Clinical trial NCT04362137
Conditions: Cytokine Storm (Covid-19)
Keywords: COVID-19 pneumonia cytokine release syndrome SARS-COV-2 ruxolitinib
Sponsor: Novartis Pharmaceuticals
Start date: 2020-05-02; Completion date: 2020-10-17
Enrollment: 432 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, double-blind, placebo-controlled, 29-day, multicenter study to assess the efficacy and safety of ruxolitinib + standard-of-care (SoC) therapy, compared with placebo + SoC therapy, in patients aged ≥12 years with COVID-19 disease.

Detailed description:
This was a Phase III, multicenter, double-blind, randomized, placebo-controlled study to assess the efficacy and safety of ruxolitinib in patients aged ≥12 years with COVID-19 disease. The study enrolled patients to ruxolitinib or placebo, in addition to standard of care (SoC) per local practice. Patients who meet the inclusion/exclusion criteria were randomized in a 2:1 ratio to either oral ruxolitinib 5 mg twice daily + SoC or oral matching-image placebo + SoC for a total of 14 days. An additional 14 days of study drug could be given if in the opinion of the investigator the patient's clinical signs and symptoms did not improve, or worsen, and the potential benefit outweighed the potential risk.

The study included:

* Screening period of 0-2 days.
* Study period of 29 days (treatment of 14 days with possible extension of treatment to 28 days).

The primary objective was to evaluate the efficacy (as measured by a composite endpoint of proportion of patients who die, develop respiratory failure \[require mechanical ventilation\], or require intensive care unit care) of ruxolitinib + standard-of-care (SoC) therapy compared with placebo + SoC therapy, for the treatment of COVID-19 by Day 29.

Arms: arm 1: Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days arm 2: Matching-image placebo for 14 days with possible extension of treatment to 28 days
Interventions: intervention 1: Ruxolitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Ruxolitinib 5 mg tablets intervention 2: Matching-image placebo

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
INC424 
CINC424J12301 (INCB 18424-368) / NCT04362137
Phase 3 randomized, double-blind, placebo-controlled, 
multi-center study to assess the efficacy and safety of 
ruxolitinib in patients with COVID-19 associated cytokine 
storm (RUXCOVID) 
Document Type 
Amended Protocol Version 
EUDRACT number: 
2020-001662-11 
Version number: 
01 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
20-May-2020
Property of Novartis / Incyte 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
 12 
Protocol summary .............................................................................................................. 15 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.1.1 
Ruxolitinib............................................................................................. 19 
1.1.2 
Additional evidence for CRS and JAK/STAT activation in severe 
respiratory disease ................................................................................. 19 
1.1.3 
Background summary ........................................................................... 20 
1.2 
Purpose .................................................................................................................. 21 
2 
Objectives and endpoints ................................................................................................... 21 
2.1 
Primary estimands ................................................................................................. 23 
3 
Study design ...................................................................................................................... 23 
4 
Rationale ............................................................................................................................ 25 
4.1 
Rationale for study design ..................................................................................... 25 
4.2 
Rationale for choice of background therapy .......................................................... 25 
4.3 
Rationale for dose/regimen and duration of treatment .......................................... 25 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 26 
4.5 
Purpose and timing of interim analyses/design adaptations .................................. 26 
4.6 
Risks and benefits .................................................................................................. 26 
5 
Study Population ............................................................................................................... 27 
5.1 
Inclusion criteria .................................................................................................... 27 
5.2 
Exclusion criteria ................................................................................................... 28 
6 
Treatment ........................................................................................................................... 29 
6.1 
Study treatment ...................................................................................................... 29 
6.1.1 
Investigational and control drugs .......................................................... 29 
6.1.2 
Supply of study treatment ..................................................................... 30 
6.1.3 
Treatment arms/group ........................................................................... 30 
6.1.4 
Treatment duration ................................................................................ 30 
6.2 
Other treatments ..................................................................................................... 30 
6.2.1 
Concomitant therapy ............................................................................. 30 


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6.2.2 
Prohibited medication ........................................................................... 31 
6.3 
Participant numbering, treatment assignment, randomization .............................. 31 
6.3.1 
Participant numbering ........................................................................... 31 
6.3.2 
Treatment assignment, randomization .................................................. 32 
6.4 
Treatment blinding ................................................................................................. 32 
6.5 
Dose escalation and dose modification .................................................................. 32 
6.5.1 
Dose modifications ................................................................................ 32 
6.6 
Additional treatment guidance ............................................................................... 33 
6.6.1 
Treatment compliance ........................................................................... 33 
6.6.2 
Recommended treatment of adverse events .......................................... 33 
6.6.3 
Emergency breaking of assigned treatment code .................................. 34 
6.7 
Preparation and dispensation ................................................................................. 35 
6.7.1 
Handling of study treatment and additional treatment .......................... 35 
7 
Informed consent procedures ............................................................................................ 35 
8 
Visit schedule and assessments ......................................................................................... 36 
8.1 
Screening ............................................................................................................... 42 
8.1.1 
Information to be collected on screening failures ................................. 42 
8.2 
Participant demographics/other baseline characteristics ....................................... 42 
8.3 
Efficacy .................................................................................................................. 42 
8.3.1 
Clinical status (9-point ordinal scale) ................................................... 42 
8.3.2 
Vital signs and oxygen saturation ......................................................... 43 
8.3.3 
National Early Warning Score 2 (NEWS2) .......................................... 43 
8.3.4 
In-hospital outcomes ............................................................................. 43 
8.3.5 
Ventilatory status .................................................................................. 44 
8.3.6 
Appropriateness of efficacy assessments .............................................. 44 
8.4 
Safety ..................................................................................................................... 44 
8.4.1 
Laboratory evaluations .......................................................................... 44 
8.4.2 
Physical Exam ....................................................................................... 45 
8.4.3 
Height, weight, BMI ............................................................................. 45 
8.4.4 
Electrocardiogram (ECG) ..................................................................... 45 
8.4.5 
Pregnancy and assessments of fertility ................................................. 45 
8.4.6 
Appropriateness of safety measurements .............................................. 46 
 
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9 
Study discontinuation and treatment ................................................................................. 47 


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9.1 
Discontinuation and completion ............................................................................ 47 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 47 
9.1.2 
Replacement policy ............................................................................... 48 
9.1.3 
Withdrawal of informed consent ........................................................... 48 
9.1.4 
Lost to follow-up ................................................................................... 48 
9.1.5 
Early study termination by the sponsor ................................................. 48 
9.2 
Study completion ................................................................................................... 49 
10 Safety monitoring and reporting ........................................................................................ 49 
10.1 
Definition of adverse events and reporting requirements ...................................... 49 
10.1.1 
Adverse events ...................................................................................... 49 
10.1.2 
Serious adverse events .......................................................................... 51 
10.1.3 
SAE reporting........................................................................................ 52 
10.1.4 
Pregnancy reporting .............................................................................. 52 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 52 
10.2 
Additional Safety Monitoring ................................................................................ 53 
10.2.1 
Liver safety monitoring ......................................................................... 53 
10.2.2 
Data Monitoring Committee ................................................................. 54 
11 Data Collection and Database management ...................................................................... 54 
11.1 
Data collection ....................................................................................................... 54 
11.2 
Database management and quality control ............................................................ 55 
11.3 
Site monitoring ...................................................................................................... 55 
12 Data analysis and statistical methods ................................................................................ 56 
12.1 
Analysis sets .......................................................................................................... 56 
12.2 
Participant demographics and other baseline characteristics ................................. 56 
12.3 
Treatments ............................................................................................................. 57 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 57 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 57 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 57 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 58 
12.4.4 
Handling of missing values not related to intercurrent event ............... 58 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 58 
12.4.6 
Supplementary analysis ......................................................................... 58 
12.4.7 
Supportive analyses ............................................................................... 58 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 58 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 58 
12.5.2 
Safety endpoints .................................................................................... 60 


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12.7 
Interim analyses ..................................................................................................... 61 
12.8 
Sample size calculation .......................................................................................... 61 
12.8.1 
Primary endpoint(s) ............................................................................... 61 
13 Ethical considerations and administrative procedures ...................................................... 62 
13.1 
Regulatory and ethical compliance ........................................................................ 62 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 62 
13.3 
Publication of study protocol and results............................................................... 62 
13.4 
Quality Control and Quality Assurance ................................................................. 63 
14 Protocol adherence ............................................................................................................ 63 
14.1 
Protocol amendments ............................................................................................. 63 
15 References ......................................................................................................................... 64 
16 Appendices ........................................................................................................................ 67 
16.1 
Appendix 1: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 67 
16.2 
Appendix 2: Clinical status 9-point scale .............................................................. 70 
16.3 
Appendix 3: National Early Warning Score 2 (NEWS2) ...................................... 71 
16.4 
Appendix 4: List of CYP3A4 inhibitors and inducers........................................... 73 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 21 
Table 6-1 
Investigational and control drug ............................................................ 30 
Table 8-1 
Assessment Schedule ............................................................................ 38 
Table 8-2 
Clinical status 9-category ordinal scale ................................................. 42 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 53 
Table 12-1 
Sensitivity of sample size assumptions to different failure rates for 
level of significance alpha = 0.05 ......................................................... 61 
Table 16-1 
Liver event and laboratory trigger definitions ...................................... 67 
Table 16-2 
Follow up requirements for liver laboratory triggers with liver 
symptoms .............................................................................................. 68 
Table 16-3 
Follow up requirements for liver laboratory triggers ............................ 69 
Table 16-4 
CYP3A4 inhibitors and inducers .......................................................... 73 
 


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List of figures 
Figure 3-1 
Study design .......................................................................................... 24 
 


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List of abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate Aminotransferase 
b.i.d. 
bis in die/twice a day 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CART 
Chimeric antigen receptor T cells 
CK 
Creatine Kinase 
CMO&PS 
Chief Medical Office and Patient Safety 
CoV 
Corona virus 
COVID-19 
Coronavirus disease 2019 
CPAP 
Continuous Positive Airway Pressure 
CrCl 
Creatinine clearance 
 
 
CRS 
Cytokine Release Syndrome 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXRAY 
Chest X-Ray 
CYP3A4 
cytochrome P450 3A4 
dL 
deciliter 
DMC 
Data Monitoring Committee 
 
 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
eSource 
Electronic Source 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
GvHD 
Graft versus host disease 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human Chorionic Gonadotrophin 
HECTD2 
HECT Domain E3 Ubiquitin Protein Ligase 2 
HHS 
Health and Human Services 


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HLH 
haemophagocytic lymphohistiocytosis 
HU 
hydroxyurea 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
Intensive Care Unit 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
JAK 
Janus kinase 
LPS 
Lipopolysaccharides 
MedDRA 
Medical dictionary for regulatory activities  
MF 
Myelofibrosis 
mg 
milligram(s) 
mL 
milliliter(s) 
MOF 
Multi organ failure 
NEWS2 
National Early Warning Score 2 
PaO2 
Partial pressure of arterial oxygen 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PET-MF 
post-essential thrombocythemia myelofibrosis 
PIAS 
Protein Inhibitor of Activated STAT 
PK 
Pharmacokinetic(s) 
PMF 
Primary myelofibrosis 
PML 
Progressive multifocal leuko-encephalopathy 
POM 
Proportional odds model 
PPV-MF 
post-polycythemia vera myelofibrosis 
PREP Act 
Public Readiness and Emergency Preparedness Act 
PT 
prothrombin time 
QMS 
Quality Management System 
RBC 
red blood cell(s) 
RDO 
Retrieved Drop Out 
RNA 
Ribonucleic acid 
RRT 
Renal Replacement Therapy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV 
severe acute respiratory syndrome-corona virus 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 


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SoC 
Standard-of-Care 
STAT 
signal transducers and activators of transcription 
TD 
Study Treatment Discontinuation 
ULN 
upper limit of normal 
WBC 
white blood cell(s) 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant  
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at 
the same time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol 
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained 
Estimand 
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable. 
Intensive care unit 
(ICU) 
An Intensive Care Unit is defined as any setting in which patients are receiving 
therapy typically associated with critical illness (e.g., vasopressors, 
mechanical ventilation, etc.) or monitoring that is typically associated with 
such care (e.g.,invasive arterial or central venous monitoring). 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Medication 
number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient) 


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Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) are 
described in the Protocol. Periods define the study phases and will be used in 
clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 


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Protocol summary 
Protocol number 
CINC424J12301 
Full Title 
Phase 3 randomized, double-blind, placebo-controlled, multi-
center study to assess the efficacy and safety of ruxolitinib in 
patients with COVID-19 associated cytokine storm 
Brief title 
RUXCOVID 
Sponsor and 
Clinical Phase 
Novartis 
III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
There are no approved treatments for COVID-19 pneumonia. 
The purpose of this study is to evaluate the efficacy and safety 
of ruxolitinib in the treatment of patients with COVID-19 
pneumonia. 
Primary Objective(s)  
To evaluate the efficacy (as measured by a composite endpoint 
of proportion of patients who die, develop respiratory failure 
[require mechanical ventilation], or require intensive care unit 
[ICU] care) of ruxolitinib + standard-of-care (SoC) therapy 
compared with placebo + SoC therapy, for the treatment of 
COVID-19 by Day 29. 
Secondary Objectives 
To evaluate the efficacy (as measured by clinical status using a 
9-point ordinal scale) of ruxolitinib + SoC therapy compared with 
placebo + SoC therapy, for the treatment of COVID-19. 
To evaluate the efficacy of ruxolitinib + standard-of-care (SoC) 
therapy compared with placebo + SoC therapy, on in-hospital 
outcomes in patients with COVID-19. 
To evaluate the efficacy of ruxolitinib + SoC therapy, compared 
with placebo + SoC therapy, in change in the National Early 
Warning Score (NEWS2) score in patients with COVID-19. 
To evaluate the efficacy of ruxolitinib + SoC therapy, compared 
with placebo + SoC therapy, in change in SpO2/FiO2 ratio in 
patients with COVID-19. 
To evaluate the efficacy of ruxolitinib + SoC therapy, compared 
with placebo + SoC therapy, in proportion of patients with no 
oxygen therapy (defined as oxygen saturation ≥ 94% on room 
air) in patients with COVID-19. 
To evaluate the safety of ruxolitinib + standard-of-care (SoC) 
therapy compared with placebo + SoC therapy, in the treatment 
of patients with COVID-19. 
Study design 
This is a randomized, double-blind, placebo-controlled, 29-day, 
multi-center study to assess the efficacy and safety of ruxolitinib 
+ SoC therapy, compared with placebo + SoC therapy, in 
patients aged ≥12 years with COVID-19 pneumonia. 
Study population 
Approximately 402 males and females ages 12 and older with 
COVID-19 pneumonia. 


