Clinical trial NCT04382651
Conditions: COVID-19 Pneumonia, Impaired Respiratory Function
Keywords: COVID-19 pneumonia SARS-Cov2 APACHE II MAS825 inflammasome
Sponsor: Novartis Pharmaceuticals
Start date: 2020-06-11; Completion date: 2021-04-21
Enrollment: 140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This clinical study was designed to assess the efficacy and safety of MAS825 for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infected patients with coronavirus disease 2019 (COVID-19) pneumonia and impaired respiratory function.

Detailed description:
This was a Phase 2, randomized, placebo -controlled, participant and investigator blinded, multi-center study to assess efficacy and safety of MAS825 for the treatment of SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired respiratory function.

The study consisted of five study periods:

Screening / Baseline / Treatment visit (Day -1 to 1): Lasted up to a maximum of 24 hours and comprised a screening / baseline assessment. This visit was used to confirm that the study inclusion and exclusion criteria were met and served as baseline assessment prior to randomization. Participants were randomized as soon as possible, but within a maximum of 24 hours after screening in a 1:1 ratio receiving a single intravenous infusion of MAS825 or placebo in addition to standard of care (SoC) on Day -1 to 1.

Treatment period (Day 2-15): Study assessments were conducted every 2 days for hospitalized participants. If participants were discharged from the hospital prior to Day 15, assessments on the day of discharge were performed according to the schedule listed under Day 15 and those participants returned to the site for the Day 15 assessment (all other visits between discharge and Day 15 were omitted).

Follow-up (Day 16-29): After completion of the treatment period, participants were observed until Day 29 or discharged from hospital, whichever was sooner. Study assessments were conducted every 2 days for domiciled participants. If participants were discharged from hospital prior to Day 29, a study visit conducted by telephone was performed on Day 29 (all other visits between discharge and Day 29 were omitted).

Safety follow-up visit assessment (Day 45): A follow-up visit for safety was conducted at Day 45 if the participant was hospitalized. If participants were discharged from the hospital prior to Day 45, a study visit was conducted by telephone on Day 45.

End of Study/Safety follow-up visit assessment (Day 127): A follow-up visit for safety was conducted at Day 127 if the participant was hospitalized. If participants were discharged from the hospital prior to Day 127, a study visit was conducted by telephone on Day 127.

Arms: arm 1: Single dose of MAS825 10 mg/kg by intravenous infusion in addition to SoC arm 2: Single dose of matching Placebo by intravenous infusion in addition to SoC
Interventions: intervention 1: MAS825 intervention 2: Placebo intervention 3: Standard of Care (SoC)
Intervention descriptions: intervention 1: MAS825 liquid solution for intravenous infusion intervention 2: Placebo liquid solution for intravenous infusion intervention 3: SoC included a variety of supportive therapies that ranged from the administration of supplementary oxygen to full intensive care support, alongside the use of antiviral treatment, convalescent plasma, corticosteroids, antibiotics or other agents.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
MAS825
CMAS825F12201 / NCT04382651
A Phase 2, randomized, placebo-controlled, participant and 
investigator blinded, multi-center study to assess efficacy 
and safety of MAS825 for the treatment of SARS-CoV-2 
infected patients with COVID-19 pneumonia and impaired 
respiratory function
Document type:
Amended Protocol Version
EUDRACT number:
NA
Version number:
v01 (Clean)
Clinical Trial Phase:
II
Release date:
03-Jul-2020
Property of Novartis
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 ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................18
1
Introduction .......................................................................................................................23
1.1
Background............................................................................................................23
1.1.1
Rationale for targeting the inflammasome effector cytokines in 
patients with COVID-19 pneumonia and impaired respiratory 
function. ................................................................................................23
1.1.2
Excessive inflammasome activation by mechanical ventilation and 
ARDS....................................................................................................24
1.1.3
Translational evidence that IL1β and IL-18 are pivotal to lung 
pathology in COVID-19 patients ..........................................................25
1.1.4
Summary ...............................................................................................25
1.2
MAS825.................................................................................................................26
1.2.1
Nonclinical data ....................................................................................26
1.2.2
Clinical data ..........................................................................................26
1.3
Purpose ..................................................................................................................27
2
Objectives and endpoints...................................................................................................27
2.1
Primary estimands .................................................................................................29
2.2
Secondary estimands .............................................................................................29
3
Study design ......................................................................................................................29
4
Rationale............................................................................................................................31
4.1
Rationale for study design .....................................................................................31
4.2
Rationale for participant numbers and endpoint....................................................32
4.3
Rationale for choice of background therapy..........................................................32
4.4
Rationale for dose/regimen, duration of treatment and follow-up ........................33
4.5
Purpose and timing of interim analyses/design adaptations..................................35
4.6
Risks and benefits..................................................................................................35
4.6.1
Potential benefits and risks to study participants ..................................35
4.6.2
Potential risks to study participants.......................................................36
4.7
Overall risk benefit ................................................................................................38
4.8
Blood sample volume ............................................................................................38
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5
Study Population ...............................................................................................................38
5.1
Inclusion criteria ....................................................................................................38
5.2
Exclusion criteria...................................................................................................39
6
Treatment...........................................................................................................................40
6.1
Study treatment......................................................................................................40
6.1.1
Investigational and control drugs..........................................................40
6.1.2
Additional study treatments ..................................................................41
6.1.3
Treatment arms/group ...........................................................................41
6.2
Other treatment(s)..................................................................................................41
6.2.1
Concomitant therapy.............................................................................41
6.3
Participant numbering, treatment assignment, randomization ..............................42
6.3.1
Participant numbering...........................................................................42
6.3.2
Treatment assignment, randomization ..................................................42
6.4
Treatment blinding.................................................................................................43
6.5
Dose escalation and dose modification..................................................................45
6.6
Additional treatment guidance...............................................................................45
6.6.1
Treatment compliance...........................................................................45
6.6.2
Recommended treatment of adverse events..........................................46
6.6.3
Emergency breaking of assigned treatment code..................................47
6.7
Preparation and dispensation.................................................................................47
6.7.1
Handling of study treatment and additional treatment..........................47
6.7.2
Instruction for prescribing and taking study treatment .........................48
7
Informed consent procedures ............................................................................................48
8
Visit schedule and assessments .........................................................................................50
8.1
Screening ...............................................................................................................53
8.1.1
Information to be collected on screening failures.................................53
8.2
Participant demographics/other baseline characteristics .......................................53
8.2.1
Demographic information.....................................................................53
8.2.2
Prior and concomitant medications.......................................................54
8.3
Efficacy..................................................................................................................54
8.3.1
Vital signs and oxygen saturation and use ............................................54
8.3.2
APACHE II severity of disease score...................................................54
8.3.3
Clinical status (9-point ordinal scale) ...................................................55
8.3.4
CRP and Ferritin ...................................................................................55
8.3.5
Appropriateness of efficacy assessments..............................................55
8.4
Safety.....................................................................................................................56


