment 1 
•
The analysis for time to improvement from baseline category to earliest 1-point
improvement in the ordinal scale was restated as time to improvement from baseline
category to earliest improvement of any kind.
•
After FDA feedback, the initial plan for treatment groups continued beyond rejection
of their specific null hypothesis at the efficacy interim analysis where final reported
p-values would be based on the highest level of significance achieved, either at the
interim or final analysis, was modified to report p-values from the final analysis at
final reporting.
•
Gender was removed from analyses of the primary and secondary endpoints and
added as a sensitivity analysis for the primary endpoint.
11.1.2. 
Amendment 1 to Amendment 2
•
The weekly overall survival futility analysis was replaced by a conditional power
analysis to occur after approximately every 50 participants enrolled have at least
2 weeks of follow-up.
•
The reference level of ARDS severity was changed to be mild/moderate instead of
severe.
11.1.3. 
Amendment 2 to Amendment 3
•
Section 3.2, Section 3.3, Section 5.1, Section 7.3.1, Section 7.3.3, Section 10,
Appendix A – The interim analysis and conditional power analysis were removed.
The only remaining analysis will be the final analysis.
•
Section 3.2, Section 5.3.3, Section 5.3.5, Section 7.2, Section 7.5.1, Section 7.5.2,
Section 7.5.3, Appendix A – The alpha control strategy for the primary efficacy
analysis was changed.  The definition of the PP population was modified, and the
PD-evaluable population was removed.  Any planned analyses that previously used
the PD-evaluable population will use the safety population instead.


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11.2. 
Changes to the Statistical Analysis Plan 
11.2.1. 
Original to Amendment 1 
The following changes to the SAP were made based upon FDA comments on the original 
Protocol and SAP: 
•
Figure 1 – Updated to account for the changes in inclusion criteria.
•
Section 7.3.1 – An estimator for the treatment group proportions and their difference
was added.
•
Section 7.3.2 – The age subgroup analyses were modified to < 18 years, 18-64 years,
or ≥ 65 years.
•
Section 7.3.3 – A tipping point analysis was added for the primary endpoint, and a
comparison of the 2 placebo images (5 mg BID and 15 mg BID) was added.
•
Section 7.4.2.1 – The proposed test for the proportional odds assumption was
removed, and a sensitivity analysis was added to the comparison of the COVID-19
9-point ordinal scale.
•
Section 7.4.3 – Additional details were added regarding the summary of SOFA
components.
•
Section 9.4 – Table 7 was added to define normal ranges for vital signs based on age
categories.
The following editorial changes were also made based upon findings and additional feedback: 
•
Section 7.3.2 – Additional subgroup analyses were added for prior or concomitant
remdesivir, prior or concomitant convalescent plasma, concomitant anticoagulant use,
concomitant corticosteroid use, and prior biologic use.
•
Section 7.4.3.1 – Editorial changes were made to the LDA model description, with
minor modifications to the SAS code provided.
•
Section 9.2.2 – AE summaries inconsistent with the planned tables and summaries
were removed.
•
Section 9.3.3 – Updated the definition of potential drug-induced liver injuries to be
consistent with the Protocol.
•
Section 10.3.1 – The formula for Dunnett's procedure was corrected to reflect that the
joint probability should be subtracted from each marginal probability.
Other minor administrative changes have been incorporated throughout and are noted in the redline 
version of the document. 


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11.2.2. 
Amendment 1 to Amendment 2 
The following changes to the SAP were made based upon findings and additional feedback: 
•
Section 4.1.4 and Section 9.2.1 – A typo was corrected for the AE follow-up period to
align with the Protocol.
•
Section 6.1.2 – Variables were modified and added to what will be summarized for
baseline disease characteristics.
•
Section 6.2 – The number and percentage of randomized participants were removed
from the disposition section since this is not part of the standard disposition table, the
count can be obtained from the analysis populations table for the ITT population.
•
Section 7.3.3, Section 10.1, Section 10.2, and Section 10.4.2 – A Cox regression
model was replaced with conditional power analysis.
•
Section 7.4.3.1 – Minor modifications were made to the SAS code.
Other minor administrative changes have been incorporated throughout and are noted in the redline 
version of the document. 
11.2.3. 
Amendment 2 to Amendment 3 
The following changes to the SAP were made based upon findings and additional feedback: 
•
Section 7.4.3.1, Appendix A – The analysis of the endpoint for Change from baseline
to Day 3, 5, 8, 11, 15, and 29 in SOFA score was changed from an LDA model to a
simple descriptive summary.
•
Section 9.5 – The electrocardiogram section was removed since that data was not
collected.
•
Section 6.1.3 – Summary of Prior Medications for COVID-19 was removed.