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Key Inclusion criteria 
• Patient or guardian/health proxy must provide informed 
consent (and assent if applicable) before any study assessment 
is performed. 
• Male and female patients aged ≥ 12 years (or ≥ the lower 
age limit allowed by Health Authority and/or Ethics 
Committee/Institutional Review Board approvals). 
• Patients with coronavirus (SARS-CoV-2) infection confirmed 
by polymerase chain reaction (PCR) test or another rapid test 
from the respiratory tract prior to randomization. 
• Patients currently hospitalized or will be hospitalized prior to 
randomization. 
• Patients, who meet at least one of the below criteria: 
• 
Pulmonary infiltrates (chest X ray or chest CT scan); 
• 
Respiratory frequency ≥ 30/min; 
• 
Requiring supplemental oxygen; 
• 
Oxygen saturation ≤ 94% on room air; 
• 
Arterial oxygen partial pressure (PaO2)/ fraction of 
inspired oxygen (FiO2) < 300mmHg (1mmHg=0.133kPa) 
(corrective formulation should be used for higher altitude 
regions (over 1000m). 
Key Exclusion criteria 
• History of hypersensitivity to any drugs or metabolites of 
similar chemical classes as ruxolitinib. 
• Presence of severely impaired renal function defined by 
serum creatinine > 2 mg/dL (>176.8 μmol/L), or have estimated 
creatinine clearance < 30 ml/min measured or calculated by 
Cockroft Gault equation or calculated by the updated bedside 
Schwartz equation. 
• Suspected uncontrolled bacterial, fungal, viral, or other 
infection (besides COVID-19). 
• Currently intubated or intubated between screening and 
randomization. 
• In intensive care unit (ICU) at time of randomization. 
• Intubated or in ICU for COVID-19 disease prior to screening. 
• Patients who are on anti-rejection, immunosuppressant or 
immunomodulatory drugs (i.e. tocilizumab, ruxolitinib, 
canakinumab, sarilumab, anakinra). 
• Unable to ingest tablets at randomization. 
• Pregnant or nursing (lactating) women. 
Study treatment 
Ruxolitinib 5 mg tablets b.i.d. or matching-image placebo for 14 
days with possible extension of treatment to 28 days 
Treatment of interest 
 
Ruxolitinib 5 mg tablets 


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Efficacy assessments 
Clinical status using a 9-category ordinal scale 
Vital signs and oxygen saturation 
National Early Warning Score (NEWS2) 
In-hospital outcomes 
Ventilatory status 
Key safety assessments 
Adverse event monitoring, physical examinations, monitoring of 
laboratory markers in blood, ECGs. 
  
 
 
Data analysis 
The primary endpoint will be analyzed using the randomized set. 
The odds of clinical failure will be analyzed by a logistic 
regression model with treatment group, country, age, and 
gender as covariates. The estimated odds ratio, p-values, and 
95% confidence intervals will be presented. 
Key words 
 
COVID-19 pneumonia, SARS-COV-2, ruxolitinib 


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1 
Introduction 
1.1 
Background 
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral 
pneumonia cases of unknown cause. This outbreak of viral pneumonia was reported to the 
World Health Organization (WHO) Country Office in China on December 31, 2019. 
Subsequently, Coronavirus (CoV) RNA was identified in some of 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 (MERS-CoV) and severe acute respiratory syndrome 
(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, an acronym for "coronavirus disease 
2019". This new coronavirus strain was not previously identified in humans and was newly 
named on 11 February 2020 by the WHO. Genetic sequencing of the virus suggests that SARS-
CoV-2 is a beta-coronavirus closely linked to the SARS virus. 
On 11 March 2020, the WHO declared a pandemic for COVID-19. According to the WHO, as 
of 24 March 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 intensive care unit (China CDC Weekly 2020). In severe cases, COVID-19 can be 
complicated by acute respiratory distress syndrome (ARDS), sepsis and septic shock, and/or 
multiorgan failure (MOF), including acute kidney injury and cardiac injury (Yang et al 2020). 
Of note, many patients with severe respiratory disease due to COVID-19 have features 
consistent with the cytokine release syndrome (CRS), also referred to as cytokine storm, and 
increased activation of the JAK/STAT pathway (Wang et al 2020; Hermans et al 2020). 
According to the WHO interim guidance of 13-Mar-2020 on the clinical management of severe 
acute respiratory infection (SARI) when COVID-19 disease is suspected, “older age and co-
morbid disease have been reported as risk factors for death, and recent multivariable analysis 
confirmed older age, higher Sequential Organ Failure Assessment (SOFA) score and d-dimer > 
1 µg/L on admission were associated with higher mortality.” The same study quoted by the 
WHO also noted that the median duration of viral RNA detection was 20.0 days (IQR 17.0–
24.0) in survivors, but SARS-CoV-2 virus was detectable until death in non-survivors. The 
longest observed duration of viral shedding in survivors was 37 days (Huang et al 2020; Zhou 
et al 2020). 
There is sparse data on 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 co-infection has been 


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observed (Cai et al 2020; Xia et al 2020). Relatively few cases have been reported of infants 
confirmed with COVID-19 and they experienced mild illness (Wei et al 2020). 
1.1.1 
Ruxolitinib 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) is a well-established, 
potent and selective inhibitor of Janus kinase (JAK)1 and JAK2, with modest to marked 
selectivity against tyrosine kinase (TYK)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 Investigator Brochure. 
JAK signaling involves recruitment of signal transducers and activators of transcription (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 majority of patients with 
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including 
myelofibrosis (MF) and polycythemia vera (PV), demonstrating that JAK inhibition is 
efficacious in these diseases. 
Ruxolitinib (JAKAVI®) is currently approved in the European Union (EU) for the treatment of 
disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (PMF) 
(also known as chronic idiopathic MF), post-polycythemia vera myelofibrosis (PPV-MF) or 
post-essential thrombocythemia myelofibrosis (PET-MF) and for the treatment of adult patients 
with PV who are resistant to or intolerant of hydroxyurea (HU). 
In the United States (US), ruxolitinib (JAKAFI®) is approved for the treatment of intermediate 
or high-risk MF, including PMF, PPV-MF and PET-MF in adults and for 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 acute graft versus host disease (GvHD). 
Ruxolitinib is currently under further development for the treatment of MF, PV, essential 
thrombocytopenia (ET), and other hematologic malignancies. 
1.1.2 
Additional evidence for CRS and JAK/STAT activation in severe 
respiratory disease 
There is preclinical evidence from both laboratory and animal models that blockade/inhibition 
of the JAK/STAT pathway could have a beneficial effect on the CRS and the course of severe 
respiratory disease/ARDS in patients with COVID-19. 
1.1.2.1 
Laboratory evidence 
Hermans et al (2020) 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 an interesting target for therapy to release symptom burden in 
mastocytosis and many other mast cell mediator related diseases such as the CRS. 
Hoffman et al (2016) demonstrated that viral and bacterial co-infection in a macrophage model 
modulates the JAK-STAT signaling pathway and leads to exacerbated IP-10 expression, which 


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could play a major role in the pathogenesis of pneumonia, suggesting that targeting this pathway 
could have a beneficial effect. 
1.1.2.2 
Animal models 
Zhao et al (2016) looked at LPS-induced lung injury in mice, which models some of the ARDS 
(e.g. cytokine increases and cell influx) manifestations, 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 (e.g. dexamethasone) is absent from the in vivo studies. Using conditional 
knockouts of SOCS3 (an antinflammatory protein which negatively regulates JAK activity) 
they provide further evidence that the effects are STAT3 pathway dependent. They also show 
increased STAT3 expression in PBMC 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 which 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. HECTD2 inhibitor reduces lung inflammation 
in the same model (no positive control). They also identify a polymorphism (loss of function) 
in the HECTD2 gene which 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 CART 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 CART 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. 
Maschalidi et al (2016) described in a mouse model of haemophagocytic lymphohistiocytosis 
(HLH) (model of CRS), administration of ruxolitinib suppressed the harmful consequences of 
macrophage activation with improvement in vital signs and hematologic parameters. 
1.1.2.3 
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 need for more toxic therapies. 
(Ahmed 2019; Goldsmith 2019). 
1.1.3 
Background summary 
It is reasonable to consider the use of ruxolitinib in the treatment of COVID-19 patients with 
severe respiratory disease because these patients have clinical features consistent with CRS and 
increased activation of the JAK/STAT pathway (Wang et al 2020; Hermans et al 2020). 
Moreover, recent literature specifically suggests consideration of molecules for treatment of 


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COVID-19 that block inflammatory pathways, including inhibition of the JAK/STAT pathway 
where a number of cytokines converge (Zumla et al 2020, Mehta et al 2020). 
In summary, the above-mentioned data provide scientific justification for the study of a 
JAK/STAT inhibitor, such as ruxolitinib, in a controlled clinical trial setting. 
1.2 
Purpose 
There are no approved treatments for COVID-19 pneumonia. The purpose of this study is to 
evaluate the efficacy and safety of ruxolitinib in the treatment of patients with COVID-19 
pneumonia. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
 
Objectives 
Endpoints 
Primary 
Objective 
To evaluate the efficacy (as 
measured by a composite endpoint 
of proportion of patients who die, 
develop respiratory failure [require 
mechanical ventilation], or require 
intensive care unit [ICU] care) of 
ruxolitinib + standard-of-care (SoC) 
therapy compared with placebo + 
SoC therapy, for the treatment of 
COVID-19 by Day 29. 
Composite endpoint defined as: 
• 
Death OR 
• 
Respiratory failure (require 
mechanical ventilation) OR 
• 
Intensive care unit (ICU) care by 
Day 29. 
Secondary 
Objectives 
To evaluate the efficacy (as 
measured by clinical status using a 
9-point ordinal scale) of ruxolitinib + 
SoC therapy compared with placebo 
+ SoC therapy, for the treatment of 
COVID-19 (WHO 18-Feb-2020). 
Clinical status assessed using a 9-point 
ordinal scale (Appendix 2) at Day 15 and 
Day 29. 
• Percentage of patients with a better 
category (lower number) in clinical status 
at Day 15 and at Day 29. 
• Percentage of patients with at least 
two-point improvement in clinical status 
at Day 15 and at Day 29. 
• Percentage of patients with at least 
one-point improvement in clinical status 
at Day 15 and at Day 29. 
• Percentage of patients with at least 
one-point deterioration in clinical status 
at Day 15 and at Day 29. 
• Time to improvement from baseline 
category to one less severe category of 
the ordinal scale. 
• Mean change in the 9-point ordinal 
scale from baseline to Days 15 and 29. 






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The study will include: 
• Screening period of 0-2 days 
• Study period of 29 days (treatment of 14 days; an additional 14 days of study drug may 
be given, if in the opinion of the investigator, the patient’s clinical signs and symptoms are 
not improved or worsen and the potential benefit outweighs the potential risk) – see 
below. 
Figure 3-1 
Study design 
 
Note: Should a patient become intubated during the Study Period, study medication may be given via 
a nasogastric tube (see Section 6.1.1 for directions). 
Eligible patients will be randomized on the same day as screening or up to two days after 
completing the screening procedures. At Day 1 (randomization visit), patients will be assigned 
in a 2:1 ratio to receive oral ruxolitinib 5 mg twice daily or oral matching-image placebo for a 
total of 14 days (Section 6.1). An additional 14 days of study drug may be given, if in the 
opinion of the investigator, the patient’s clinical signs and symptoms are not improved or 
worsen and the potential benefit outweighs the potential risk. 
Study treatment will be given in combination with SoC therapy according to the investigator’s 
clinical judgement. Should a patient become intubated during the Study Period, study 
medication may be given via a nasogastric tube (see Section 6.1.1 for directions). 
Randomization will be stratified by region (North America, Europe). 
Patients who do not meet the criteria for participation in this study (screen failures) may not be 
re-screened. 
Assessments during the Study Period will occur per the schedule of study assessments (See 
Section 8) for specific assessments and timing for these assessments). The primary endpoint for 
the study will be the proportion of patients who die, develop respiratory failure (require 
mechanical ventilation), or require ICU care by Day 29. Should a patient be discharged from 
the hospital during the 29-day study period, daily assessment of clinical status will be made via 
a telephone call to the patient each day (between 7 AM and 12 PM), with the exception of Day 
15 and Day 29, during which discharged patients will return for an in-clinic visit. For Day 15 
and Day 29, if an in-clinic visit is not possible, the visit may be performed in an appropriate 
setting, including at home, with appropriate study personnel. 


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This study will include an internal data monitoring committee (DMC) which will function 
independently of all other individuals associated with the conduct of this clinical trial, including 
the site investigators participating in the study. 
4 
Rationale 
4.1 
Rationale for study design 
This randomized, double-blind, parallel-group, placebo-controlled, design supports the rigorous 
assessment of efficacy as well as safety of ruxolitinib as add-on to SoC therapy for patients with 
COVID-19 pneumonia. 
Screening Period 
The screening period allows for assessment of patient entry criteria to ensure suitable patients 
are entered into the study. Screening and randomization may occur on the same day. 
Study Period 
During this period, oral ruxolitinib 5 mg twice daily or oral matching-image placebo twice daily 
(randomized 2:1) will be administered 14 days. An additional 14 days of study drug may be 
given, if in the opinion of the investigator, the patient’s clinical signs and symptoms are not 
improved or worsen and the potential benefit outweighs the potential risk. The endpoints 
included in this study measure clinical status, clinical and in-hospital outcomes, and laboratory 
values during the 29-day Study Period. These measurements are consistent with endpoints and 
measurement times for other studies of therapies in the treatment of COVID-19 (WHO 18-Feb-
2020; Cao et al 2020). 
4.2 
Rationale for choice of background therapy 
Although there are no approved treatments for COVID-19, SoC therapy for patients with 
COVID-19 pneumonia generally includes supportive care and anti-viral treatments. Thus, 
placebo + SoC therapy is appropriate as a control in this study. 
4.3 
Rationale for dose/regimen and duration of treatment 
The ruxolitinib dose regimen chosen in this study is the lowest efficacious dose based on 
pharmacokinetic data. Ruxolitinib 5 mg twice daily is the approved starting dose for treatment 
of steroid-refractory acute graft versus host disease in the US with demonstrated anti-
inflammatory effect (Jagasia et al 2020). Ruxolitinib 5 mg twice daily is also the starting dose 
recommended for patients with myleofibrosis when platelets are 50 x 109/ L – <100 x 109/L. 
Cao et al (2020) reported the median hospital stay for COVID-19 was 12 days with an 
interquartile range of 1 to 14 days. Therefore, a duration of treatment for 14 days seems 
reasonable and has been selected for this study. An additional 14 days of study drug may be 
given, if in the opinion of the investigator, the patient’s clinical signs and symptoms are not 
improved or worsen and the potential benefit outweighs the potential risk. 