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8.4.1
Laboratory evaluations..........................................................................56
8.4.2
Physical examination ............................................................................57
8.4.3
Height and weight .................................................................................57
8.4.4
Electrocardiogram (ECG) .....................................................................57
8.4.5
Pregnancy and assessments of fertility .................................................58
8.4.6
Other safety evaluations........................................................................58
8.4.7
Appropriateness of safety measurements..............................................58
8.5
Additional assessments..........................................................................................59
9
Study discontinuation and completion ..............................................................................61
9.1
Discontinuation and completion............................................................................61
9.1.1
Study treatment discontinuation and study discontinuation..................61
9.1.2
Withdrawal of informed consent...........................................................62
9.1.3
Lost to follow-up...................................................................................63
9.1.4
Study stopping rules..............................................................................63
9.1.5
Early study termination by the sponsor.................................................63
9.2
Study completion and post-study treatment ..........................................................64
10 Safety monitoring and reporting........................................................................................64
10.1
Definition of adverse events and reporting requirements......................................64
10.1.1
Adverse events ......................................................................................64
10.1.2
Serious Adverse Events.........................................................................66
10.1.3
SAE reporting........................................................................................67
10.1.4
Pregnancy reporting ..............................................................................67
10.1.5
Reporting of study treatment errors including misuse/abuse................68
10.2
Additional safety monitoring.................................................................................68
10.2.1
Liver safety monitoring.........................................................................68
10.2.2
Data Monitoring Committee .................................................................69
11 Data Collection and Database management......................................................................69
11.1
Data collection.......................................................................................................69
11.2
Database management and quality control............................................................69
11.3
Site monitoring ......................................................................................................70
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12 Data analysis and statistical methods ................................................................................71
12.1
Analysis sets ..........................................................................................................71
12.2
Participant demographics and other baseline characteristics.................................71
12.3
Treatments .............................................................................................................71
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................72
12.4.1
Definition of primary endpoint(s)/estimand(s) .....................................72
12.4.2
Statistical model, hypothesis, and method of analysis..........................72
12.4.3
Handling of remaining intercurrent events of primary estimand..........72
12.4.4
Handling of missing values not related to intercurrent event ...............72
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................72
12.4.6
Supplementary analysis.........................................................................72
12.4.7
Supportive analyses...............................................................................72
12.5
Analysis of secondary endpoints/estimands..........................................................72
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................72
12.5.2
Safety endpoints....................................................................................73
12.6
Analysis of exploratory endpoints.........................................................................74
12.9
Sample size calculation..........................................................................................75
12.9.1
Primary endpoint(s)...............................................................................75
12.9.2
Secondary endpoint(s)...........................................................................75
13 Ethical considerations and administrative procedures ......................................................75
13.1
Regulatory and ethical compliance........................................................................75
13.2
Responsibilities of the investigator and IRB/IEC..................................................76
13.3
Publication of study protocol and results...............................................................76
13.4
Quality Control and Quality Assurance.................................................................76
14 Protocol adherence ............................................................................................................77
14.1
Protocol amendments.............................................................................................77
15 References .........................................................................................................................78
16 Appendices ........................................................................................................................82
16.1
Appendix 1: Anaphylaxis ......................................................................................82
16.2
Appendix 2: 9-point ordinal scale determination ..................................................83
16.3
Appendix 3: Liver event and laboratory trigger definitions & follow-up 
requirements ..........................................................................................................84
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16.4
Appendix 4: ICU scores.........................................................................................86
16.5
Appendix 5: Severity of hepatic impairment (Child-Pugh)...................................91
List of tables
Table 2-1
Objectives and related endpoints ..........................................................27
Table 6-1
Investigational and control drug............................................................40
Table 6-2
Blinding and unblinding plan................................................................45
Table 6-3
Dose and treatment schedule.................................................................48
Table 8-1
Assessment schedule.............................................................................50
Table 8-2
Clinical laboratory tests (local).............................................................57
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................68
Table 16-1
Liver event and laboratory trigger definitions ......................................84
Table 16-2
Follow up requirements for liver laboratory triggers............................85
Table 16-3
APACHE II...........................................................................................86
Table 16-4
Estimating PaO2 from a given SpO2 .....................................................87
Table 16-5
Estimating FiO2.....................................................................................88
Table 16-8
GLASGOW COMA SCORE................................................................90
List of figures
Figure 3-1
Study design..........................................................................................30
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List of abbreviations
AE
Adverse Event
AIDS
Acquired immune deficiency syndrome
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AKI
Acute Kidney Injury
ANCOVA
Analysis of covariance
APACHE II
Acute Physiology and Chronic Health Evaluation II
APTT
Activated Partial Thromboplastin Time
ARDS
Acute Respiratory Distress Syndrome
AST
Aspartate Aminotransferase
ATC
Anatomic Therapeutic Classification
AUC
Area Under the Curve
BLRM
Bayesian Logistic Regression Model
BMI
Body Mass Index
BNP
Brain Natriuretic Peptide
bpm
Beats per minute
BUN
Blood Urea Nitrogen
CIs
Confidence Intervals
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMO&PS 
Chief Medical Office and Patient Safety
COVID-19
Coronavirus Disease 2019
CPAP
Continuous positive airway pressure
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSR
Clinical study report
CT scan
Computed Tomography Scan
CTC
Common Terminology Criteria
CV
coefficient of variation
CVD
Cardiovascular Disease
DBP
Diastolic Blood Pressure
dL
deciliter
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DQF
Data Query Form
DMC
Data Monitoring Committee
eATP
Extracellular adenosine triphosphate 
ECG
Electrocardiogram
ECMO
Extracorporeal membrane oxygenation 