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12.
REFERENCES
Dunnett CW.  New tables for multiple comparisons with a control.  Biometrics 1964;20:482-491. 
Ge M, Durham KL, Meyer DR, Xie W, Neal T. Covariate-adjusted difference in proportions 
from clinical trials using logistic regression and weighted risk differences. Drug Inf J 
2011;45:481-493. 
Novak C, Gill P. Pediatric Vital Signs Reference Chart. Peds Cases. 2018. 
Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of SpO2/FiO2 
ratio to impute for PaO2/FiO2 ratio in the respiratory component of the Sequential Organ Failure 
Assessment score. Crit Care Med 2009;37:1317-1321. 
SAS Institute Inc. SAS/STAT® 13.1 User's Guide High-Performance Procedures. Cary, NC: SAS 
Institute Inc. 2013. 
Vincent JL, de Mendonça A, Cantraine F, et al. Use of the SOFA score to assess the incidence of 
organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. 
Working group on "sepsis-related problems" of the European Society of Intensive Care 
Medicine. Crit Care Med 1998;26:1793-1800. 
Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) 
score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related 
Problems of the European Society of Intensive Care Medicine. Intensive Care Med 
1996;22:707-710. 
World Health Organization. Clinical management of severe acute respiratory infection when 
novel coronavirus (2019-nCoV) infection is suspected: interim guidance v. 1.2, 13 March. 
Geneva, Switzerland: World Health Organization; 2020. 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the Clinical Study 
Report.  Shells are provided in a separate document for tables that are not in the Standard Safety 
Tables v1.7. 
The lists of tables, figures, and listings are to be used as guidelines.  Modifications of the lists 
that do not otherwise affect the nature of the analysis will not warrant an amendment to the SAP. 
Tables 
Table 
No. 
Title 
Population 
Standard 
Baseline and Demographic Characteristics 
1.1  Disposition 
1.1.1 
Analysis Populations 
ITT 
X 
1.1.2 
Summary of Participant Disposition 
ITT 
X 
1.1.3 
Summary of Number of Participants Enrolled by Country and Site 
ITT 
X 
1.1.4 
Summary of Protocol Deviations 
ITT 
X 
1.2  Demography and Baseline Characteristics 
1.2.1 
Summary of Demographics and Baseline Characteristics 
ITT 
X 
1.3  Baseline Disease Characteristics 
1.3.1 
Summary of Baseline Disease Characteristics and History 
ITT 
1.4  Prior Medication and Concomitant Medication 
1.4.1 
Summary of Prior Medications 
ITT 
X 
1.4.2 
Summary of Concomitant Medications 
ITT 
X 
1.5+  Others 
1.5.1 
Summary of General Medical History 
ITT 
X 
Efficacy 
2.1  Primary Efficacy 
2.1.1 
Summary of 28-Day Mortality Analyzed by Logistic Regression 
Model 
ITT 
2.1.2 
Summary of 28-Day Mortality Analyzed by Logistic Regression 
Model 
PP 
2.1.3 
Summary of 28-Day Mortality Analyzed by Logistic Regression 
Model Using Actual PaO2/FiO2 at Randomization  
ITT 
2.1.4 
Summary of 28-Day Mortality Analyzed by Logistic Regression 
Model Treating Participants who are Lost to Follow-Up on or 
Before Day 29 as Deaths 
ITT 
2.1.6 
Summary of Tipping Point Analysis for 28-Day Mortality 
ITT 
2.1.7 
Summary of 28-Day Mortality for Participants Assigned Placebo by 
Treatment Image 
ITT 
2.2  Secondary Efficacy 
2.2.1 
Summary of Day 29 In-Hospital Outcomes by Treatment Group 
ITT 
2.2.2.1 
Summary of COVID-19 Ordinal Scale at Day 1, Day 15, and Day 
29  
ITT 
2.2.2.2.1 
Summary of COVID-19 Proportional Odds Model at Day 15 and 
Day 29 
ITT 