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4.4 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
The study will evaluate the efficacy and safety of oral ruxolitinib + SoC therapy, compared with 
matching-image placebo + SoC therapy. Despite the lack of targeted treatments for COVID-19, 
SoC for patients with severe COVID-19 respiratory disease generally includes supportive care 
and may include available anti-viral agents. Therefore, SoC + placebo treatment is appropriate 
as a control in this study. 
4.5 
Purpose and timing of interim analyses/design adaptations 
No interim analysis is planned. An internal Data Monitoring Committee at Novartis will be 
established to conduct periodic unblinded safety reviews. 
4.6 
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 the CRS and the course of severe 
respiratory disease/ARDS in patients with COVID-19. Additionally, there is some clinical 
evidence of efficacy with ruxolitinib in pilot studies in another recognized disease with CRS: 
secondary HLH (See Section 1.1.1). However, ruxolitinib has not previously been studied in 
patients with COVID-19 pneumonia. 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 patients with myelofibrosis, 
which involved longer-term dosing and, in general, higher doses than that proposed in this 
protocol, the most frequent treatment-emergent adverse events (AEs) were dose-dependent, 
reversible thrombocytopenia, anemia, and neutropenia. The above events could increase the 
risk of infection, including pneumonia and bronchitis, 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 non-hematologic AEs were mild, reversible increases in alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST); bruising; hypercholesterolemia; 
dizziness; headache; and urinary tract infections. Tuberculosis has been infrequently reported 
in patients receiving ruxolitinib to treat myelofibrosis (<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 myelofibrosis, particularly those who have stopped taking ruxolitinib suddenly, 
have reported return of MF symptoms such as fatigue, bone pain, fever, pruritus, night sweats, 
symptomatic splenomegaly and weight loss. In very few patients, respiratory distress, 
disseminated intravascular coagulation (DIC), 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 


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disease called progressive multifocal leuko-encephalopathy (PML), has been reported with 
ruxolitinib. It is important to note that PML and infections are complications associated with 
MF that has been previously described in the absence of ruxolitinib. Additionally, non-
melanoma skin cancers (NMSCs), including basal cell, squamous cell, and a rare and aggressive 
type of skin cancer called merkel cell carcinoma has been reported in patients who took 
ruxolitinib, it is unknown whether this was due to ruxolitinib treatment. 
In the presence of potent CYP3A4 inhibitors, there is the possibility of increased exposure to 
ruxolitinib and more frequent monitoring of hematology parameters is recommended, although 
no automatic dose adjustment of ruxolitinib is required. See Appendix 4 for a list of cytochrome 
P450 3A4 (CYP3A4) inhibitors and inducers. 
For a comprehensive assessment of the risks of ruxolitinib, refer to the Investigator Brochure. 
5 
Study Population 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Patient or guardian/health proxy must provide informed consent (and assent if applicable) 
before any study assessment is performed. 
2. Male and female patients aged ≥ 12 years (or ≥ the lower age limit allowed by Health 
Authority and/or Ethics Committee/Institutional Review Board approvals). 
3. Patients with coronavirus (SARS-CoV-2) infection confirmed by polymerase chain 
reaction (PCR) test or another rapid test from the respiratory tract prior to randomization. 
4. Patient is currently hospitalized or will be hospitalized prior to randomization. 
5. Patients, who meet at least one of the below criteria: 
• Pulmonary infiltrates (chest X ray or chest CT scan); 
• Respiratory frequency ≥ 30/min; 
• Requiring supplemental oxygen; 
• Oxygen saturation ≤ 94% on room air; 
• Arterial oxygen partial pressure (PaO2)/ fraction of inspired oxygen (FiO2)  
< 300mmHg (1mmHg=0.133kPa) (corrective formulation should be used for higher 
altitude regions (over 1000m). 


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5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. History of hypersensitivity to any drugs or metabolites of similar chemical classes as 
ruxolitinib. 
2. Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL 
(>176.8 μmol/L), or have estimated creatinine clearance < 30 ml/min measured or 
calculated by Cockroft Gault equation or calculated by the updated bedside Schwartz 
equation. 
3. Suspected uncontrolled, active bacterial, fungal, viral, or other infection (besides COVID-
19). 
4. Current or history of active TB infection. 
5. History of progressive multifocal leukoencephalopathy (PML). 
6. Currently intubated or intubated between screening and randomization. 
7. In intensive care unit (ICU) at time of randomization. 
8. Patients who are on anti-rejection, immunosuppressant or immunomodulatory drugs (i.e. 
tocilizumab, ruxolitinib, canakinumab, sarilumab, anakinra). 
9. Intubated or in ICU for COVID-19 disease prior to screening. 
10. Participating in any other investigational or interventional trials. 
11. Unable to ingest tablets at randomization. 
12. ALT ≥ 5 x ULN detected at screening (according to local laboratory reference ranges). 
13. Patients who have evidence of liver cirrhosis (Child A to C). 
14. ANC < 1000/µL at screening. 
15. Platelet count < 50,000/µL at screening. 
16. Pregnant or nursing (lactating) women. 
17. Females ≥ 12 and < 18 years of age and of childbearing potential (e.g. are menstruating) 
who do not agree to abstinence or, if sexually active, do not agree to the use of highly 
effective contraception as defined below, throughout the study and for up to 30 days after 
stopping treatment, 
OR 
Females ≥ 18 years of age and of child-bearing 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 include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six 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. 


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• Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that patient. 
• Use of oral, injected or implanted hormonal methods of contraception. Placement of 
an intrauterine device (IUD) or intrauterine system (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, 
patients should have been using the same pill on a stable dose for a minimum of 3 
months before Screening). 
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. 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 child bearing potential. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Ruxolitinib 5 mg tablets or matching placebo will be administered orally twice per day 
approximately 12 hours apart (morning and night) without regards to food. 
Dose reductions or interruptions for any toxicity attributed to study drug are permitted in order 
to allow the patient to continue on the study treatment. See Section 6.6.2. 
If a patient becomes intubated during the course of the study, study drug can be administered 
as follows (Jakafi 2011): 
• For patients unable to ingest tablets, study drug can be administered through a nasogastric 
tube (8 French or greater) as follows: 
• Suspend one tablet in approximately 40 mL of water with stirring for approximately 
10 minutes. 
• Within 6 hours after the tablet has dispersed, the suspension can be administered 
through a nasogastric tube using an appropriate syringe. 
• The tube should be rinsed with approximately 75 mL of water 


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Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
INC424 5mg 
Tablet 
Oral use 
Double-blind supply; 
bottles 
INC424 Placebo to 
5mg  
Tablet 
Oral use 
Double-blind supply; 
bottles 
6.1.2 
Supply of study treatment 
No additional treatment beyond ruxolitinib 5 mg or matching image placebo will be provided. 
6.1.3 
Treatment arms/group 
Participants will be assigned at randomization to one of the following treatment arms/groups in 
a ratio of 2:1: 
• ruxolitinib 5 mg tablets twice daily; or 
• matching image placebo tablets twice daily. 
6.1.4 
Treatment duration 
The planned duration of treatment is 14 days. An additional 14 days of study drug may be given, 
if in the opinion of the investigator, the patient’s clinical signs and symptoms are not improved 
or worsen and the potential benefit outweighs the potential risk. Participants may be 
discontinued from treatment earlier due to unacceptable toxicity, disease progression and/or 
treatment is discontinued at the discretion of the investigator or the participant. Treatment will 
not be provided upon completion of the study. 
6.2 
Other treatments 
6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate electronic Case Report Forms (eCRFs). 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. 
The patient must be told to notify the Treating Physician about any new medications he/she 
takes after the start of study drug. 


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6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Patients may receive: anti-virals, inhaled or systemic corticosteroids, heparin, low molecular 
weight heparin (LMWH), direct oral anticoagulants, anti-emetics, calcineurin inhibitors, azole 
fungal prophylaxis, broad spectrum antibiotics (either semi-synthetic penicillin or third 
generation cephalosporin with vancomycin, gentamycin or equivalent), acyclovir prophylaxis, 
G-CSF, steroid pre-meds prior to RBC/platelet transfusions, narcotics, and sedatives warrant 
close monitoring of potential drug-drug interaction effects of these concurrent drugs. 
Use of oral, injected or implanted hormonal methods of contraception are allowed while on 
study drug. 
In patients taking warfarin, heparin, LMWH, or direct oral anticoagulants, the degree of 
thrombocytopenia should be considered, platelet counts and coagulation parameters monitored, 
and the dose of anti-coagulant or non-steroidal anti-inflammatory drug adjusted accordingly. 
In patients taking drugs that affect platelet function/count, the degree of thrombocytopenia 
should be considered, platelet counts and coagulation parameters monitored, and the dose of 
drug adjusted accordingly. 
In the presence of potent CYP3A4 inhibitors, there is the possibility of increased exposure to 
ruxolitinib and more frequent monitoring of hematology parameters is recommended, although 
no automatic dose adjustment is required. See Appendix 4 for a list of cytochrome P450 3A4 
(CYP3A4) inhibitors and inducers. 
The patient and the treating physician should be aware of potential signs of overdose of the 
concomitant medications and in the event of suspected study drug related toxicity; 
administration of study drug should be dose reduced or held according to the treating 
physician’s judgement. 
For additional information, please refer to the Investigator Brochure. 
6.2.2 
Prohibited medication 
The following medications are prohibited until treatment discontinuation: 
• Concomitant use of another JAK inhibitor 
• Aspirin in doses >150 mg/day 
• Fluconazole > 200 mg daily 
For additional information, please refer to the Investigator Brochure. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigative site) with a sequential participant 
number suffixed to it, so that each participant’s participation is numbered uniquely across the 


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entire database. Upon completion of informed consent, the participant is assigned to the next 
sequential Participant No. available. 
Screen failures cannot be rescreened. Screen failures should be called into IRT. 
6.3.2 
Treatment assignment, randomization 
At the randomization visit, all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the participant fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
Randomization will be stratified by regions. Stratification ensures a balanced allocation of 
subjects to treatment groups within the strata. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
Participants, investigator staff, persons performing the assessments, and CTT will remain blind 
to the identity of the treatment from the time of randomization until database lock, using the 
following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding and will not be accessible by anyone else involved in the study, (2) the identity of 
the treatments will be concealed by the use of study treatment 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. 
6.5 
Dose escalation and dose modification 
Study drug dose adjustments and/or interruptions are described in Section 6.6.2. 
6.5.1 
Dose modifications 
Dose reductions or interruptions for patients that do not tolerate the dosing schedule and are 
attributed to study drug are permitted in order to allow the patient to continue on the study 
treatment (see Section 6.6.2 for more guidance). 
Dose modifications must be reported in the appropriate eCRFs. 


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For subjects with moderate renal impairment (creatinine clearance (CrCl) 30–59 mL/min) or any 
level of hepatic impairment, i.e. Mild, Moderate, or Severe (Child-Pugh categories A, B, C), AND 
platelet counts between 50 – 100 X 109 /L, the dose should be reduced to one tablet per day. 
If renal/hepatic impairment AND platelet count improves > 100x 109/L, dosing may be resumed at 
one tablet twice per day. 
6.5.1.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe DILI, and should be considered as clinically important events 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT > 2 x baseline]OR [AST or ALT >300 U/L]whichever occurs first combined with 
[total bilirubin > 2 x baseline AND > 2.0 x ULN] 
As 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, 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, GGT, 
GLDH (if available at local laboratory), prothrombin time (PT)/INR, alkaline phosphatase, 
albumin, and creatine kinase. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Treatment will be recorded on the appropriate eCRF. 
6.6.2 
Recommended treatment of adverse events 
Dose reductions or interruptions for patients that do not tolerate the dosing schedule and are 
attributed to study drug are permitted in order to allow the patient to continue on the study 
treatment. Adverse events will be assessed and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0 as described in Section 10.1.1. 
Neutropenia (Growth factor supplementation and transfusion should be provided as clinically 
indicated.) 


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Grade 3 (ANC < 750 - 500/mm3): Reduce dose to one tablet per day, monitor ANC daily until 
resolved to ≤Grade 2, then resume initial dose level. 
Grade 4 (ANC < 500/mm3): Hold dose, monitor ANC daily until resolved to ≤ Grade 3, then 
resume with reduced dose of one tablet per day. If resolves to ≤ Grade 2, can resume initial 
dose level. 
Thrombocytopenia (transfusion support should be provided as clinically indicated) 
For platelet counts < 20,000/mm3: Hold dose until resolved to > 35,000/mm3, then resume at 
a reduced dose level of one tablet per day. If counts are stable, dose may be cautiously re-
escalated. 
Dose reductions or interruptions for non-hematologic toxicity are permitted in order to allow 
the patient to continue on the study treatment. Dose adjustments for different ranges of non-
hematologic toxicity are described below. The objective of the dose adjustment rules is to 
optimize treatment response for each individual patient while avoiding significant non-
hematologic toxicities. 
AST/ALT elevation 
See Appendix 1 for stopping or interrupting study drug for elevated ALT/AST. 
Other adverse events (non-hematological) attributed to study drug 
Recommendation for Grade 1 or 2: Maintain dose level. 
Grade 3: Hold dose until resolved to baseline or Grade 1. 
Grade 4: Discontinue from study treatment. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate eCRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Blinding codes may also be broken after a participant discontinues treatment 
due to disease progression if deemed essential to allow the investigator to select the participant’s 
next treatment regimen, and after discussion and agreement with the Novartis. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study participant who presents with an emergency condition. Emergency treatment 
code breaks are performed using the IRT. When the investigator contacts the system to break a 
treatment code for a participant, he/she must provide the requested participant identifying 
information and confirm the necessity to break the treatment code for the participant. The 
investigator will then receive details of the investigational drug treatment for the specified 
participant and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• participant number 


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In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
A unique medication number is printed on the study medication label. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
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 Investigator’s Brochure. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
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 site visits or remotely and at the completion of the trial. 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. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site or destroyed as per local regulation. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
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 informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 




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• Efficacy assessments: clinical status, clinical signs and symptoms, oxygen saturation, 
consciousness, ventilatory status; 
• Safety assessments: vital signs, review of adverse events, concomitant medications; 
Laboratory samples: on days indicated in schedule of assessments. 
Results from tests or examinations done as part of routine care prior to the screening visit may 
be used for the study as indicated in Table 8-1 (Assessment Schedule). However, the above-
mentioned efficacy assessments (clinical status, clinical signs and symptoms, oxygen 
saturation, consciousness, ventilatory status) must be done in the morning of 
randomization between 7 AM and 12 PM, prior to administering study drug. 
If a patient is discharged from the hospital during the study period, the Clinical Status 
Evaluation with 9-point ordinal scale will be performed via telephone call (between 7 AM and 
12 PM local time) daily except for Day 15 and Day 29 when it will be performed in clinic. For 
Day 15 and Day 29, if an in-clinic visit is not possible, the visit may be performed in an 
appropriate setting, including at home, with appropriate study personnel. 


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Table 8-1 
Assessment Schedule 
All assessments will be obtained while patient is in hospital. Once patient is discharged, assessments will be done via the telephone as indicated 
in the table below with the exception of Day 15 and Day 29 which require in-clinic assessments. For Day 15 and Day 29, if an in-clinic visit 
is not possible, the visit may be performed in an appropriate setting, including at home, with appropriate study personnel. 
 