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eCRF
Electronic Case Report Forms
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
EOI
End of Infusion
eSAE
Electronic Serious Adverse Event
FAS
Full Analysis Set 
FIH
First-in-human 
FiO2
Fraction of inspired oxygen
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GFR
Glomerular Filtration Rate
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice
h
Hour
HA
Health Authority
HDL
High Density Lipoprotein
HBsAg
Hepatitis B surface antigen
HV(s)
Healthy Volunteers
i.v.
intravenous
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 Committeee
IFN-g
Interferon Gamma
IL 1β
Interleukin 1 beta
IMM
Inflammatory monocyte macrophage
IN
Investigator Notification
INR
International Normalized Ratio
IP-10/CXCL10
Interferon gamma-induced protein 10 / C-X-C motif chemokine 10
IRB
Institutional Review Board
IRT
Interactive Response Technology
kg
kilogram
LDH
lactate dehydrogenase
LDL
Low density lipoprotein
LFT
Liver function test 
LLN
lower limit of normal
m
Meter
M2
Squared meter
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MedDRA
Medical dictionary for regulatory activities 
min
minute
mg
milligram(s)
mL
milliliter(s)
mm3
Cubic millimeter
mmHg
Millimeters Mercury
MR scan
Magnetic Resonance Scan
Nab
Neutralizing antibody
NK cells
Natural Killer cells
pM
picomolar
PA
posteroanterior
PaO2
Partial Pressures of Oxygen
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic(s)
PEF
Peak Expiratory Flow
PerfO
Performance Outcomes
PoC
Proof of Concept
PoM
Proof of Mechanism
PPD
Premature Participant Discontinuation
PPT
Partial Prothrombin time
PR
Pulse Rate
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RBC
red blood cell(s)
RRT
Renal Replacement Therapy
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic Blood Pressure
sCR
serum creatinine
SD
standard deviation
SMQ
Standardized MedDRA Query
SoC
Standard of Care
SpO2
Peripheral oxygen saturation
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total Bilirubin
TD
Study Treatment Discontinuation
TLR
Toll Like Receptors
TNF alpha
Tumor Necrosis Factor alpha
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ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization 
WoC
Withdrawal of Consent
WOCBP
Women of Child Bearing Potential
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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
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days)
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 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and other 
oversight authorities, as appropriate
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.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
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 
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Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a 
multiple dose part, or a part in participants with established disease and in those 
with newly-diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient)
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) 
which 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
Run-in Failure
A participant who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to participant’s intervention or other 
treatment)
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 
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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 
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Protocol summary
Protocol number
CMAS825F12201
Full Title
A Phase 2, randomized, placebo-controlled, participant and investigator 
blinded, multi-center study to assess efficacy and safety of MAS825 for the 
treatment of SARS-CoV-2 infected patients with COVID-19 pneumonia and 
impaired respiratory function
Brief title
Study of efficacy and safety of MAS825 in patients with COVID-19
Sponsor and 
Clinical Phase
Novartis
Phase II  
Investigation type
Drug 
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the efficacy and safety of MAS825 
in addition to current standard of care (SoC) compared with placebo and SoC 
in controlling the inflammatory syndrome and resultant acute respiratory 
distress syndrome (ARDS) in hospitalized patients presenting with COVID-
19 pneumonia and impaired respiratory function.
Severe COVID-19 patients develop ARDS due to a hyperinflammatory 
syndrome that is characterized by pro-inflammatory cytokine release and cell 
death, resulting in severe pulmonary damage and dysfunction requiring 
mechanical ventilation. Specifically, patients with severe COVID-19 and 
respiratory failure have grossly elevated levels of IL-1β and its downstream 
cytokine IL-6, as well as IFN-g and IP-10 (CXCL10), both downstream 
markers of IL-18 pathway activation. MAS825 is expected to neutralize all 
inflammasome-dependent and independent-sources of IL-1β and IL-18 to 
arrest the autoinflammatory response, limiting further alveolar damage and 
improving clinical outcomes. 
Primary Objective(s) 
To evaluate the effect of MAS825, compared with placebo, on the Acute 
Physiology and Chronic Health Evaluation II (APACHE II) score
Secondary 
Objectives
The secondary objectives of this study are:

To evaluate the effect of MAS825, compared with placebo, on
inflammatory status

To evaluate the effect of MAS825, compared with placebo, on clinical
status

To evaluate the safety of MAS825, compared with placebo
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Study design
This is a Phase 2, randomized, placebo -controlled, participant and 
investigator blinded, multi-center study to assess efficacy and safety of 
MAS825 for the treatment of SARS-CoV-2 infected patients with COVID-19 
pneumonia and impaired respiratory function.
The study consists of five parts:
1.
Screening / Baseline / Treatment (Day -1 to 1): lasts up to a maximum
of 24 hours and comprises a screening / baseline assessment. This visit
will be used to confirm that the study inclusion and exclusion criteria are
met and serves as baseline assessment prior to randomization. Baseline
blood tests will be performed in all patients; those who screen fail
because of study inclusion / exclusion criteria (e.g., serum CRP, liver
function tests), will not undergo randomization. Eligible patients will
receive a single i.v. infusion of 
 MAS825 or placebo on Day -1
to 1.
2.
Treatment period (Day 2-15): Study assessments to be conducted
every 2 days for hospitalized patients. If patients are discharged from the
hospital prior to Day 15, assessments on the day of discharge should be
performed according to the schedule listed under Day 15 and patient
should return to the site for the Day 15 assessment (all other visits
between discharge and Day 15 can be omitted). If hospital visit is not
possible at Day 15, then home nursing services may be used to support
this last visit where these are available in accordance with local
guidelines and should include all possible assessments (e.g. oxygen
saturation with portable monitors). In case home nursing is not possible,
patients will be contacted by phone on day 15.
3.
Follow-up (Day 16-29): After completion of the treatment period,
patients will be observed until Day 29 or discharged from hospital,
whichever is sooner. Study assessments to be conducted every 2 days
for domiciled patients.
Where patients are discharged from hospital prior to Day 29, a study visit
conducted by telephone will occur on Day 29 (all other visits between
discharge and Day 29 can be omitted).
4.
Safety follow-up visit assessment (Day 45): A follow-up visit will be
conducted at Day 45 if the patient is hospitalized. If patients are
discharged from hospital prior to Day 45, a study visit will be conducted
by telephone on Day 45.
5.
End of Study/Safety follow-up visit assessment (Day 127): A follow-
up visit for safety will be conducted at Day 127 if the patient is
hospitalized. If patients are discharged from hospital prior to Day 127, a
study visit will be conducted by telephone on Day 127.
Study population
Approximately 120 male and female patients  aged 18 years and above .
The study population includes adult male and female SARS-CoV-2 infected 
patients who are hospitalized and diagnosed with COVID-19 pneumonia and 
impaired respiratory function.
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Key Inclusion 
criteria
Participants eligible for inclusion in this study must meet all of the following 
criteria:
1.
Male and female patients aged ≥18 years at screening
2.
Signed Informed Consent Form (ICF) by patient capable of giving 
consent, or, when the patient is not capable of giving consent, by his or 
her legal/authorized representative (if allowed according to local 
requirements) 
3.
Clinically diagnosed with the SARS-CoV-2 virus by polymerase chain 
reaction (PCR) or by other approved diagnostic methodology within 
7 days prior to randomization
4.
Hospitalized with COVID-19-induced pneumonia evidenced by chest x-
ray, computed tomography scan (CT scan) or magnetic resonance scan 
(MR scan) (taken within 5 days prior to randomization)
5.
Impaired respiratory function, defined as peripheral oxygen saturation 
(SpO2) ≤93% on room air or partial pressure of oxygen (PaO2) / fraction 
of inspired oxygen (FiO2) <300 millimeter of mercury (mmHg) at time of 
screening For cities located at altitudes greater than 2500 m above sea 
level, these will be substituted with SpO2 <90% and PaO2/FiO2 <250 
mmHg
6.
Acute Physiologic Assessment and Chronic Health Evaluation 
(APACHE) II score of ≥10 at time of screening 
7.
CRP ≥20 mg/L or ferritin level ≥600 μg/L at screening
8.
Body weight between 45 kg and 145 kg, inclusive, at screening
9.
Ability to comply with the study protocol, in the investigator's judgment
Key Exclusion 
criteria
1.
History of hypersensitivity to the investigational treatment or their 
excipients or to drugs of similar chemical classes
2.
Suspected active or chronic bacterial (including Mycobacterium 
tuberculosis), fungal, viral, or other infection with the exception of SARS-
CoV-2
3.
In the opinion of the investigator, progression to death is imminent and 
inevitable within the next 24 hours, irrespective of the provision of 
treatment
4.
Intubated prior to randomization
5.
Patients who have explicitly expressed the wish not to receive intensive 
care support when this would be indicated based on their condition
6.
Previous treatment with anti-rejection and immunomodulatory drugs 
within the past 2 weeks, or within the past 30 days or 5 half-lives 
(whichever is the longer) for immunomodulatory therapeutic antibodies 
or prohibited drugs (see Section 6.2.1.1, with the exception of anti-viral
therapies orcorticosteroids 

For COVID-19 infection, ongoing corticosteroid treatment is 
permitted at doses as per local SoC

For non-COVID-19 disorders, ongoing corticosteroid treatment is 
permitted at doses up to and including prednisolone 10 mg daily or 
equivalent (see Section 6.2.1 Concomitant therapy)
7.
Serum alanine transaminase (ALT) or aspartate transaminase 
(AST) >5 times upper limit of normal detected within 24 hours at 
screening/baseline (according to local laboratory reference ranges) or 
other evidence of severe hepatic impairment (Child-Pugh Class C, see 
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8.
Absolute peripheral blood neutrophil count of ≤1000/mm3
9.
Estimated GFR (eGFR) ≤30 mL/min/1.73m2 (based on CKD-EPI
formula)
10. Pregnant or breastfeeding, or positive urine or serum pregnancy test in
a pre-dose examination
11. Any serious medical condition or abnormality of clinical laboratory tests
that, in the investigator’s judgment, precludes the patient’s safe
participation in and completion of the study
12. Women of child-bearing potential, defined as all women physiologically
capable of becoming pregnant, unless they agree to abstain from any
sexual intercourse for a total of 29 days after randomization (the 14-day
treatment period plus a 14-day follow-up period).
13. Current participation in any other investigational trials, with the
exception of (not yet) approved COVID-19 therapies that are
considered (local) standard of care (also see Section 6.2.1.1. for
Prohibited drugs).
Study treatment
Patients will receive a single dose of MAS825 
 i.v. in addition to
Standard of Care, or placebo in addition to Standard of Care
Treatment of 
interest
The randomized treatment (the investigational treatment MAS825 in addition 
to SoC or control treatment of SoC alone)
Efficacy 
assessments