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Table 
No. 
Title 
Population 
Standard 
2.2.2.2.2 
Summary of COVID-19 Proportional Odds Model at Day 15 and 
Day 29 
PP 
2.2.2.3.1 
Summary of Participants With a 2-Point Improvement in 
COVID-19 Ordinal Scale on Day 15 or Day 29 
ITT 
2.2.2.3.2 
Summary of Participants With a 1-Point Improvement in 
COVID-19 Ordinal Scale on Day 15 or Day 29 
ITT 
2.2.3.4 
Kaplan-Meier Analysis of Time From Randomization to First 
Improvement in COVID-19 Ordinal Scale  
ITT 
2.2.4 
Summary of Change in COVID-19 Ordinal Scale at Study Day 15 
and 29 
ITT 
2.2.5 
Summary of COVID-19 Ordinal Scale by Study Day 
ITT 
2.2.6.1 
Summary of Change in SOFA Score at Days 3, 5, 8, 11, 15, 29 
ITT 
2.2.6.2 
Summary of SOFA Score at Study Days 1, 3, 5, 8, 11, 15, and 29 
ITT 
2.2.6.3 
Summary of SOFA Score Components at Study Days 1, 3, 5, 8, 11, 
15, and 29 
ITT 
2.3  Exploratory Endpoint 
2.3.1 
Summary of Participants Receiving IL-6, IL-6R, IL-1RA, IL-1 
beta, GM-CSF, BTK, or JAK Directed Therapies by Day 15 
and by Day 29 
Safety 
2.3.2 
Summary of Serum Markers of Inflammation at Baseline, Day 15, 
and Day 29 by Treatment Group 
Safety 
2.3.3.1 
Summary of SARS-CoV2 Virology at Baseline, Day 15, and Day 
29  
Safety 
2.3.3.2 
Summary of SARS-CoV2 Antibody Testing at Baseline, Day 15, 
and Day 29 
Safety 
Safety 
3.1  Dose Exposure 
3.1.1 
Summary of Exposure and Duration of Exposure to 
Ruxolitinib/Placebo 
Safety 
X 
3.1.2 
Summary of Average Daily Dose by Study Day 
Safety 
X 
3.1.3 
Summary of Study Medication Compliance 
Safety 
X 
3.2  Adverse Events 
3.2.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
X 
3.2.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety 
X 
3.2.3 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.4 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Maximum Severity 
Category 
Safety 
X 
3.2.6 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.7 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety 
X 
3.2.8 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
X 


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Table 
No. 
Title 
Population 
Standard 
3.2.9 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.10 
Summary of Ruxolitinib/Placebo Treatment-Related Treatment-
Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.11 
Summary of Ruxolitinib/Placebo Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA Preferred Term 
in Decreasing Order of Frequency 
Safety 
X 
3.2.13 
Summary of Ruxolitinib/Placebo Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, and Maximum Severity Category 
Safety 
X 
3.2.14 
Summary of Grade 3 or Higher Ruxolitinib/Placebo Treatment-
Related Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term 
Safety 
X 
3.2.15 
Summary of Ruxolitinib/Placebo Treatment-Related Serious 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.16 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.18 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib/Placebo Dose Reduction by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.19 
Summary of Treatment-Emergent Adverse Events Leading to 
Ruxolitinib/Placebo Dose Interruption by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.20 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Ruxolitinib/Placebo by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.21 
Summary of Treatment-Emergent Adverse Events Requiring 
Concomitant Medications by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.3  Laboratory 
3.3.1.1 
Summary of Laboratory Values - Hematology 
Safety 
X 
3.3.1.2 
Summary of Laboratory Values - Chemistry 
Safety 
X 
3.3.3.1 
Shift Summary of Hematology Laboratory Values in CTC Grade - 
to the Worst Abnormal Value  
Safety 
X 
3.3.3.2 
Shift Summary of Chemistry Laboratory Values in CTC Grade - to 
the Worst Abnormal Value 
Safety 
X 
3.3.3.3 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Hematology 
Safety 
X 
3.3.3.4 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Chemistry 
Safety 
X 
3.3.5.1 
Shift Summary of Hematology Laboratory Values in CTC Grade - 
to the Last Value 
Safety 
X 
3.3.5.2 
Shift Summary of Chemistry Laboratory Values in CTC Grade - to 
the Last Value 
Safety 
X 
3.4  Vital Signs 
3.4.1 
Summary of Systolic Blood Pressure 
Safety 
X 
3.4.2 
Summary of Diastolic Blood Pressure 
Safety 
X 