 
Screening 
Study Period 
Study Day 
Screening 
Day 1 
(Randomization) 
Day 2-14 
(every day 
unless otherwise 
specified below) 
Day 15 
Day 16-28 
(every day 
unless 
otherwise 
specified below) 
Day 29 
(End of 
study) 
Informed consent (and assent if applicable)1 
x 
 
 
 
 
 
Inclusion / Exclusion criteria  
x 
x 
 
 
 
 
Demographics / medical history (including co-morbidities 
checklist) 
x 
 
 
 
 
 
SARS-CoV-2 virus confirmation2 
s 
 
 
 
 
 
Vital signs3 
(between 7 AM and 12 PM local time) 
x4 
x 
x 
(while in hospital) 
x 
x 
(while in hospital) 
x 
SpO2 assessment 
(between 7 AM and 12 PM local time – done at same 
time as vital signs) 
x4 
x 
x  
(while in hospital) 
x 
x 
(while in hospital) 
x 
SpO2 assessment on room air (for patients on oxygen by 
nasal cannula (≤ 2L/min) (based on investigator medical 
judgement) 
(between 7 AM and 12 PM local time – done at same 
time as vital signs) 
 
 
(only on day of 
discharge) 
x 
(only on day of 
discharge) 
x 
FiO2 assessment 
(between 7 AM and 12 PM local time – done at same 
time as vital signs) 
x4 
x 
x 
(while in hospital) 
x 
x 
(while in hospital) 
x 




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Screening 
Study Period 
Study Day 
Screening 
Day 1 
(Randomization) 
Day 2-14 
(every day 
unless otherwise 
specified below) 
Day 15 
Day 16-28 
(every day 
unless 
otherwise 
specified below) 
Day 29 
(End of 
study) 
Serum pregnancy test (local labs); results must be 
reviewed prior to randomization 
x8 
 
 
 
 
x 
Chest x-ray (CXR) or chest CT scan9 
x 
 
 
 
 
 
ECG (local)4 
s 
 
 
 
 
 
Adverse events 
x 
x 
x 
(via telephone if 
not in hospital) 
x 
x 
(via telephone if 
not in hospital) 
x 
Prior and concomitant non-drug therapies (including 
surgeries and procedures) 
x 
x 
x 
(via telephone if 
not in hospital) 
x 
x 
(via telephone if 
not in hospital) 
x 
Prior/concomitant medications 
x 
x 
x 
(via telephone if 
not in hospital) 
x 
x 
(via telephone if 
not in hospital) 
x 
In-hospital outcomes10 
x 
x 
x 
(while in hospital) 
x 
x 
(while in hospital) 
x 
Contact IRT11 
x 
x 
 
 
 
 


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Screening 
Study Period 
Study Day 
Screening 
Day 1 
(Randomization) 
Day 2-14 
(every day 
unless otherwise 
specified below) 
Day 15 
Day 16-28 
(every day 
unless 
otherwise 
specified below) 
Day 29 
(End of 
study) 
1. Informed consent must be obtained prior to any study-related procedure. 
2. SARS-CoV-2 virus to be measured by polymerase chain reaction (PCR) test or another rapid test from the respiratory tract prior to randomization (may use test 
done as part of routine care prior to screening). If no SARS-CoV-2 virus test available from routine care, test should be obtained at screening. 
3. Vital signs include pulse rate, respiratory rate (if not on mechanical ventilation), systolic and diastolic blood pressure and body temperature. 
4. Results from tests or examinations done as part of routine care and performed up to 24 hours prior to the screening visit may be used for the screening visit values. 
5. Hematology, clinical chemistry
 should be measured by the local laboratory. Hematology, clinical chemistry, 
 
 obtained as part of routine care may be used. 
6. Hematology, clinical chemistry, 
 done as part of routine care and performed up to 48 hours prior to the screening visit may be used for 
the screening visit values. Also, blood drawn and banked up to 48 hours prior to the screening visit may be used to obtain the screening visit laboratory values. 
7.  If the randomization visit occurs on the same day as the screening visit, the screening hematology, clinical chemistry, 
 values can 
serve as the randomization laboratory values. If the randomization visit occurs on a day different from the screening visit, hematology, clinical chemistry, 
 
 are to be obtained on that day prior to randomization. 
8. Pregnancy test: Only for females of childbearing potential, serum pregnancy test (serum hCG). Pregnancy tests done as part of routine care up to 24 hours prior to 
the screening visit may be used. Also, blood drawn and banked up to 24 hours prior to the screening visit may be used to obtain the required pregnancy test. 
9. Chest X-ray or chest CT scan prior to randomization (may use chest X-ray or chest CT done as part of routine care prior to screening). If no chest X-ray or chest CT 
scan available from routine care, chest X-ray or chest CT scan should be obtained at screening. 
10. In-hospital outcomes to be reported as described on eCRFs. 
11. Screen failures must be called into IRT. 
(s) = assessment to be recorded in source documents only; assessment will not be entered into the eCRFs; 
(x) = assessment to be recorded in source documents and entered into the eCRF 


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8.1 
Screening 
No rescreening will be allowed. 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and 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 Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see 
Section 10.1.3 for reporting details). If the participant fails to be randomized, the IRT must be 
notified within 2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
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. 
8.3 
Efficacy 
8.3.1 
Clinical status (9-point ordinal scale) 
Assessment of clinical status using a 9-category ordinal scale (WHO 18-Feb-2020) will be 
recorded at baseline on Day 1 and then again once daily every morning (between 7AM and 
12PM) through Day 29 of the Study Period. If a patient is discharged from the hospital, the 
assessment will be made by phone (between 7AM and 12PM). Each day, the worse score for 
the previous day will be recorded, i.e. on Day 3, Day 2 score is obtained and recorded as Day 
2. The scale is as follows: 
Table 8-2 
Clinical status 9-category ordinal scale 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatory (defined as 
not in hospital or in 
hospital and ready for 
discharge) 
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 


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Patient State 
Descriptor 
Score 
Hospitalized 
Severe Disease 
Non-invasive ventilation or high-flow oxygen 
5 
Intubation and mechanical ventilation 
6 
Ventilation + additional organ support – pressors, RRT (renal 
replacement therapy), ECMO (extracorporeal membrane 
oxygenation) 
7 
Dead 
Death 
8 
8.3.2 
Vital signs and oxygen saturation 
Results from tests or examinations done as part of routine care may be used as specified in the 
table of assessments (See Table 8-1). 
Vital sign measurement include respiratory rate, pulse rate, systolic and diastolic blood pressure, 
and body temperature. Peripheral oxygen saturation (SpO2) should also be measured at the same 
time as the vitals. For patients on oxygen by nasal cannula (≤ 2L/min), SpO2 assessment on 
room air (based on investigator medical judgement) will also be performed at the same time as 
the vitals on Days 15, 29 and at discharge. For patients requiring supplemental oxygen, the 
oxygen flow rate (L/min) and/or fraction of inspired oxygen (FiO2) should be recorded at the 
same time as the vitals. 
In order to allow assessment of the NEWS2 score (Appendix 3), the vital sign parameters and 
oxygen saturation should be recorded together once per day (between 7AM and 12PM), for the 
duration of the hospitalization during the study. Following hospital discharge these parameters 
should be recorded once on Days 15 and 29. 
8.3.3 
National Early Warning Score 2 (NEWS2) 
In addition to the vital signs, the patient’s level of consciousness and the presence/absence of 
respiratory support must be recorded. The NEWS2 parameter for respiratory support is the 
selection of either air or “oxygen” can include other forms of ventilation to maintain oxygen 
saturation (see Appendix 3). 
These should be recorded at the same time points as the vital sign measurements  
(between 7AM and 12 PM) (see Section 8.3.2). 
NEWS2 values will be calculated electronically by Novartis based on vital sign parameters and 
NEWS2 related assessments recorded by the investigator in the appropriate eCRFs. 
8.3.4 
In-hospital outcomes 
In addition to endpoints mentioned above, the following in hospital outcomes will be captured 
on eCRFs: 
• Start and end date of mechanical ventilation 
• Start and end date of hospital stay 
 
 
 
 
 
 
 
 


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8.3.5 
Ventilatory status 
Ventilatory status (mechanical ventilation, supplemental oxygen, intubation and non-invasive 
ventilation [e.g. CPAP, BIPAP, etc.]) will be collected at timepoints designated in Table 8-1 
and recorded by the investigator in the appropriate eCRFs. 
8.3.6 
Appropriateness of efficacy assessments 
Efficacy endpoints are those employed in other studies of patients with COVID-19 pneumonia 
(WHO 2020; Cao et al 2020). 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to Section 10.1.1. 
8.4.1 
Laboratory evaluations 
Laboratory evaluations will be performed by a local laboratory. Results from tests or 
examinations done as part of routine care may be used as specified in the table of assessments 
(See Table 8-1). 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured according to the assessment schedule in Table 8-1. 
Chemistry 
BUN/urea, creatinine, creatine kinase, total bilirubin, AST, ALT, alkaline phosphatase, sodium, 
potassium, chloride, calcium, bicarbonate, total protein, albumin, and glucose will be measured 
according to the assessment schedule in Table 8-1. 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 times the upper limit of normal range, 
the total bilirubin will differentiated into the direct and indirect reacting bilirubin. 
 
 
 
 
 
 
 
 
 
 
 
Sample(s) will be collected at the time point(s) defined in the Assessment Schedule  
(Table 8-1). If a given test is not available locally, this should be documented on the eCRF. 


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Drug-induced liver injury monitoring 
For patients with elevated liver tests, additional laboratory tests as denoted in Appendix 1 
(Table 16-1, Table 16-2 and Table 16-3) should be obtained as specified. 
8.4.2 
Physical Exam 
A physical examination will be performed at Screening and any abnormalities will be recorded 
in source documents. Results from tests or examinations done as part of routine care may be 
used as per Table 8-1. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to informed consent being granted must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
eCRF. Significant findings made after informed consent is given which meet the definition of 
an Adverse Event must be recorded on the Adverse Event screen of the patient’s eCRF. 
8.4.3 
Height, weight, BMI 
Results from tests or examinations done as part of routine care may be used as specified in the 
table of assessments (See Table 8-1). 
If possible, height will be measured at the Screening visit as specified in the table of assessments 
(See Table 8-1). Otherwise, patient or guardian/health proxy reported height will be obtained. 
Body weight will be measured at the Screening visit as specified in the table of assessments 
(See Table 8-1). 
Body Mass Index (BMI) will be calculated as the weight in kg divided by the height in meters 
squared. 
8.4.4 
Electrocardiogram (ECG) 
Results from tests or examinations done as part of routine care may be used as specified in the 
table of assessments (See Table 8-1). 
An ECG will be taken at Screening and recorded in source documents. 
The ECG should be recorded after 10 minutes of rest in the supine position to ensure a stable 
baseline. 
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF page as appropriate. 
If necessary, a cardiologist may be consulted. 
8.4.5 
Pregnancy and assessments of fertility 
Results from tests or examinations done as part of routine care may be used as specified in the 
table of assessments (See Table 8-1). 
All women of child bearing potential will have a serum pregnancy test at Screening and at 
designated visits (Table 8-1). 


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A positive pregnancy test at any time will result in study discontinuation. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are appropriate for this protocol which utilizes a marketed 
compound where the safety profile has been established. The assessments are relevant to the 
critical care setting and will enable determination of therapeutic response in this setting. 


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9 
Study discontinuation and treatment 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
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 impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Abnormal liver laboratory results as specified in Appendix 1 
• Grade 4 non-hematologic adverse events attributed to study drug 
• 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, prevents 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 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the participant/pre-designated contact as specified in the lost to follow-up 
section. 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 pre-designated 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/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 


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If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 
9.1.2 
Replacement policy 
Patients discontinuing the study will not be replaced. 
9.1.3 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore, 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort to understand the primary 
reason for the participant’s decision to withdraw his/her consent and record this information. 
Where consent to the use of personal and coded data is not required, participant therefore 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 
communicating 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. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
9.1.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
9.1.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 


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Reasons for early termination: 
• 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 taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat 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 (e.g. Each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them). 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.3): 


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1. Adverse events will be assessed and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0. 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.3 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. Its outcome (i.e. recovery status or whether it was fatal) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 


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10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 


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10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until the last study visit must be reported to Novartis safety 
within 24 hours of learning of its occurrence. Detailed instructions regarding the submission 
process and requirements are to be found in the investigator folder provided to each site. 
Screen Failures (e.g. a participant who is screened but is not treated or randomized): SAEs 
occurring after the participant has provided informed consent until the time the participant is 
deemed a Screen Failure must be reported to Novartis. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the after the last study visit should only be reported to Novartis 
Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up 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. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 


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Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective Sections. 
10.2 
Additional Safety Monitoring 
Not applicable. 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Appendix 1 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-1 should 
be followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-2 and 
Table 16-3. Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to 
confirm elevation. 
These liver chemistry repeats should be performed using the local laboratory used by the site. 
Repeated laboratory test results must be reported as appropriate. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
Section 9.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include 


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• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
10.2.2 
Data Monitoring Committee 
This study will include an internal data monitoring committee (DMC) which will function 
independently of all other individuals associated with the conduct of this clinical trial, including 
the site investigators participating in the study. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol and defined in the 
Assessment Schedule (Table 8-1) into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs, 
allow modification and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on eCRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
This study may also incorporate electronic technology (eSource DDE) to capture source 
documents and source data electronically, consistent with final (CDER 2013) FDA guidance 
regarding electronic source and regulations related to the maintenance of adequate participant 
case histories (21 CFR 312.62 [b]). 
A Novartis representative will review the protocol and data capture requirements (i.e. eSource 
DDE and/or eCRFs) with the investigators and their staff. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 


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11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at an initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE and/or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will check the completeness of participant records, the accuracy of data 
capture / data entry, the adherence to the protocol and to Good Clinical Practice, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor in 
conducting these activities. Continuous monitoring of each site’s data will be performed 
throughout the conduct of the study. Additionally, a central analytics organization may analyze 
data & identify risks & trends for site operational parameters, and provide reports to Novartis 
clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to the respective source documents.  


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The investigator must also keep the original informed consent form signed by the participant 
and/or legal representative (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Source data verification may be done on-
site, if possible, or remotely, if the field monitor does not have access or have limited access to 
the site due to the current COVID-19 pandemic. Different approaches can be used depending 
on site medical records, and some of them could include sharing the information through 
electronic systems or platforms provided by a third party. In all cases investigator and sponsor 
must adhere to the recommendations established by the applicable Health Authorities. 
Novartis monitoring standards require verification for the presence of all informed consents, 
adherence to the inclusion/exclusion criteria, documentation of SAEs, and of data that will be 
used for all primary variables. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Randomized Analysis Set (RAS) consists of all randomized participants. 
According to the intent to treat principle, participants will be analyzed according to the 
treatment they have been assigned to during the randomization procedure. 
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized/assigned treatment if the participant took at least one dose 
of that treatment or the first treatment received if the randomized/assigned treatment was never 
received. 
The analysis of the primary objective and all other efficacy variables will be performed on the 
RAS. The Safety Set will be used in the analysis of all safety variables. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the RAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group. 


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12.3 
Treatments 
The duration of exposure in days to ruxolitinib and standard of care therapies will be 
summarized by means of descriptive statistics using the Safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
The primary analysis for this study will be conducted on the RAS according the intention to 
treat principle. 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
The estimand framework for the primary objective is as follows: 
• Treatment – ruxolitinib added to SoC therapy 
• Population – Hospitalized patients with coronavirus (SARS-CoV-2) infection confirmed by 
polymerase chain reaction (PCR) test or another rapid test from the respiratory tract prior to 
randomization as described in Section 5.1. 
• Endpoint – Primary efficacy endpoint is clinical failure, defined as the occurrence of death, 
respiratory failure (require mechanical ventilation), or ICU care by Day 29. 
• Population-level summary – Odds-ratio comparing ruxolitinib added to SoC therapy to 
placebo added to SoC therapy. 
• Intercurrent event(s) – Discontinuation of study treatment 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The statistical hypothesis tested for clinical failure is that there is no difference in the proportion 
of subjects developing clinical failure by Day 29 with ruxolitinib + SoC versus placebo + SoC 
therapy. 
Let pi denote the proportion of clinical failures by Day 29 for treatment groups j, j = 0, 1 where 
• 0 corresponds to placebo + SoC 
• 1 corresponds to ruxolitinib + SoC 
The following statistical hypothesis will be tested to address the primary objective: 
H0: p0 = p1, H1: p0 ≠ p1. 
The odds of clinical failure will be analyzed by a logistic regression model with treatment group, 
region (North America, Europe), baseline clinical status based on the 9-point ordinal scale (≤4, 
≥5), age, and gender as covariates. The estimated odds ratio, p-values, and 95% confidence 
intervals will be presented. 
The study will be considered positive, if ruxolitinib demonstrates a statistically significant 
greater reduction in clinical failure. This implies observing an odds ratio of < 1. 