APACHE II severity of disease score on Day 15 or on day of discharge
(whichever is earlier) with worst case imputation for death

9-point ordinal scale (Appendix 2):

Survival without the need for invasive mechanical ventilation at
Days 15 and 29

At least one level improvement in clinical status at Days 15 and
29

Clinical status over time

Serum CRP levels and ferritin
Pharmacodynamic 
assessments 
The pharmacodynamic objective for this study is to characterize the 
pharmacodynamic effects of MAS825 in patients with COVID-19 pneumonia 
via 
longitudinal 
measures 
of a 
number 
of analytes 
relative 
to 
baseline including the following:

CRP, ferritin, LDH, absolute whole blood neutrophil count, D-dimer,
troponin
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Key safety 
assessments

Incidence and severity of adverse events / serious adverse events

Clinically significant changes in laboratory measures

Vital signs, electrocardiogram (ECG), height and weight

Physical examination

Chest X-ray (CXR), CT or MR scan
Other assessments 
Data analysis
The primary endpoint will be evaluated by an analysis of covariance model 
including treatment group and the three stratification factors (age, anti-viral 
therapy, and presence of ≥1 comorbidities) as factors and baseline 
APACHE-II score as a covariate.
For efficacy and pharmacodynamics endpoints, descriptive statistics (mean, 
standard deviation, median, minimum and maximum) will be provided for 
variables that are of the numeric or continuous type, while frequency 
distributions 
(with 
number 
and 
percent) 
will 
be 
provided 
for categorical variables.
All listings and tables will be presented by treatment group.
Key words
COVID-19, pneumonia, SARS-Cov2, APACHE II, MAS825, inflammasome
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1
Introduction
1.1
Background
As of April 16, 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 
has been confirmed in over 2 Million people worldwide, with over 137,000 deaths to date due 
to coronavirus disease 2019 (COVID-19). The mortality rate of approximately 4-5% is 
significantly higher than that seen with seasonal influenza (less than 1%) and between 5-10% 
of COVID-19 patients develop lung injury, respiratory distress progressing to acute respiratory 
distress syndrome (ARDS) requiring prolonged ventilator support over weeks that results in 
intensive care units, hospitals and health care systems becoming overwhelmed.
ARDS is characterized by pro-inflammatory cytokine release, inflammatory cellular infiltrate 
and cell death resulting in severe pulmonary damage and the development of respiratory failure 
that requires mechanical ventilation with high positive end-expiratory pressures (PEEP) to 
maintain life. In patients with a prior history of hypertension, diabetes and cardiovascular 
disease, poor outcomes have been reported that may be as result of poor underlying cardiac 
reserve meaning that patients develop cardiac failure in response to ventilation, with pulmonary 
edema further exacerbating respiratory failure (Zhou et al 2020).
Targeted treatment of the underlying hyper-inflammatory syndrome that occurs after initial 
SARS-CoV-2 infection in COVID-19 patients with respiratory failure has the potential to 
reduce the requirements for mechanical ventilation, the duration of mechanical ventilation and 
to improve the outcome for patients while also significantly reducing the demand on health care 
systems.
1.1.1
Rationale for targeting the inflammasome effector cytokines in 
patients with COVID-19 pneumonia and impaired respiratory function.
The innate immune system is the first line of defense against pathogens, including viruses. 
Pattern recognition receptors (PRR) are part of this system and are sensors for microbial 
structures. To safeguard the immune response, viruses can be sensed by many partially 
redundant, but also distinct classes of innate immune receptors, such as the nucleic-acid sensors, 
MDA-5 and RIG-I or members of inflammasome and Toll-like receptor (TLR) families. 
These sensors initiate a protective response that begins with the production of pro-inflammatory 
cytokines, such as type I interferons that restrict viral replication. In a subsequent wave of the 
host reaction to viruses, danger signals are released as tissues are damaged and cells are killed 
by the virus. The recognition of these danger signals by innate immune signaling receptors 
trigger further inflammatory responses (Horvath et al 2011, Franchi et al 2014). 
A key sensor for danger signals released from dying cells is the NLRP3 inflammasome, which, 
upon activation, leads to the production and release of active IL-1β and IL-18. At low levels 
during initial stages of the disease, these cytokines amplify the innate immune response against 
viruses and promote the development of adaptive immune responses against the viruses 
(Tate et al 2016), providing long-term protection and reducing the risk of re-infection 
(Ichinohe et al 2009). However, when tissue damage from the virus or immune response is 
extensive, NLRP3 activation and the subsequent IL-1β and IL-18 production can be excessive 