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Table 
No. 
Title 
Population 
Standard 
3.4.3 
Summary of Pulse 
Safety 
X 
3.4.4 
Summary of Respiration Rate 
Safety 
X 
3.4.6 
Summary of Weight 
Safety 
X 
3.4.7 
Summary of Pulse Oximetry 
Safety 
3.4.8 
Summary of Mean Arterial Pressure 
Safety 
Figures 
Figure No. 
Title 
4.1  Primary Efficacy 
4.1.2 
Forest Plot of Odds Ratio and 95% CIs for 28-Day Mortality Rate 
4.2  Secondary Efficacy 
4.2.1 
Kaplan-Meier Estimates of Time From Randomization to First Improvement in COVID-19 
Ordinal Scale 
4.2.2 
Stacked Bar Chart of COVID-19 Ordinal Scale by Treatment Group 
4.3  Exploratory Efficacy 
4.3.1 
Box-and-Whisker Plot of Ferritin by Study Visit 
4.3.2 
Box-and-Whisker Plot of CRP by Study Visit 
4.3.3 
Box-and-Whisker Plot of D-Dimer by Study Visit 
4.3.4 
Box-and-Whisker Plot of Procalcitonin by Study Visit 
4.3.5 
Box-and-Whisker Plot of IL-6 by Study Visit 
4.6  Laboratory Data 
4.6.1 
Box-and-Whisker Plot of Selected Laboratory Values by Study Visit 
Listings 
Listing No. 
Title 
2.1.1 
Participant Disposition Status 
2.1.2 
Participant Enrollment and Site Information 
2.2.1 
Protocol Deviations 
2.2.2 
Randomized Participants With Inclusion/Exclusion Criteria Violations 
2.3 
Analysis Population 
2.4.1 
Demographic and Baseline Characteristics 
2.4.2 
Medical History 
2.4.3 
COVID-19 Baseline Disease Characteristics 
2.4.4 
Prior Medications for COVID-19 
2.4.5 
Prior and Concomitant Medications 
2.4.6 
PBRC/Platelet Transfusions 
2.4.7 
Procedures and Non-Drug Therapies 
2.5.1 
Ruxolitinib/Placebo Exposure and Compliance 
2.6.1 
Deaths and 28-Day Mortality 
2.6.2 
COVID-19 Ordinal Scale by Study Day 
2.6.4 
COVID-19 Improvement Events and Assessment 
2.6.5 
Hospitalization, Ventilation, and Intubation Status 
2.6.6 
SOFA Scores and Components by Study Day 


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Listing No. 
Title 
2.6.7 
Arterial Blood Gas Analyses 
2.6.8 
Deaths 
2.6.9 
Chest Imaging 
2.6.10 
Concomitant IL-6, IL-6R, IL-1RA, IL-1 beta, GM-CSF, BTK, or JAK Directed Therapies 
2.6.11 
Serum Markers of Inflammation 
2.6.12 
SARS-CoV2 Virology 
2.6.13 
SARS-CoV2 Serology 
2.7.1 
Adverse Events 
2.7.2 
Serious Adverse Events 
2.7.3 
Grade 3 and Higher Adverse Events 
2.7.4 
Fatal Adverse Events 
2.7.5 
Ruxolitinib/Placebo Treatment-Related Adverse Events 
2.7.6 
Serious Ruxolitinib/Placebo Treatment-Related Adverse Events 
2.7.7 
Adverse Events Leading to Ruxolitinib/Placebo Dose Interruption 
2.7.8 
Adverse Events Leading to Ruxolitinib/Placebo Dose Reduction 
2.7.9 
Adverse Events Leading to Discontinuation of Ruxolitinib/Placebo 
2.8.1.1 
Abnormal Clinical Laboratory Values - Hematology 
2.8.1.2 
Clinical Laboratory Values - Hematology 
2.8.1.3 
Abnormal Clinical Laboratory Values - Chemistry 
2.8.1.4 
Clinical Laboratory Values - Chemistry 
2.8.1.5 
Potential Drug Induced Liver Injuries 
2.8.2.1 
Abnormal Vital Sign Values 
2.8.2.2 
Vital Sign Values 