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12.4.3 
Handling of remaining intercurrent events of primary estimand 
Discontinuation of study treatment for any reason: Retrieved drop out (RDO) data after 
study treatment discontinuation will be collected. If RDO data is available up to Day 29 this 
will be used for analysis. If no RDO data was collected after study treatment discontinuation or 
the RDO data is not complete to Day 29 then the patient will be considered as a clinical failure, 
unless they are in one of the scenarios below: 
• There was no occurrence of death, mechanical ventilation, nor ICU care in all the 
available data and patients were discharged from the hospital 
• The last available data (either on-treatment or off-treatment) is from Day 15 or later, and 
there was no occurrence of death, mechanical ventilation, nor ICU care in all the available 
data 
12.4.4 
Handling of missing values not related to intercurrent event 
For patients who withdraw from the study, their clinical failure status will be handled similarly 
as in Section 12.4.3. Other missing data handling rules will be specified in the SAP. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
In order to determine the robustness of the logistic regression model used for the primary 
analysis of clinical failure by Day 29, a non-parametric regression model (Koch et al 1998) will 
also be evaluated using the same explanatory variables as the logistic regression model. 
12.4.6 
Supplementary analysis 
To assess the effect of classifying patients’ clinical failure status with missing data, a multiple 
imputation based analysis will be conducted. More details of this approach will be included in 
the study analysis plan. Other imputation approaches, for example, a worst case analysis, will 
be considered and may be included in the study analysis plan. 
12.4.7 
Supportive analyses 
The primary analysis of the clinical failure will be repeated for each of the events in the 
composite endpoint: occurrence of death, mechanical ventilation, and ICU care. Separate 
logistic regression models will be fitted to compare the odds between treatment groups for each 
of the endpoints. The analysis will be performed for both Days 15 and 29. 
As there is uncertainty around the covariates to be included in the primary analysis model for 
the clinical failure by Day 29, analyses will be performed considering additional covariates, for 
example, co-morbidities. These analyses will be defined further in the study analysis plan. 
12.5 
Analysis of secondary endpoints/estimands 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Full details of all planned analyses will be included in the study analysis plan. However, a brief 
description of the approaches used for each endpoint are given below. 


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12.5.1.1 9-category ordinal scale 
The odds of observing a better category (lower number) of clinical status (9-category ordinal 
scale, WHO 18-Feb-2020) at Day 15 will be analyzed with a proportional odds model (POM). 
The odds ratio for treatment group (ruxolitinib + SoC therapy vs. placebo + SoC therapy) 
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 (e.g. 
the cutoff of level 5 ‘Non-invasive ventilation or high-flow oxygen’ will combine levels 0, 1, 
2, 3, and 4 versus combined levels 5, 6, 7 and 8). The assumption of POM is that the effect of 
treatment is identical across all possible cutoff points of the ordinal outcome. The proportional 
odds assumption will be checked by a score test. The model will include treatment group, 
country, age, gender, and baseline clinical status as covariates. The estimated odds ratios, p-
values and 95% confidence intervals will be presented. The analysis will be repeated for the 
data at Day 29. 
The treatment groups will also be compared in terms of at least a one-point improvement, at 
least a two-point improvement, and at least a one-point deterioration in clinical status at Days 
15 and 29 using respective logistic regression models with the same covariates as for the POM. 
Time to improvement from baseline category to one less severe category of the ordinal scale 
will be analyzed using a competing risk analysis framework (death will be treated as a 
competing risk). Baseline clinical status will also be included in the model. 
Mean change from baseline in the clinical status on the 9-point ordinal scale to Days 15 and 29 
will be summarized by treatment arm. This endpoint will also be analyzed using an analysis of 
covariance (ANCOVA) model with factors for treatment group and country, as well as the 
baseline clinical status as a continuous linear covariate. 
12.5.1.2 Oxygen saturation 
The proportion of patients with no oxygen therapy (defined as oxygen saturation ≥ 94% on 
room air) at Days 15 and 29 will be analyzed separately using a logistic regression model with 
the same covariates as for the primary analyses, with baseline oxygen therapy status included. 
12.5.1.3 In-hospital outcomes 
Duration of hospitalization will be analyzed using a competing risk analysis framework (death 
will be treated as a competing risk). More details will be provided in the statistical analysis plan. 
The analyses of mortality rates at Day 15 and at Day 29, and proportion of patients requiring 
mechanical ventilation by Day 29 are described in Section 12.4.7. 
12.5.1.4 National Early Warning Score (NEWS2) 
Time to discharge or to a National Early Warning Score (NEWS2) of ≤2 and maintained for 24 
hours (whichever comes first) will be analyzed using a competing risk analysis framework 
(death will be a competing risk) (Royal College of Physicians 2017). The model will also 
include treatment group, age, and gender (in the case of the analysis of NEWS2, the baseline 
NEWS2 score will also be included). 






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13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
(Applicable to US only) This study is being conducted to determine whether ruxolitinib can 
safely and effectively be used to mitigate, treat, or cure COVID-19 or limit the harm of the 
COVID-19 pandemic in accordance with the Secretary of the Department of Health and Human 
Services’ (HHS’s) Declaration under the Public Readiness and Emergency Preparedness Act 
for medical countermeasures against COVID-19 (COVID-19 Declaration) effective February 
4, 2020. The purpose of this study is to test the efficacy and safety of ruxolitinib in patients with 
COVID-19 associated cytokine storm. This study is authorized to proceed under an approved 
investigational new drug application (IND) in accordance with the public health and medical 
response of FDA, an Authority Having Jurisdiction as described under the PREP Act, to 
prescribe, administer, deliver, distribute or dispense this Covered Countermeasure as defined 
by and following the HHS’s COVID-19 Declaration. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
Available upon request 
Ahmed, A., Merrill, S.A., Alsawah, F., Bockenstedt, P., Campagnaro, E., Devata, S., Gitlin, 
S.D., Kaminski, M., Cusick, A., Phillips, T. and Sood, S., (2019). Ruxolitinib in adult patients 
with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. 
The Lancet Haematology, 6(12), pp.e630-e637. 
Cai, J., Xu, J., Lin, D., Xu, L., Qu, Z., Zhang, Y., Zhang, H., Jia, R., Wang, X., Ge, Y. and 
Xia, A., (2020). A Case Series of children with 2019 novel coronavirus infection: clinical and 
epidemiological features. Clinical Infectious Diseases. 
Calbet, M, Ramis, I, Calama, E, et al. (2019) Novel inhaled pan-JAK inhibitor, LAS194046, 
reduces allergen-induced airway inflammation, late asthmatic response, and PSTAT 
activation in brown Norway rats. Journal of Pharmacology and Experimental Therapeutics; 
370 (2):137-147. 
Cao, B, Wang, Y, Wen, W., et al A Trial of Lopinavir–Ritonavir in Adults Hospitalized with 
Severe Covid-19 (2020) New England Journal of Medicine DOI: 10.1056/NEJMoa2001282 
Published 18-Mar-2020 and updated 20-Mar-2020. 
China CDC Weekly. (2020) Vital surveillances: the epidemiological characteristics of an 
outbreak of 2019 novel coronavirus diseases (COVID-19) – China.;2(8):113-22. 
Coon, TA, McKelvey, AC, Lear, T, et al. (2015) The proinflammatory role of HECTD2 in 
innate immunity and experimental lung injury. Science Translational Medicine; 7 
(295):295ra109. 
Goldsmith, S.R., Rehman, S.S.U., Shirai, C.L., Vij, K. and DiPersio, J.F., (2019). Resolution 
of secondary hemophagocytic lymphohistiocytosis after treatment with the JAK1/2 inhibitor 
ruxolitinib. Blood Advances, 3(23), p.4131. 
Hermans, M.A., Schrijver, B., van Holten‐Neelen, C.C., Gerth van Wijk, R., van Hagen, 
P.M., van Daele, P.L. and Dik, W.A., (2018). The JAK1/JAK2‐inhibitor ruxolitinib inhibits 
mast cell degranulation and cytokine release. Clinical & Experimental Allergy, 48(11), 
pp.1412-1420. 
Hoffmann, J., Machado, D., Terrier, O., Pouzol, S., Messaoudi, M., Basualdo, W., Espínola, 
E.E., Guillen, R.M., Rosa-Calatrava, M., Picot, V. and Bénet, T., (2016). Viral and bacterial 
co-infection in severe pneumonia triggers innate immune responses and specifically enhances 
IP-10: a translational study. Scientific reports, 6, p.38532. 
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X. and 
Cheng, Z., (2020). Clinical features of patients infected with 2019 novel coronavirus in 
Wuhan, China. The Lancet, 395(10223), pp.497-506. 
Jagasia, M., Perales, M.A., Schroeder, M.A., Ali, H., Shah, N.N., Chen, Y.B., Fazal, S., 
Dawkins, F.W., Arbushites, M.C., Tian, C. and Connelly-Smith, L., (2020). Ruxolitinib for 
the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label, phase 
2 trial. Blood Journal, pp.blood-2020004823. 


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Jakafi® [package insert]. Wilmington, DE. Incyte; (2011). 
Kenderian, S.S., Ruella, M., Shestova, O., Kim, M., Klichinsky, M., Chen, F., Kengle, N., 
Lacey, S., Melenhorst, J., June, C.H. and Gill, S.I., (2017). Ruxolitinib prevents cytokine 
release syndrome after car T-cell therapy without impairing the anti-tumor effect in a 
xenograft model. Biology of Blood and Marrow Transplantation, 23(3), pp.S19-S20. 
Koch, G.G., Tangen, C.M., Jung, J.W. and Amara I.A., (1998). Issues for covariance analysis 
of dichotomous and ordered categorical data from randomized clinical trials and non-
parametric strategies for addressing them. Statistics in Medicine, 17(15-16), pp.1863-1892. 
Maschalidi, S., Sepulveda, F., Garrigue, A. et al. (2016) Therapeutic effect of JAK1/2 
blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood 
128:60-71. 
Mehta, P., McAuley, D., Brown, M., et al. (2020) COVID-19: consider cytokine storm 
syndromes and immunosuppression. Lancet 395: 1033-34. 
Royal College of Physicians (2017) National Early Warning Score (NEWS) 2: Standardising 
the assessment of acute-illness severity in the NHS. Updated report of a working party. 
London: RCP. 
Wang, W., He, J. and Wu, S., (2020). The definition and risks of Cytokine Release Syndrome-
Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and 
Retrospective Analysis. Medrxiv. 
Wei, M., Yuan, J., Liu, Y., Fu, T., Yu, X. and Zhang, Z.J., (2020). Novel coronavirus 
infection in hospitalized infants under 1 year of age in China. JAMA. 
WHO (18-Feb 2020). WHO R&D Blueprint. Novel coronavirus. COVID-19 Therapeutic 
Trial Synopsis (Dated 18-Feb-2020). 
World Health Organization, (2020). Clinical management of severe acute respiratory infection 
when novel coronavirus (2019-nCoV) infection is suspected: interim guidance, 28 January 
2020 (No. WHO / nCoV / Clinical / 2020.3). World Health Organization. 
Xia, W., Shao, J., Guo, Y., Peng, X., Li, Z. and Hu, D., (2020). Clinical and CT features in 
pediatric patients with COVID‐19 infection: Different points from adults. Pediatric 
Pulmonology. 
Yang, X., Yu, Y., Xu, J., Shu, H., Liu, H., Wu, Y., Zhang, L., Yu, Z., Fang, M., Yu, T. and 
Wang, Y., (2020). Clinical course and outcomes of critically ill patients with SARS-CoV-2 
pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet 
Respiratory Medicine. 


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Zhao, J., Yu, H., Liu, Y., Gibson, S.A., Yan, Z., Xu, X., Gaggar, A., Li, P.K., Li, C., Wei, S. 
and Benveniste, E.N., (2016). Translational Research in Acute Lung Injury and Pulmonary 
Fibrosis: Protective effect of suppressing STAT3 activity in LPS-induced acute lung 
injury. American Journal of Physiology-Lung Cellular and Molecular Physiology, 311(5), 
p.L868. 
Zhou, F., Yu, T., Du, R., Fan, G., Liu, Y., Liu, Z., Xiang, J., Wang, Y., Song, B., Gu, X. and 
Guan, L., (2020). Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 
Zumla, A., Hui, D.S., Azhar, E.I., Memish, Z.A. and Maeurer, M., (2020). Reducing mortality 
from 2019-nCoV: host-directed therapies should be an option. The Lancet, 395(10224), 
pp.e35-e36. 


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16 
Appendices 
16.1 
Appendix 1: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-1 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at baseline:  
• 
ALT or AST > 5 × ULN 
• 
ALP > 2 × ULN (in the absence of known bone 
pathology) 
• 
Total bilirubin > 3 × ULN (in the absence of known 
Gilbert syndrome) 
• 
ALT or AST > 3 × ULN and INR > 1.5 
• 
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP 
to > 2 × ULN) 
• 
Any clinical event of jaundice (or equivalent term) 
• 
ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, 
or rash with eosinophilia 
• 
Any adverse event potentially indicative of a liver 
toxicity* 
If ALT or AST abnormal at baseline: 
• 
ALT or AST > 2x baseline or > 300 U/L (whichever 
occurs first) 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: upper limit of 
normal 


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Table 16-2 
Follow up requirements for liver laboratory triggers with liver 
symptoms 
  
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
  
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For patients with 
Gilbert’s syndrome: 
No change in 
baseline TBL 
None 
• 
No change to 
study treatment 
• 
Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, albumin, 
CK, and GLDH (if 
available at local 
laboratory) in 48-72 
hours. 
• 
Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
  
If normal at 
baseline: 
ALT > 5 x ULN for 
more than two 
weeks 
Normal 
For patients with 
Gilbert’s syndrome: 
No change in 
baseline TBL 
None 
• 
Interrupt study 
drug 
• 
Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, albumin, 
CK, and GLDH (if 
available at local 
laboratory) in 48-72 
hours. 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
• 
Study drug can 
be restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline. 
If elevated at 
baseline: 
ALT > 3 x baseline 
and > 10x ULN 
  
If normal at 
baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
  
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN 
For patients with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x baseline 
 
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at 
baseline: 
ALT > 2 x baseline 
 


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Table 16-3 
Follow up requirements for liver laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
  
  
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Interrupt treatment 
• 
Repeat LFT within 48-72 hours 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, 
lab) in the appropriate eCRF 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total bilirubin, 
Alb, PT/INR, ALP and GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and contributing 
factors(e.g. conmeds, med hx, 
lab)in the appropriate eCRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutiona (frequency at 
investigator discretion) 
Any AE potentially indicative of a 
liver toxicity* 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors(e.g., conmeds, med hx, 
lab)in the appropriate eCRF 
Investigator discretion 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: upper limit of 
normal 
a Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 


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16.2 
Appendix 2: Clinical status 9-point scale 
Clinical status (9-point ordinal scale): 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatory (defined as 
not in hospital or in 
hospital and ready for 
discharge) 
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 – pressors, RRT (renal 
replacement therapy), ECMO (extracorporeal membrane 
oxygenation) 
7 
Dead 
Death 
8 
 
Reference: WHO (18-Feb-2020). WHO R&D Blueprint. Novel coronavirus. COVID-19 
Therapeutic Trial Synopsis (Dated 18-Feb-2020). 