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and beyond what is required to support an adaptive response, contributing to morbidity and 
mortality.
The concerted actions of the inflammasome will lead to exacerbated edema by direct activation 
of endothelial cells, increased tissue damage through neutrophil reactive species, and excessive 
type II interferon through IL-18 on T cells and natural killer cells (NK cells), and elicit or 
exacerbate other broad pro-inflammatory pathways, including IL-6, IL-17 and tumor necrosis 
factor alpha (TNF(McAuley et al 2013, Ren et al 2017). Consistent with NLRP3 playing an 
underlying role in pulmonary pathology during viral infection, it has been shown in mice 
infected with influenza that inhibition of the NLRP3 inflammasome in the symptomatic phase 
of the infection reduces systemic inflammation as well as lung pathology without impairing 
viral clearance (Tate et al 2016, Coates et al 2017, Jia et al 2018).
Tissue damage may also result in NLRP3-independent release of IL-1β and IL-18 and the 
inactive pro-forms of these cytokines may be cleaved into the mature bio-active forms not only 
by caspase-1 but also by other proteases present in situ, such as neutrophil-derived elastases, 
mast cell derived chymases, and T cell- and NK cell-derived granzyme B (Afonina et al 2015). 
Particularly, IL-18 is already constitutively expressed in the airway epithelium and parenchyma 
of human bronchial biopsies and its expression is largely further increased under inflammatory 
conditions such as in pulmonary sarcoidosis (Cameron et al 1999). IL-18 may not only activate 
Type 1 and Type 2 helper T cells and cytotoxic T cells but has been reported to promote NK 
cell -mediated tissue damage. This was shown in the context of fulminant hepatitis A viral 
infection, in which inherited IL-18BP deficiency (the natural scavenger of bioactive IL-18) 
resulted in excessive NK cell activation by IL-18 and lead to the uncontrolled killing of human 
hepatocytes (Belkaya et al 2019). Together, IL-1β and IL-18 can trigger innate and adaptive 
immune responses at the same time leading to exacerbated inflammation (Vanden Berghe et al 2014).
1.1.2
Excessive inflammasome activation by mechanical ventilation and 
ARDS
In severe COVID-19, non-invasive and invasive mechanical ventilation is applied as a life
supporting therapy. Mechanical stretch especially in the inflamed and stressed tissue is leading 
to extracellular ATP (eATP) release. eATP is sensed by the purinergic receptor P2X7 leading 
to potent NLPR3 inflammasome activation (Eckle et al 2007, Matsuyama et al 2008, 
Kuipers et al 2012, Liu et al 2019, Lv et al 2018, Wu et al 2013, Hasan et al 2017, Liu et al 2019, 
Lv et al 2018, Wu et al 2013, Hasan et al 2017). This cascade of events further amplifies tissue 
inflammation and ARDS. In mice, IL-18 expression is increased in the lungs after 
intraperitoneal administration of lipopolysaccharide (LPS) or the occurrence of hemorrhage 
(reviewed in Kawayama et al 2012). Furthermore, a neutralizing anti-IL-18 antibody has been 
shown to reduce the lung inflammatory damage in a murine acute lung injury model (Abdel 
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1.1.3
Translational evidence that IL1β and IL-18 are pivotal to lung 
pathology in COVID-19 patients
Infections with highly pathogenic respiratory viruses, such as SARS-CoV-1 and SARS-CoV-2, 
initiate a cytokine burst that causes acute lung injury and ARDS. Patients manifest lung injury 
at the time during which viral load is actually falling, indicating that, in humans, significant 
damage to the lungs is likely mediated by an excessive immune response rather than direct viral 
cytopathic effects. 
One of the key cytokines driving inflammation in the bronchoalveolar space in patients with 
ARDS is IL-1(Pugin et al 1996). It enhances the production of other cytokines with a longer 
half-life, such as IL-6, which accumulates in a sustained manner during the disease and 
(Olman et al 2004, Zhang et al 2004) The pathogenic role of IL-1in the lungs is supported by 
findings in rat that transient lung expression of IL-1via adenoviral gene transfer causes a local 
increase of the pro-inflammatory cytokines IL-6 and TNF-α and a vigorous acute inflammatory 
tissue response, which then leads to progressive interstitial fibrogenesis (Kolb et al 2001). 
Another cytokine that may have a pathogenic effect is IL-18. Levels of IL-18 are elevated in 
the serum of patients with SARS-CoV-1 (Huang et al 2005). IL-18 promotes lung fibrosis 
(Zhang et al 2019) and the production of Th1 cytokines that mediate alveolar epithelial cell 
death. Consistent with this hypothesis, the expression of IL-18 in the lung induces type 1, type 
2, and type 17 cytokines and stimulates alveolar destruction causing vascular remodeling and 
airway fibrosis (Kang et al 2012). Interestingly, an interferon-gamma type cytokine storm was 
described post SARS coronavirus infection (Kawayama et al 2012). Thus, the existing data 
provide evidence for an important role of IL-18 in lung injuries of different origins.
1.1.4
Summary
The inflammasome and the pivotal mediators IL-1β, IL-18 and NLPR3 are known contributors 
to the hyper-inflammatory response that results in severe pulmonary tissue damage after initial 
SARS-CoV-1 and SARS-CoV-2 infections. Treatment with a bispecific anti-IL-1/18 mAb 
(MAS825) in patients with severe COVID-19 pulmonary disease is expected to reduce 
inflammation, reverse lung pathology and may improve ventilation and clinical outcomes. 
Importantly, available evidence strongly supports the concept that this treatment would not
increase viral persistence or other morbidity related to a SARS-CoV-2 infection especially 
when administered at the later stage of the disease when respiratory failure develops.
MAS825, a bispecific anti-IL-1β/IL-18 mAb rapidly neutralizes 
 of IL-1β and IL-18. 
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1.2
MAS825
1.2.1
Nonclinical data
1.2.2
Clinical data
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The overall preclinical and preliminary clinical, safety and laboratory assessments are is 
considered adequate to justify the continued development of MAS825 in patients with 
COVID-19 pneumonia and impaired respiratory function.
1.3
Purpose
The purpose of this study is to evaluate the efficacy and safety of MAS825 in addition to current 
standard of care (SoC) compared with placebo and SoC in controlling the inflammatory 
syndrome and resultant ARDS in hospitalized patients presenting with COVID-19 pneumonia 
and impaired respiratory function.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To evaluate the effect of MAS825,
compared with placebo, on the Acute
Physiology and Chronic Health Evaluation II
(APACHE II) score
Endpoint(s) for primary objective(s)