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APPENDIX B. COVID-19 9-POINT ORDINAL SCALE 
Participant State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatorya 
No limitation of activities 
1 
Limitation of activities 
2 
Hospitalized 
Mild Disease 
Hospitalized, no oxygen therapy (defined as SpO2 ≥ 94% on room air) 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalized 
Severe Disease 
Noninvasive ventilation or high-flow oxygen 
5 
Intubation and mechanical ventilation 
6 
Ventilation + additional organ support – vasopressors, RRT, ECMO 
7 
Dead 
Death 
8 
a Defined as not in hospital or in hospital and ready for discharge. 
Source:  WHO 2020. 


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APPENDIX C. SEQUENTIAL ORGAN FAILURE ASSESSMENT 
The SOFA score is a scoring system to determine the extent of a person's organ function or rate 
of failure (Vincent et al 1996, Vincent et al 1998).  The score is based on six different scores, one 
each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems.  
Baseline assessment should be based on data collected closest to (but also prior to) 
randomization.  Each subsequent day should use the worst value for each parameter in the 
preceding 24-hour period. 
Respiratory System 
When using PaO2: 
PaO2/FiO2 (mmHg) 
0 = PaO2/FiO2 ≥ 400 
1 = PaO2/FiO2 < 400 
2 = PaO2/FiO2 < 300 
3 = PaO2/FiO2 < 200 and mechanically ventilated 
4 = PaO2/FiO2 < 100 and mechanically ventilated 
PaO2 should be used if available.  However, if PaO2 is not available, the following table can be 
used to generate the SOFA score with SpO2 (Pandharipande et al 2009): 
Use of SpO2/FiO2 in SOFA Score 
SOFA Respiratory 
System Points 
(Using SpO2) 
SpO2/FiO2 Ratio 
PEEP < 8 or 
Not Intubated 
PEEP 8-12 
PEEP > 12 
0 
≥ 457 
≥ 515 
≥ 425 
1 
< 457 
< 515 
< 425 
2 
< 370 
< 387 
< 332 
3 
< 240 
< 259 
< 234 
4 
< 115 
< 130 
< 129 
Note:  The original SpO2/FiO2 Ratio as published would require a SpO2 > 110% to achieve a SOFA score of 0.  
Therefore, this score has been modified to accept a SpO2 of 96% or greater on room air as normal (ie, an 
SpO2/FiO2 ratio of ≥ 457 would be a SOFA score = 0). 
Nervous System 
Glasgow coma score 
0 = GCS score of 15 
1 = GCS score of 13-14 
2 = GCS score of 10-12 
3 = GCS score of 6-9 
4 = GCS score of < 6  


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Cardiovascular System 
Mean arterial pressure (MAP) OR administration of vasopressors required (vasopressor drug 
doses are in mcg/kg/min) 
0 = No hypotension 
1 = MAP < 70 mmHg 
2 = dopamine ≤ 5 or dobutamine (any dose) 
3 = dopamine > 5 OR epinephrine ≤ 0.1 OR norepinephrine ≤ 0.1 
4 = dopamine > 15 OR epinephrine > 0.1 OR norepinephrine > 0.1 
Liver 
Total bilirubin (mg/dL) 
0 = Total Bilirubin < 1.2 
1 = Total Bilirubin 1.2 - 1.9 
2 = Total Bilirubin 2.0 - 5.9 
3 = Total Bilirubin 6.0 - 11.9 
4 = Total Bilirubin ≥ 12.0  
Coagulation 
Platelets×103/µL 
0 = Platelets ≥ 150 × 103/µL 
1 = Platelets < 150 × 103/µL 
2 = Platelets < 100 × 103/µL 
3 = Platelets < 50 × 103/µL 
4 = Platelets < 20 × 103/µL 
Renal System 
Creatinine (mg/dL) (or urine output) 
0 = Creatinine < 1.2 mg/dL 
1 = Creatinine 1.2 - 1.9 mg/dL 
2 = Creatinine 2.0 - 3.4 mg/dL 
3 = Creatinine 3.5 - 4.9 mg/dL, or urine output < 500 mL/d 
4 = Creatinine ≥ 5.0 mg/dL, or urine output < 200 mL/d, or dialysis requirement 
Source:  Pandharipande et al 2009, Vincent et al 1996, Vincent et al 1998.