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16.3 
Appendix 3: National Early Warning Score 2 (NEWS2) 
 
SpO2 = oxygen saturation. 
 
The oxygen saturation should be scored according to either the SpO2 Scale 1 or 2 presented in 
the table above. The SpO2 Scale 2 is for patients with a target oxygen saturation requirement of 
88%-92% (e.g., in patients with hypercapnic respiratory failure related to advanced lung 
diseases, such as chronic obstructive pulmonary disease [COPD]). This should only be used in 
patients confirmed to have hypercapnic respiratory failure by blood gas analysis on either a 
prior or their current hospital admission. 
The decision to use the SpO2 Scale 2 should be made by the treating physician and should be 
recorded in the eCRF. In all other circumstances, the SpO2 Scale 1 should be used. 
For physiological parameter “Air or Oxygen?”: Any patients requiring the use of oxygen or 
other forms of ventilation to maintain oxygen saturations and support respiration should be 
assigned a score of 2. 
The consciousness level should be recorded according to the best clinical condition of the 
patient during the assessment. Patients who are assessed as “Alert” (A) should be assigned a 
score of 0. Patients assessed as “New Confusion” (C), “Responsive to Voice” (V), “Responsive 
to Pain” (P), or “Unconscious” should be assigned a score of 3. 
Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and temperature 
according to the table above. 
NEWS2 values will be calculated electronically throughout the study by the Sponsor based 
upon entry of vital sign parameters by the investigator in the appropriate eCRF. 


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Example Case Calculation: 
An 82-year-old lady was admitted, tested positive to COVID-19 and admitted to high 
dependency unit for non-invasive ventilation. Her taken observations and corresponding 
NEWS2 score are as follows: 
 
Physiological Parameter 
Observation 
Component Score 
Respiratory rate (per min) 
26 
3 
Oxygen saturation (SpO2 %) 
95% 
1 
Supplemental Oxygen  
Yes 
2 
Systolic blood pressure (mmHg) 
95 
2 
Pulse Rate (bpm) 
109 
1 
Conscious level 
New confusion 
3 
Temperature (oC) 
39 
1 
 
Total NEWS2 Score 
13 
 
Reference: 
Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the 
assessment of acute-illness severity in the NHS. Updated report of a working party. London: 
RCP, 2017. 


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16.4 
Appendix 4: List of CYP3A4 inhibitors and inducers 
Table 16-4 
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. Please 
refer to Section 6.2. 
Category 
Drug Names 
Strong inhibitorsa of CYP3A 
boceprevir, clarithromycin, cobicistat, 
conivaptan, danoprevir/ritonavir, 
eltegravir/ritonavir, grapefruit juice1, idelalisib, 
indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, LCL161, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, sequinavir/ritonavir, telaprevir, 
telithromycin, voriconazole, indinavir/ritonavir, 
tipranoavir/ritonavir, troleandomycin, 
Moderate inhibitorsb of CYP3A 
amprenavir, aprepitant, atazanavir, 
atazanavir/ritonavir,, casopitant, cimetidine, 
ciprofloxacin, crizotinib, cyclosporin, duranavir, 
darunavir/ritonavir, diltiazem, dronedarone, 
erythromycin, faldaprevilr, fluconazole2, 
fosamprenavir, grapefruit juice1, imatinib, 
lomitapide, netupitant,nilotinib, schisandra 
sphenanthera3, tofisopam, verapamil 
Strong inducersc of CYP3A 
avasimibe, carbamazepine, enzalutamide, 
mitotane,phenytoin, rifampin, St. John’s wort3, 
rifabutin, phenobarbital, 
Moderate inducersd of CYP3A 
bosentan, efavirenz, etravirine, genistein3, 
lersivirine, lopinavir, modafinil, nafcillin, ritonavir, 
semagacestat4, talviraline4, thioridazine, 
tipranavir, 
The list of CYP inhibitors and inducers was compiled from the FDA’s “Guidance for Industry, Drug 
Interaction Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” Table 
and from the University of Washington’s Drug Interaction Database. Note that this may not be an 
exhaustive list. For a complete and most updated drug list, please check the website 
https://.crediblemeds.org/healthcareproviders/drug-list. 
1 Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. 
2 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. 
3 Herbal product. 
4 Drugs not available in the US Market. 
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. 
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 


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c  
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%. 
d. 
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%. 
 

SAP_001.pdf: 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 8 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 11 
2.2.1 
Subgroup of interest .............................................................................. 11 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 12 
2.3.1 
Patient disposition ................................................................................. 12 
2.3.2 
Patient demographics and other baseline characteristics ...................... 12 
2.3.3 
Medical history/current medical condition ........................................... 13 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 13 
2.4.1 
Study treatment / compliance ................................................................ 13 
2.4.2 
Prior, concomitant and post therapies ................................................... 13 
2.5 
Analysis of the primary objective .......................................................................... 14 
2.5.1 
Primary endpoint ................................................................................... 14 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 15 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 15 
2.5.4 
Supportive analyses ............................................................................... 15 
2.6 
Analysis of the key secondary objective ............................................................... 17 
2.7 
Analysis of secondary efficacy objectives ............................................................. 17 
2.7.1 
Secondary endpoints ............................................................................. 17 
2.8 
Safety analyses ....................................................................................................... 20 
2.8.1 
Adverse events (AEs) ............................................................................ 20 
2.8.2 
Deaths .................................................................................................... 22 
2.8.3 
Laboratory data ..................................................................................... 22 
2.8.4 
Other safety data ................................................................................... 22 
 
 23 
 
 23 
 
 23 
 
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2.11 
Interim analysis ...................................................................................................... 25 
3 
Sample size calculation ..................................................................................................... 25 
4 
Change to protocol specified analyses .............................................................................. 26 
5 
Appendix ........................................................................................................................... 27 
5.1 
Imputation rules ..................................................................................................... 27 
5.1.1 
Study drug ............................................................................................. 27 
5.1.2 
AE date imputation ............................................................................... 27 
5.1.3 
Concomitant medication date imputation ............................................. 27 
5.2 
AEs coding/grading ............................................................................................... 27 
5.3 
Laboratory parameters derivations ........................................................................ 27 
5.4 
Statistical models ................................................................................................... 27 
5.4.1 
Primary analysis .................................................................................... 27 
5.4.2 
Key secondary analysis ......................................................................... 29 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 30 
5.6 
Type of pulmonary/ventilatory support ................................................................. 30 
6 
References ......................................................................................................................... 31 
 
List of tables 
Table 1-1 
Objectives and related endpoints ............................................................ 8 
Table 3-1 
Sensitivity of sample size assumptions to different proportion of 
patients meeting the primary composite endpoint for level of 
significance alpha = 0.05....................................................................... 25 
Table 5-1 
Type of pulmonary/Ventilatory support based on the level of 
oxygen requirement from low to high ................................................... 30 
 
List of figures 
Figure 1-1 
Study design ............................................................................................ 7 
 


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List of abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical Therapeutic Classification 
BMI 
Body mass index 
 
 
CRS 
Case Retrieval Strategy 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee  
ICU 
Intensive Care Unit 
IRT 
Interactive Response Technology 
J2R 
Jump-to-reference 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NEWS2 
National Early Warning Score 
PCR 
Polymerase chain reaction 
PD 
Protocol deviation 
PDS 
Programming Dataset Specification 
POM 
Proportional odds model 
PT 
Preferred Term 
RAS 
Randomized Set 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SoC 
Standard-of-Care 
SOC 
System Organ Class 
WHO 
World Health Organization 


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1 
Introduction 
This document contains details of the statistical methods that will be used in the phase III 
clinical trial CINC424J12301. This study is designed to evaluate the efficacy and safety of 
ruxolitinib in the treatment of patients with COVID-19 pneumonia. The primary endpoint is a 
composite endpoint (also referred as “clinical failure” in the protocol) defined as the proportion 
of patients who die, develop respiratory failure (require mechanical ventilation), or require 
intensive care unit (ICU) care by Day 29. 
Data will be analyzed according to Section 12 of the study protocol. 
The following document was referred while writing the SAP: 
CINC424J12301 Clinical Trial Protocol Final version 01 dated 20-May-2020. 
Important information is given in the following sections and details are provided, as applicable, 
in Section 5: Appendix. 
1.1 
Study design 
This is a randomized, double-blind, placebo-controlled, 29-day, multicenter study to assess the 
efficacy and safety of ruxolitinib + SoC therapy, compared with placebo + SoC therapy, in 
patients aged ≥12 years with COVID-19-induced pneumonia (Figure 1-1). 
The study will include: 
• Screening period of 0-2 days 
• Study period of 29 days (treatment of 14 days; an additional 14 days of study drug may 
be given, if in the opinion of the investigator, the patient’s clinical signs and symptoms are 
neither improved nor worsened and the potential benefit outweighs the potential risk) – 
see below. 
Figure 1-1 
Study design 
 
Eligible patients will be randomized on the same day as screening or up to two days after 
completing the screening procedures. At Day 1 (randomization visit), patients will be assigned 
in a 2:1 ratio to receive oral ruxolitinib 5 mg twice daily or oral matching-image placebo for a 
total of 14 days. An additional 14 days of study drug may be given, if in the opinion of the 


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investigator, the patient’s clinical signs and symptoms are neither improved nor worsened and 
the potential benefit outweighs the potential risk. 
Approximately 402 patients in total are needed (268 randomized to ruxolitinib and 134 to 
placebo). Detailed information regarding sample size calculation is provided in Section 3. 
Randomization will be stratified by geographic region (North America, West Europe, East 
Europe, Latin America, and Other). 
The primary endpoint will be assessed over 29 days. 
No interim analysis is planned. A Data Monitoring Committee (DMC) at Novartis will be 
established to conduct periodical unblinded safety reviews. The analysis plan for the DMC will 
be created separately. 
1.2 
Study objectives and endpoints 
Section 2 of the study protocol lists the following primary, secondary, 
 
objectives. 
Table 1-1 
Objectives and related endpoints 
 
Objectives 
Endpoints 
Primary 
Objective 
To evaluate the efficacy (as measured 
by a composite endpoint of proportion of 
patients who die, develop respiratory 
failure (require mechanical ventilation), 
or require intensive care unit (ICU) care) 
of ruxolitinib + standard-of-care (SoC) 
therapy compared with placebo + SoC 
therapy, for the treatment of COVID-19 
by Day 29. 
Composite endpoint defined as: 
• 
Death OR 
• 
Respiratory failure (require mechanical 
ventilation) OR 
• 
Intensive care unit (ICU) care by 
Day 29. 
Secondary 
Objectives 
To evaluate the efficacy (as measured 
by clinical status using a 9-point ordinal 
scale) of ruxolitinib + SoC therapy 
compared with placebo + SoC therapy, 
for the treatment of COVID-19 
(WHO 18-Feb-2020). 
Clinical status assessed using a 9-point 
ordinal scale (Section 2.7.1.1) at Day 15 and 
Day 29. 
• 
Percentage of patients with a better 
category (lower number) in clinical status at 
Day 15 and at Day 29. 
• 
Percentage of patients with at least two-
point improvement in clinical status at Day 15 
and at Day 29. 
• 
Percentage of patients with at least one-
point improvement in clinical status at Day 15 
and at Day 29. 
• 
Percentage of patients with at least one-
point deterioration in clinical status at Day 15 
and at Day 29. 
• 
Time to improvement from baseline 
category to one less severe category of the 
ordinal scale. 
• 
Mean change in the 9-point ordinal scale 
from baseline to Days 15 and 29. 






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When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available: 
Change from baseline = post-baseline value – baseline value. 
If not stated otherwise for efficacy analyses, on-treatment values are defined as values taken 
post-baseline but no later than 1 day after last dose of double-blind treatment. Off-treatment 
values are defined as post-baseline values taken more than 1 day after last dose of double-blind 
treatment. All on- and off- treatment values will be used in the efficacy analyses, unless 
otherwise specified. 
For safety analyses other than adverse events (AEs), e.g. laboratory, vital signs, treatment-
emergent values are defined as values taken post-baseline and up to the last study visit (Day 
29). 
AEs will be considered as treatment-emergent if the event starts after the first dose of double-
blind treatment or the event is present prior to start of double-blind treatment but increased in 
severity based on preferred term and up to the last study visit (Day 29). 
Details on calculation of post-baseline values are provided in the latter sections. 
2.2 
Analysis sets 
The Randomized Analysis Set (RAS) consists of all randomized patients. Following the intent-
to-treat principle, patients will be analyzed according to the treatment they were assigned to at 
randomization. 
The Safety Set will include all patients who received at least one dose of double-blind treatment. 
Patients will be analyzed according to the treatment they received, where treatment received is 
defined as the randomized/assigned treatment if the participant took at least one dose of that 
treatment or the first treatment received if the randomized/assigned treatment was never 
received. 
In cases where an incorrect randomization stratum is entered in the interactive response 
technology (IRT) system the corrected stratum information as per the case report form data will 
be used for reporting and analysis. 
2.2.1 
Subgroup of interest 
Subgroup analyses are conducted to assess consistency of the treatment effect among the 
subgroups, without multiplicity adjustments. The following subgroups will be evaluated for the 
primary endpoint, i.e., defined as the proportion of patients who die, develop respiratory failure 
(require mechanical ventilation), or require ICU care by Day 29: 
• Age category (< 18, 18 - < 65, ≥ 65 years) 
• Gender (male, female) 
• Race (White, Asian, Black, other) 
• Ethnicity (Hispanic, non-Hispanic) 
• Region (North America, East Europe, West Europe, and Latin America) 
• Body mass index (BMI) (≤ 30.0 kg/m2, > 30.0 kg/m2) 
• Baseline steroid use (Yes, No) 


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• Baseline clinical status based on 9-point scale (3, 4, 5) 
• Baseline hypertension (Yes, No) 
• Baseline diabetes (Yes, No) 
 
 
• Time between onset of COVID-19 symptoms and randomization (≤ 10, > 10 days) 
Baseline steroid use is defined as usage between onset of symptoms and randomization 
(inclusive). Baseline hypertension/diabetes is defined as “Yes” if patients have the comorbidity 
ongoing at randomization. 
In addition to the primary endpoint, subgroups of patients with different baseline clinical status 
based on 9-point scale (3, 4, 5) will be evaluated for the following endpoints: 
• Mortality by Day 29 
 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
No inferential testing on the differences in patient disposition, demographics and other baseline 
characteristics between treatment arms will be performed. 
2.3.1 
Patient disposition 
The RAS will be used for the summary and listing of patient disposition. The screening 
disposition and the analysis sets table will be based on all screened patients. 
The number of patients in the RAS will be summarized by region, country, center and treatment 
group. Further, the overall number of patients who entered, completed, and discontinued study 
will be summarized including the reasons for discontinuation for each period: pre-
randomization, and double-blind treatment. Patients who permanently discontinued from the 
planned treatment phase will be listed including reason and date of discontinuation. 
Number of patients with protocol deviations will be tabulated by category (e.g., selection 
criteria not met, subject not withdrawn as per protocol, treatment deviation, prohibited 
concomitant medication, other) and deviation. 
The number of patients included in each analysis set will be tabulated. Patients exclusion from 
analysis sets will be listed for all patients with reasons for exclusion (i.e. including both protocol 
and non-protocol deviations). 
2.3.2 
Patient demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the RAS. 
Demographic characteristics, including age, gender, race, ethnicity, country, height, weight, and 
BMI will be summarized by treatment and overall. 
Baseline disease characteristics, including number of days between onset of symptoms and 
randomization, number of days between diagnosis and randomization, clinical status based on 