APACHE II severity of disease score on
Day 15 or on day of discharge (whichever is
earlier) with worst case imputation for death
Secondary Objective(s)

To evaluate the effect of MAS825,
compared with placebo on inflammatory
status
Endpoint(s) for secondary objective(s)

Serum C-reactive protein (CRP) levels and
ferritin
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Objective(s)
Endpoint(s)

To evaluate the effect of MAS825,
compared with placebo, on clinical status
Endpoints based on the 9-point ordinal scale 
(Appendix 2):

Survival without the need for invasive
mechanical ventilation at Days 15 and 29

At least one level improvement in clinical
status at Days 15 and 29

Clinical status over time

To evaluate the safety of MAS825,
compared with placebo

Number of participants with Adverse Events
(AE), Serious Adverse Events (SAE),
clinically significant changes in laboratory
measures, and vital signs
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2.1
Primary estimands
The primary clinical question of interest is: What is the effect of MAS825 compared with 
placebo in SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired respiratory 
function on APACHE-II severity of disease score taking into account early discharge from 
hospital or death but regardless of treatment discontinuation?
The justification for the primary estimand is that it will capture the combined effect of the study 
drug in patients who remain in hospital for 14 days, the effect on early discharge within 14 days 
and the effect on death rate within 14 days, in a manner than reflects clinical practice.
The primary estimand is described by the following attributes:
1. Population: SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired 
respiratory function. Further details about the population are provided in Section 5.
2. Endpoint: APACHE II severity of disease score on Day 15 or on day of discharge 
(whichever is earlier) with worst case imputation for death. Patients who die on Day 15 or 
earlier will be assigned the highest APACHE II score by any of the patients at any time 
during the trial. Note this imputation takes precedence over the APACHE II score on day 
of discharge.
3. Treatment of interest: the randomized treatment (the investigational treatment of MAS825 
or placebo)
4. Handling of remaining intercurrent events: Treatment discontinuation for any reason will 
be ignored and thus follow a treatment policy strategy i.e. participants who discontinue 
treatment will be treated in the same manner as those that continue the treatment as planned.
5. Summary measure: The difference in variable means between treatments.
2.2
Secondary estimands
Not applicable
3
Study design
This is a Phase 2, randomized, placebo -controlled, participant and investigator blinded, multi-
center study to assess the efficacy and safety of MAS825 for the treatment of SARS-CoV-2 
infected patients with COVID-19 pneumonia and impaired respiratory function 
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Figure 3-1
Study design
The study consists of five parts:
1. Screening / Baseline / Treatment (Day -1 to 1): lasts up to a maximum of 24 hours and
comprises a screening / baseline assessment. This visit will be used to confirm that the study
inclusion and exclusion criteria are met and serves as baseline assessment prior to
randomization. Baseline blood tests will be performed in all patients; those who screen fail
because of study inclusion / exclusion criteria (e.g., serum CRP, liver function tests), will
not undergo randomization.
Eligible patients will receive a single i.v. infusion of 
 MAS825 or placebo on
Day -1 to 1 and will be observed until Day 15. Patients will be randomized as soon as
possible, but within a maximum of 24 hours after screening in a 1:1 ratio to receive either
treatment with MAS825 or placebo in addition to SoC. Randomization will be stratified
according to the following, all of which may influence outcome in COVID-19:

age (≤65years, >65years)

administration of any anti-viral therapy (e.g., hydroxychloroquine, chloroquine,
convalescent plasma, remdesivir, faripivavir, ritonavir, lopinavir) as SoC (yes / no)