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the 9-category ordinal scale, SpO2/FiO2, pneumonia (Yes, No), remdesivir use (Yes, No), and 
steroid use (Yes, No) will be summarized. 
Categorical data will be presented as frequencies and percentages including a categroy for 
missing data if any. For continuous data, mean, standard deviation, median, minimum, and 
maximum will be presented. For selected parameters, 25th and 75th percentiles will also be 
presented. 
No statistical analyses will be provided for baseline comparability between the treatment groups. 
In addition, the following categorizations of continuous variables will be done: 
• Age into < 18, 18 - < 65 years, and ≥ 65 years; 
• BMI into ≤ 30.0 kg/m2 and > 30.0 kg/m2. 
2.3.3 
Medical history/current medical condition 
Medical history and current medical conditions will be coded with the Medical Dictionary for 
Regulatory Activities terminology (MedDRA) using the most recent version at the time of 
database lock. History/conditions, including pre-specified protocol solicited events, will be 
summarized for the RAS by primary system organ class and preferred term. In addition, the 
pre-specified protocol solicited events will be summarized be pre-specified medical history 
term. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
All summaries of treatments will be performed on the Safety Set. 
2.4.1 
Study treatment / compliance 
The duration of exposure in days to ruxolitinib and standard of care therapies will be 
summarized by means of descriptive statistics. The categorized duration of exposure (≤ 7 
days, 8 - ≤ 15 days, 16 - ≤ 21 days, 22 - ≤ 28 days, ≥ 29 days) will also be summarized by 
treatment group. 
Duration of exposure to double-blind treatment will be calculated as the number of days 
between the first dose date and the last dose date exposed to that treatment over the specified 
period (expressed as: Duration of exposure = Date of last known dose of double-blind treatment 
– Date of first dose of double-blind treatment + 1). 
The number of patients who permanently discontinued from double-blind treatment and the 
reasons will be summarized by treatment group. 
The number of patients who had any dose modifications/interruptions and the reasons will be 
summarized by treatment. 
2.4.2 
Prior, concomitant and post therapies 
Summaries will be performed separately for medications prior to screening (medications 
starting and ending prior to screening), for concomitant medications (medications which were 
taken anytime between the first dose and last dose of randomized treatment, inclusive), and for 


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concomitant medications related to study indication. These medications will be listed and 
summarized according to the Anatomical Therapeutic Chemical (ATC) classification system 
and PT by treatment group. More than one ATC class per medication is possible and the 
medication will be reported under all applicable classes. Patients taking any of the tocilizumab, 
canakinumab, sarilumab or anakinra will also be summarized.  
Patients taking prohibited concomitant medications will be noted in the summary of protocol 
deviations. 
Surgical and medical procedures (non-drug therapies) will be listed and summarized by primary 
system organ class (SOC) and PT by treatment group, separately for prior and concomitant 
procedures. 
2.5 
Analysis of the primary objective 
The primary objective of the study is to evaluate the efficacy, as measured by a composite 
endpoint of proportion of patients who die, develop respiratory failure (require mechanical 
ventilation), or require intensive care unit (ICU) care, of ruxolitinib + standard-of-care (SoC) 
therapy compared with placebo + SoC therapy, for the treatment of COVID-19 by Day 29. The 
primary analysis for this study will be conducted using the treatment policy strategy. 
2.5.1 
Primary endpoint 
The primary clinical question of interest is: Does ruxolitinib + SoC decrease the probability of 
meeting the primary composite endpoint (death, respiratory failure (require mechanical 
ventilation), or ICU care by Day 29) compared with placebo + SoC in patients with COVID-
19-induced pneumonia, regardless of other subsequent clinical interventions? 
The justification for this primary estimand is that it captures the clinical outcome of most 
interest after the assignment of double-blind treamtent, which reflects also any effects of 
additional subsequent interventions potentially due to such clinical decision. In the ongoing 
COVID-19 pandemic with evolving treatment guidelines and healthcare system burdens, this 
primary estimand is deemed better to reflect actual clinical practices. 
The estimand framework for the primary objective is defined as below. 
• Treatment – ruxolitinib or placebo added to SoC therapy 
• Population – Hospitalized patients with coronavirus (SARS-CoV)-2 infection confirmed 
by polymerase chain reaction (PCR) test or another rapid test from the respiratory tract 
prior to randomization as described in Section 5.1 of the protocol. 
• Endpoint – Primary efficacy endpoint is defined as the proportion of patients who died, 
developed respiratory failure (require mechanical ventilation – defined as in Table 5-1), or 
required ICU care over 1-29 days 
• Population-level summary – Odds-ratio comparing ruxolitinib added to SoC therapy to 
placebo added to SoC therapy. 
• Intercurrent event – Discontinuation of study treatment; the handling of the event is 
discussed in Section 2.5.3. 


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2.5.2 
Statistical hypothesis, model, and method of analysis 
The statistical hypothesis tested for the primary endpoint is that there is no difference in the 
proportion of subjects meeting the composite primary endpoint by Day 29 with ruxolitinib + 
SoC versus placebo + SoC therapy. 
Let pi denote the proportion of patients meeting the primary endpoint for treatment groups j, j = 
0, 1 where 
• 0 corresponds to placebo + SoC 
• 1 corresponds to ruxolitinib + SoC 
The following statistical hypothesis will be tested to address the primary objective: 
H0: p0 = p1, H1: p0 ≠ p1. 
The odds of meeting the primary endpoint will be analyzed by a logistic regression model with 
treatment group, region, baseline clinical status based on the 9-point ordinal scale (≤ 3, ≥ 4), 
age, and gender as covariates. The estimated odds ratio, p-values, and 95% confidence intervals 
will be presented. 
The study will be considered positive, if ruxolitinib demonstrates a statistically significant 
greater reduction in the proportion of patients who die, develop respiratory failure (require 
mechanical ventilation), or ICU care by Day 29. This implies observing an odds ratio of < 1. 
In case of separability (often occurs when the event is rare), Firth’s penalized maximum 
likelihood estimation will be performed to reduce bias in the parameter estimates (Heinze and 
Schemper 2002; Firth 1993). The estimated odds ratio, p-values and 95% CI (all computed by 
penalized profile likelihood) will be presented. 
The numbers and percentages of patients who met the primary composite endpoint will be 
summarized by treatment groups. 
Mis-randomized patients who had developed respiratory failure and/or required ICU care at 
randomization (thus meeting the exclusion criteria) are excluded from the analysis. 
2.5.3 
Handling of missing values/censoring/discontinuations 
If there is any missing data over 1-29 days, the patient will be considered as meeting the primary 
composite endpoint, unless they are in one of the scenarios below: 
• There was no occurrence of death, respiratory failure (require mechanical ventilation), nor 
ICU care in all the available data and patients were discharged from the hospital. 
• The last available observed data is from Day 15 or later, and there was no occurrence of 
death, respiratory failure (require mechanical ventilation), nor ICU care in all the available 
data. 
2.5.4 
Supportive analyses 
Sensitivity analysis 
In order to determine the robustness of the logistic regression model used for the primary 
analysis, a non-parametric regression model (Koch et al 1998) will also be evaluated using the 


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same covariates as the logistic regression model in the primary analysis. This methodology has 
minimal assumptions and the estimated odds ratio, p-values, and 95% confidence intervals will 
be presented. 
A tipping point analysis will be implemented to test the robustness of the primary analysis 
results to different missing data mechanism. Specifically, all possible combinations of the 
missing values in the primary endpoint in the ruxolitinib + SoC group and the placebo + SoC 
group will be varied (responder/non-responder) to see if there is any tipping point. For each 
combination, the contingency table of treatment * response will be tested using a one-sided Z-
test. 
The between group difference in the primary endpoint will also be assessed by risk difference 
using the marginal standardization method, for which the risk difference will be derived from 
the predicted risks for every patient as if they had received the ruxolitinib + SoC or the placebo 
+ SoC using a logistic regression model (Ge et al 2011). The model will include the same 
covariates as in the primary analysis. The estimated treatment group-specific risks, risk 
difference, p-value, and 95% CI will be presented. 
The primary analysis will be repeated, excluding patients who were randomized but received 
no double-blind treatment. 
The primary analysis will be repeated, including mis-randomized patients who had developed 
respiratory failure and/or required ICU care at randomization. 
Details are provided in Section 5.4.1. 
Supplementary analysis 
To assess the effect of classifying patients’ primary endpoint with missing data, a multiple 
imputation based analysis will be conducted. 
This analysis quantifies the treatment effect in all randomized patients with an adherence to 
treatment like we would see in clinical practice. The binary outcome of the primary endpoint 
will be imputed for patients whose value could not be derived (for patients with missing data 
who died, or developed respiratory failure (required mechanical ventilation) or had ICU care at 
any time during the 29 days, their primary endpoint is derivable and will be considered as 
meeting the primary composite endpoint). 
• Missing data in the ruxolitinib + SoC arm will be multiply imputed based on placebo + 
SoC arm data using jump-to-reference (J2R) assumption. 
• Missing data in the placebo + SoC arm will be multiply imputed based on the missing at 
random (MAR) assumption. 
Results will be presented similarly to those of primary analyses. 
Details are provided in Section 5.4.1. 
Supportive analyses 
The primary analysis will be repeated for Day 15. The proportion of patients who died, 
developed respiratory failure, or received ICU care by Day 15 will be analyzed with the same 
logistic regression model as for the primary endpoint. 


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The primary analysis will be repeated for each and combinations of the three events in the 
composite endpoint: death, respiratory failure (requires mechanical ventilation), ICU care, 
respiratory failure (or death), and ICU care (or death). Separate logistic regression models will 
be fit to compare the odds between treatment groups for each of the endpoints. Missing data 
will be handled similarly as outlined for the primary analysis. The estimated odds ratios, p-
values, and 95% CIs will be presented. The analyses will be performed for up to Day 15 and 
Day 29 respectively. The between group difference in these endpoints will also be assessed by 
risk difference using the marginal standardization method (Ge et al 2011). 
The subgroup analyses (subgroups defined in Section 2.2.1) will be explored for the primary 
estimand and the same logistic regression model as described for the primary analysis with the 
additional term of subgroup factor (if not already included in the model) and the interaction 
term of subgroup and treatment. In case of analyses on subgroups with extremely imbalanced 
sample sizes, the subgroup levels can be combined, if appropriate, while fitting the analysis 
model, or Firth’s penalized maximum likelihood estimation will be performed. The point 
estimate and 95% CI for odds ratio for each subgroup will be presented using forest plots.  
2.6 
Analysis of the key secondary objective 
There is no key secondary objective defined in the protocol. 
2.7 
Analysis of secondary efficacy objectives 
2.7.1 
Secondary endpoints 
No multiplicity adjustment will be carried out for secondary analyses described below. 
All analysis of secondary endpoints will be performed on the RAS. 
2.7.1.1 
9-category ordinal scale 
The clinical status of the patient is assessed using a 9-category ordinal scale (WHO 18-Feb-
2020). The scale is as follows: 
 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence of infection 
0 
Ambulatory (defined 
as not in hospital or in 
hospital and ready for 
discharge) 
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 – pressors, RRT 
(renal replacement therapy), ECMO (extracorporeal 
membrane oxygenation) 
7 


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Dead 
Death 
8 
The baseline value is defined as the last assessment of clinical status prior to first dose of double-
blind treatment. If missing, the baseline value will be assumed to be missing at random as 
assessments are performed prior to any knowledge of treatment allocation and will be imputed 
using the median value of all patients with non-missing baseline values in the RAS. 
Descriptive statistics 
Summary statistics (mean, median, standard deviation, q1, q3, min, max, frequencies and 
percentages in each category) of clinical status at baseline, Day 15, and Day 29 as well as change 
from baseline at Day 15 and Day 29 will be summarized by treatment arm. 
The mean clinical status on a daily basis over 29 days will be plotted by treatment arm with the 
95% confidence interval. A stacked bar chart will also be plotted to display the distribution of 
clinical status on a daily basis over 29 days. 
No imputation will be done for missing data. 
Inferential statistics for the clinical status 
The odds of observing a better category (lower number) of clinical status at Day 15 will be 
analyzed with a proportional odds model (POM). The odds ratio for treatment group (ruxolitinib 
+ SoC therapy vs. placebo + SoC therapy) 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 (e.g. the cutoff of level 5 ‘Non-invasive ventilation or high-
flow oxygen’ will combine levels 0, 1, 2, 3, and 4 versus combined levels 5, 6, 7 and 8). The 
assumption of POM is that the effect of treatment is identical across all possible cutoff points 
of the ordinal outcome. The proportional odds assumption will be checked by a score test. The 
model will include treatment group, region, age, gender, and baseline clinical status (≤ 3, ≥ 4) 
as covariates. The estimated odds ratios, p-values and 95% confidence intervals will be 
presented. The analysis will be repeated for the data at Day 29. 
Missing data at Day 15/29 will not be imputed and thus will be excluded from the analysis. 
Change from baseline in clinical status 
Responder analysis 
The treatment groups will also be compared in terms of at least a one-point improvement, at 
least a two-point improvement, and at least a one-point deterioration in clinical status at Days 
15 and 29 using respective logistic regression models with the same covariates as for the POM. 
The estimated odds ratios, p-values, and 95% CIs will be presented. 
If a patient has missing data at Day 15/29, the patient will be treated as a non-responder in the 
respective analysis. 
Change from baseline 
Mean change from baseline in the clinical status on the 9-point ordinal scale to Days 15 and 29 
will be analyzed using an analysis of covariance (ANCOVA) model with factors for treatment 


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group, age, gender, and region, as well as the baseline clinical status as a continuous linear 
covariate. The estimated treatment differences, p-values, and 95% CIs will be presented. 
Missing data at Day 15/29 will not be imputed and thus will be excluded from the analysis. 
Time to improvement from baseline category 
Time to improvement from baseline category to one less severe category of the ordinal scale 
will be analyzed using a competing risk analysis framework where death will be treated as a 
competing risk. Specifically, a proportional hazards model for the subdistribution  
(Fine and Gray 1999) of time to improvement will be performed. Same covariates will be used 
as for the primary analysis. Patients who did not achieve improvement and did not die will be 
censored at their last clinical status assessment date. The estimated hazard ratios, p-values, and 
and 95% CIs wil be presented. The cumulative incidence functions of improvement and death 
over study days will be plotted by treatment. 
In addition, the median time to improvement by treatment as well as the 95% CI will be 
estimated using the Kaplan-Meier approach, while dead patients will be censored at the 
maximum follow-up time in the study. 
2.7.1.2 
Oxygen saturation 
The proportion of patients with no oxygen therapy (defined as having a clinical status score of 
0, 1, 2, or 3, or oxygen saturation ≥ 94% when measured on room air) at Days 15 and 29 will 
be analyzed using logistic regression models with the same covariates as for the primary 
analyses, with baseline SpO2/FiO2 added. The estimated odds ratios, p-values, and 95% CIs 
will be presented. 
Missing data at Day 15/29 will not be imputed and thus will be excluded from the analysis. 
2.7.1.3 
In-hospital outcomes 
Duration of hospitalization (time to hospital discharge) will be analyzed using a competing risk 
analysis framework (death will be treated as a competing risk). Specifically, a proportional 
hazards model for the subdistribution (Fine and Gray 1999) of time to hospital discharge will 
be performed. Same covariates will be used as for the primary analysis. Patients who were not 
discharged and did not die will be censored at their last assessment date. The estimated hazard 
ratios, p-values, and and 95% CIs wil be presented. The cumulative incidence functions of 
hospital discharge and death over study days will be plotted by treatment. 
In addition, the median time to hospital discharge by treatment as well as the 95% CI will be 
estimated using the Kaplan-Meier approach, while dead patients will be censored at the 
maximum follow-up time in the study. 
The analyses of mortality rates at Day 15 and at Day 29, and proportion of patients requiring 
mechanical ventilation by Day 29 are described in Section 2.5.4. 
The subgroups of patients with different baseline clinical status will be evaluated for mortality 
using a similar logistic regression model as described for the primary analysis, replacing the 
baseline clinical status (≤ 3, ≥ 4) by baseline clinical status as a categorical variable, and adding 


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the interaction term of baseline clinical status and treatment. The point estimate and 95% CI for 
odds ratio for each subgroup will be summarized. 
2.7.1.4 
National Early Warning Score (NEWS2) 
Time to discharge or to a National Early Warning Score (NEWS2) of ≤ 2 and maintained for 
24 hours (whichever comes first; maintained for 24 hours is defined as score being ≤ 2 for two 
days in a row as the score is collected once per day) will be analyzed using a competing risk 
analysis framework (death will be a competing risk). A proportional hazards model for the 
subdistribution will be performed. Patients who did not achieve discharge, nor had a NEWS2 
of <= 2 maintanied for 24 hours, nor died will be censored at their last assessment date. The 
estimated hazard ratios, p-values, and and 95% CIs wil be presented. The cumulative incidence 
functions will be plotted by treatment by competing risks. The model will include the same 
covariates as in the primary analysis, with baseline NEWS2 score added. 
In addition, the median time to hospital discharge or to a NEWS2 of ≤ 2 and maintained for 24 
hours by treatment as well as the 95% CI will be estimated using the Kaplan-Meier approach, 
while dead patients will be censored at the maximum follow-up time in the study. 
Summary statistics of change from baseline to Days 3, 5, 8, 11, 15, and 29 in the NEWS2 will 
be provided by treatment. No missing data will be imputed. 
2.7.1.5 
SpO2/FiO2 ratio 
Summary statistics of change from baseline to Days 15 and 29 in SpO2/FiO2 ratio will be 
provided by treatment. In addition, the following categorization will be done: 
• Severity of acute respiratory distress syndrome (ARDS): normal: > 314; mild (235 - 
314); moderate: 150 - 234; severe: < 150 
2.8 
Safety analyses 
Safety summaries include only data from the treatment-emergent period with the exception of 
baseline data which will also be summarized where appropriate (e.g. change from baseline 
summaries). 
All safety analysis will be performed on the Safety Set. 
2.8.1 
Adverse events (AEs) 
Adverse events will be summarized by treatment group. 
The number (and percentage) of subjects with treatment-emergent adverse events, defined as 
events start after the first dose of double-blind medications or events present prior to start of 
double-blind treatment but increase in severity based on preferred term and up to last study visit, 
will be summarized in the following ways: 
• by treatment and preferred term (PT). 
• by treatment, SOC and PT. 


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• by treatment, SOC, PT and maximum severity (based on CTCAE grades, categorized as 
Grades 3-4, Grade 5, and All grades). For this summary an AE with missing CTCAE 
grade will be included in the ‘All grades’ column of the summary tables. 
Separate summaries by SOC and PT will be provided for: 
• AEs suspected to be study medication related 
• deaths 
• serious adverse events (SAEs) 
• AEs leading to treatment discontinuation 
• AEs leading to dose interruptions and/or adjustments 
Further SAEs will be summarized by PT. 
Unless otherwise specified, SOCs will be sorted alphabetically and, within each SOC, the PTs 
will be sorted in descending order of frequency in the ruxolitinib + SoC arm. A subject with 
multiple adverse events within a SOC or PT is only counted once towards the total of the SOC 
or PT. 
Listings will be provided for all AEs, SAEs, AEs leading to treatment discontinuation, and 
deaths. 
2.8.1.1 
AE reporting for CT.gov and EudraCT 
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
2% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.1.2 
Adverse events of special interest / grouping of AEs 
The number and percentage of patients who reported treatment-emergent adverse events of 
special interest (AESI) will be summarized by risk name, PT, maximum severity (based on 
CTCAE grades) and treatment group. 




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2.8.4.2 
Vital signs 
Summaries of vital signs data will include treatment-emergent measurements, which are 
defined as measurements taken post-baseline and up to the last study visit. 
Absolute values and change from baseline (where applicable) will be summarized for vital sign 
parameters (height, weight, temperature, pulse rate, systolic blood pressure, diastolic blood 
pressure, and respiratory rate) by treatment group, visit and time point including the minimum 
and maximum treatment-emergent value. 
The baseline value is the last value prior to first dose of double-blind treatment. 


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2.11 
Interim analysis 
No interim analysis is planned. A DMC at Novartis will be established to conduct periodic 
semi-blinded or unblinded safety reviews to monitor safety data. The DMC analysis does not 
inflate the Type I error for the primary efficacy hypothesis testing. Thus no adjustment for 
multiplicity is required. 
More details will be outlined in the DMC charter and a separate DMC SAP. 
3 
Sample size calculation 
Assuming a true treatment difference in proportion of patients meeting the primary composite 
endpoint of 15% for ruxolitinib added to SoC therapy compared to placebo added to SoC 
therapy, a sample size of approximately 402 participants provides at least 80% power that the 
primary analysis will be statistically significant at the two-sided 5% significance level. This 
holds for a variety of different assumptions with respect to the proportion of patients meeting 
the primary composite endpoint (Table 3-1). 
These sample size assumptions were evaluated in East Version 6.4. 
Table 3-1 
Sensitivity of sample size assumptions to different proportion of 
patients meeting the primary composite endpoint for level of 
significance alpha = 0.05 
Proportion of patients meeting 
the primary composite 
endpoint in placebo + SoC (%) 
Proportion of patients meeting 
the primary composite 
endpoint in ruxolitinib + SoC 
(%) 
Power (%) 
80 
65 
91 
70 
55 
85 
60 
45 
82 
50 
35 
82 
40 
25 
85 
30 
15 
91 




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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing/partial start date or end date of double-blind treatment will not be imputed. 
5.1.2 
AE date imputation 
Partial AE start and end dates will be imputed. If there is uncertainty whether an AE occurred 
treatment-emergent or not, imputation will be performed, such that AE will be considered as 
treatment-emergent. Rules for imputing AE end date or start date will be provided in 
Programming Dataset Specification (PDS) document in details. 
5.1.3 
Concomitant medication date imputation 
Rules for imputing the CM end date or start date will be provided in PDS document in details. 
5.2 
AEs coding/grading 
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events. 
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
CTCAE Grade 5 is not defined for laboratory values. 
5.4 
Statistical models 
5.4.1 
Primary analysis 
The null hypothesis for the primary analysis is that there is no difference in the proportion of 
patients meeting the primary composite endpoint between ruxolitinib + SoC and placebo + SoC 
treatment groups. The alternative hypothesis is that there is a difference between the two 
treatment groups. 
The null hypothesis will be tested using a logistic regression model with treatment, age, gender, 
region, and baseline clinical status based on the 9-point ordinal scale (≤ 3, ≥ 4) as covariates. 
The SAS procedure LOGISTIC will be used to conduct the analysis. 
The estimated odds ratio, associated two-sided 95% confidence interval, and two-sided p-value 
will be presented for treatment contrasts between ruxolitinib + SoC and placebo + SoC. 
In case of separability, Firth’s penalized maximum likelihood estimation will be performed. 
The SAS macro %fl (Heinze and Ploner 2004) will be used for performing the estimation. 


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• Sensitivity analysis of the primary endpoint 
Non-parametric analysis 
In order to determine the robustness of the logistic regression model used for the primary 
analysis, nonparameteric randomization-based analysis of covariance model (Koch et al 1998) 
will be evaluated using the same covariates as in the primary analaysis model. 
A SAS macro (%NParCov4) has been developed to facilitate the implementation of this analysis 
(Dmitrienko and Koch 2017). 
To test the treatment effect, the most appropriate variance matrix is the one that applies to the 
randomization distribution under the null hypothesis of no treatment differences: a first model 
will be obtained using this assumption (i.e. parameter HYPOTH = NULL). 
It is also of interest to obtain CI for the odds ratio. The most appropriate variance matrix in this 
case is the one that applies under the alternative: a second model will be obtained using this 
assumption (i.e. parameter HYPOTH = ALT). 
Risk difference based on the marginal standardization method 
The sensitivity analysis will assess the between group comparison based on the risk difference 
using the marginal standardization method. The estimated risk difference can be derived from 
a logistic regression model fit to the binary outcome variable with the same covariates as in the 
primary analysis model. The fitted logistic regression model is used to predict the response risk 
for every subject in the study as if they had received ruxolitinib + SoC or placebo + SoC, and 
the difference in risks between treatment groups is computed. The delta method is used to 
calculate a standard error for the difference.  
The method will be implemented using SAS macro (%margins) or the SAS macro provided in 
the paper by Ge et al 2011. 
• Multiple imputation for supplementary analysis 
For supplemental analysis the following imputation steps need to be performed for missing data. 
Missing data of the composite endpoint will be imputed using J2R assumption for the ruxolitinib 
+ SoC arm and MAR assumption for placebo arm. 
1. Impute missing data: 
Select all patients, impute missing values using the MI approach based on the logistic 
regression method for 100 time and obtain 100 imputed dataset. A pattern-mixture model 
approach (Ratitch and O’Kelly 2011) that uses a control-based pattern imputation will be 
implemented. That is, an imputation model for the missing observations in the ruxolitinib 
+ SoC group is constructed not from the observed data in the ruxolitinib + SoC group but 
rather from the observed data int the placebo + SoC group. This model is also the 
imputation model that is used to impute missing observations in the placebo + SoC group. 
The imputation model will include age, gender, region, BMI ((≤ 30.0 kg/m2, > 30.0 
kg/m2), and baseline clinical status (assessed by the 9-point ordinal scale) as predictors. If 
any of these predictors cause separability issues for the logistic regression, the levels of 
the predictors will be combined accordingly. 
This results in 100 imputed datasets. 


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2. The primary composite endpoint will be analyzed (by imputed dataset) using the final 
multiply-imputed dataset where all missing values are filled, using a logistic regression 
model with treatment, age, gender, region, and baseline clinical status (assessed by the 9-
point ordinal scale) as predictors. 
3. The results for the treatment effect from the 100 datasets will then be combined using 
Rubin’s rule. 
5.4.2 
Key secondary analysis 
There is no key secondary analysis defined in the protocol. 


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5.5 
Rule of exclusion criteria of analysis sets 
The following table provides the protocol deviations (PD) and other criteria leading to partial 
or complete exclusion from the analyses sets. 
 
Deviation ID 
Description of Deviation 
Deviations leading to exclusion from RAS and Safety set 
INCL01B 
Patient or guardian / health proxy did not sign informed consent 
5.6 
Type of pulmonary/ventilatory support 
Table 5-1 
Type of pulmonary/Ventilatory support based on the level of oxygen 
requirement from low to high 
Type of support 
Require supplemental 
oxygen 
Require (invasive) 
mechanical ventilation 
Low flow nasal oxygen 
Yes 
No 
High flow nasal oxygen 
Yes 
No 
Oxgen via face mask 
Yes 
No 
Non-invasive ventilation 
Yes 
No 
Mechanical ventilation 
Yes 
Yes 
Intubation 
Yes 
Yes 
Tracheostomy 
Yes 
Yes 
ECMO 
Yes 
Yes 


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6 
References 
Available upon request 
Cao, B, Wang, Y, Wen, W., et al A Trial of Lopinavir–Ritonavir in Adults Hospitalized with 
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Published 18-Mar-2020 and updated 20-Mar-2020. 
Dmitrienko, A. and Koch, G.G., (2017). Analysis of clinical trials using SAS: a practical 
guide. SAS Institute. 
Fine, J.P. and Gray, R.J., (1999). A proportional hazards model for the subdistribution of a 
competing risk. Journal of the American statistical association, 94(446), pp.496-509. 
Firth, D., 1993. Bias reduction of maximum likelihood estimates. Biometrika, 80(1), pp.27-
38. 
Ge, M., Durham, L.K., Meyer, R.D., Xie, W. and Thomas, N., 2011. Covariate-adjusted 
difference in proportions from clinical trials using logistic regression and weighted risk 
differences. Drug information journal: DIJ/Drug Information Association, 45(4), pp.481-493. 
Heinze, G. and Ploner, M., (2004). A SAS macro, S-PLUS library and R package to perform 
logistic regression without convergence problems. Medical University of Vienna, Vienna. 
Heinze, G. and Schemper, M., (2002). A solution to the problem of separation in logistic 
regression. Statistics in medicine, 21(16), pp.2409-2419. 
Kalbfleisch, J.D. and Prentice, R.L., (2011). The statistical analysis of failure time data (Vol. 
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Kaplan, E.L. and Meier, P., 1958. Nonparametric estimation from incomplete observations. 
Journal of the American statistical association, 53(282), pp.457-481. 
Koch, G.G., Tangen, C.M., Jung, J.W. and Amara I.A., (1998). Issues for covariance analysis 
of dichotomous and ordered categorical data from randomized clinical trials and non-
parametric strategies for addressing them. Statistics in Medicine, 17(15-16), pp.1863-1892. 
Little, R. and Yau, L., (1996). Intent-to-treat analysis for longitudinal studies with drop-outs. 
Biometrics, pp.1324-1333. 
Molenberghs, G. and Kenward, M., (2007). Missing data in clinical studies (Vol. 61). John 
Wiley & Sons. 
Ratitch, B. and O’Kelly, M., (2011). Implementation of pattern-mixture models using 
standard SAS/STAT procedures. Proceedings of PharmaSUG. 
WHO (2020). A Multi-center, Adaptive, Randomized Blinded Controlled Trial of the Safety 
and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 
WHO (18-Feb 2020). WHO R&D Blueprint. Novel coronavirus. COVID-19 Therapeutic 
Trial Synopsis (Dated 18-Feb-2020). 
Williams, B., Alberti, G., Ball, C., Ball, D., Binks, R. and Durham, L., (2012). Royal College 
of Physicians, National Early Warning Score (NEWS2), Standardising the assessment of 
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World Health Organization, (2020). Clinical management of severe acute respiratory infection 
when novel coronavirus (2019-nCoV) infection is suspected: interim guidance, 28 January 
2020 (No. WHO / nCoV / Clinical / 2020.3). World Health Organization.