presence of ≥1 of the following comorbidities: diabetes, hypertension, cardiovascular
disease, chronic lung disease (yes / no)
2. Treatment period (Day 2-15): Study assessments to be conducted every 2 days for
hospitalized patients. If patients are discharged from the hospital prior to Day 15,
assessments on the day of discharge should be performed according to the schedule listed
under Day 15 and patient should return to the site for the Day 15 assessment (all other visits
between discharge and Day 15 can be omitted). If a hospital visit is not possible at Day 15,
then home nursing services may be used to support this last visit where these are available
in accordance with local guidelines and should include all possible assessments (e.g. oxygen
saturation with portable monitors). In case home nursing is not possible, patients will be
contacted by phone on day 15.
3. Follow-up (Day 16-29): After completion of the treatment period, patients will be observed
until Day 29 or discharged from hospital, whichever is sooner. Study assessments to be
conducted every 2 days for domiciled patients.
If patients are discharged from hospital prior to Day 29, a study visit conducted by
telephone will occur on Day 29 (all other visits between discharge and Day 29 can be
omitted).
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4. Safety follow-up visit assessment (Day 45): A follow-up visit will be conducted at Day 45
if the patient is hospitalized. If patients are discharged from hospital prior to Day 45, a study
visit will be conducted by telephone on Day 45.
5. End of Study/Safety follow-up visit assessment (Day 127): A follow-up visit for safety
will be conducted at Day 127 if the patient is hospitalized. If patients are discharged from
hospital prior to Day 127, a study visit will be conducted by telephone on Day 127.
4
Rationale
4.1
Rationale for study design
This is a randomized, placebo-controlled, participant- and investigator-blinded, multicenter 
study in hospitalized adult patients (≥18 years) with COVID-19-associated pneumonia and 
impaired respiratory function. This design supports the assessment of preliminary efficacy and 
as well as proof of concept and safety of MAS825 in addition to SoC in this critically ill patient 
population.
The Screening / Baseline/Treatment visit will be used to confirm that the study inclusion and 
exclusion criteria are met and for performing baseline clinical observations and biological 
sampling (blood, urine). Patients meeting the inclusion and exclusion criteria will be acutely 
unwell and it is anticipated that recruitment and randomization will take place relatively rapidly, 
with entry into the study taking place within a maximum of 24 hours of screening. This is 
justified based upon the clinical severity of illness in patients admitted with COVID-19 
associated pneumonia and impaired respiratory function and their likelihood of deterioration 
shortly after hospital admission.
During the Treatment period patients will be randomized in a 1:1 ratio to receive either 
treatment with MAS825
i.v infusion or matching placebo in addition to SoC.
Randomization is justified as there is at present no clinical evidence that MAS825 will be 
efficacious in reducing disease severity in COVID-19 patients. The 1:1 randomization ratio was 
chosen to maximize the statistical power for the primary analysis whilst minimizing the overall 
sample size. Stratification of randomization for age (≤65 years, >65 years), administration of 
any anti-viral therapy (yes / no) and presence of comorbidities (yes / no) is justified as these 
factors may influence outcome in COVID-19 patients and we wish to ensure equal distribution 
of these variables between the two study arms.
The Study Endpoints measure clinical status, clinical and in-hospital outcomes, and laboratory 
values, including serum CRP, a key biomarker of inflammasome inhibition and safety during 
and after the 14-day treatment period. These measurements are consistent with endpoints and 
measurement times for other studies of therapies for COVID-19.
The Study Follow-up period rationale is described in rationale for dose/regimen, duration of 
treatment and follow-up (Section 4.4)
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4.2
Rationale for participant numbers and endpoint
The total sample size of 120 participants randomized in a 1:1 ratio to the two treatment groups 
is based on limitations in the available drug supply at this point in time. The current drug supply 
for MAS825 allow a maximum of 60 participants to be treated.
The primary endpoint for this study is the APACHE II score (range 0 to 71) on day 15 or on 
day of discharge (whichever is earlier) with worst case imputation for death as this disease 
severity score provides a comprehensive structured assessment of the clinical, physiological 
and laboratory parameters that have been routinely employed by physicians in the current 
situation to access the overall clinical status of COVID-19 patients with pneumonia and 
respiratory failure (Yang et al 2020, Wang et al 2020). In particular, the APACHE II disease 
severity score captures the clinically relevant physiologic variables for an aggregate score, with 
higher scores indicating more severe disease, with a median score of 18 reported for non-
survivors of COVID-19. The APACHE II score will not be used by investigators to direct 
medical management of patients in this study. 
To establish clinical efficacy based on APACHE II score, a sample size of 60 patients per 
treatment group provides 80% power when testing on an 10% 1-sided alpha level under the 
assumption that MAS825 in addition to SoC reduces the APACHE II score by 3.6 points more 
than placebo in addition to SoC (assumed standard deviation of 9.2 based on Yang et al 2020).
Other clinical endpoints such as those derived from the 9-point ordinal scale were considered 
as primary endpoints. However, since these endpoints were binary in nature, the sample sizes 
required to have sufficient power to show statistically significant differences were much higher 
than those feasible with the limited available drug supply.
4.3
Rationale for choice of background therapy
There is at present no health authority (HA) approved treatments for COVID-19 or its sequelae, 
including the cytokine storm which develops in those most severely affected. Current SoC in 
the European Union (EU) and United States of America (US) includes a variety of supportive 
therapies, ranging from the administration of supplementary oxygen to full intensive care 
support, alongside the use of antiviral agents and corticosteroids, though there is considerable 
inter-center variability regarding the use of these. Local SoC is permitted in all patients 
participating in the study, though every effort will be made by investigators to standardize this 
within individual centers.
Randomization for this study stratifies for the administration of antiviral therapy e.g., 
hydroxychloroquine, chloroquine, remdesivir, faripivavir, ritonavir, lopinavir, to ensure that 
treated and untreated patients are evenly distributed between the two treatment arms.
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4.4
Rationale for dose/regimen, duration of treatment and follow-up
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Similarly, the efficacious dose of MAS825 to neutralize IL-1β has been estimated from IL-1β 
measurements in COVID-19 patients 
with 
pneumonia and respiratory failure (Huang et al 2020). The MAS825 dose level 
for 
the study is further justified by;

The dose will lead to rapid and simultaneous neutralization of all systemic free IL-I8 and
IL-1β.

This dose enables the treatment of severe COVID-19 where hyper-elevated levels of IL-1β
and IL-18 is expected
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
The dose of MAS825 has been administered to heathy volunteers with no identified safety
concerns
The median hospital stay for COVID-19 has been reported to be 12 days with an interquartile 
range of 1 to 14 days (Cao et al 2020), justifying treatment period selected. 
4.5
Purpose and timing of interim analyses/design adaptations
4.6
Risks and benefits
4.6.1
Potential benefits and risks to study participants 
 Clinically, there 
is evidence of efficiency with blockade of the downstream inflammasome pathway cytokine 
IL-6 (tocilizumab) in patients with cytokine release syndrome in the context of CAR-T therapy
and some evidence from case reports in COVID-19 patients with a placebo-controlled Phase III 
clinical trial recently initiated (Zhang et al 2020, Mehta et al 2020, Ascierto et al 2020, 
NCT04320615).
However, neither MAS825 nor other selective inhibitors of IL-1 and/or 
IL-18 have previously been studied in patients with COVID-19 pneumonia. Therefore, it 
remains currently unknown as to whether there will be a benefit for patients being treated with 
MAS825 in this disease.
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The patients enrolled in this study will have COVID-19-associated pneumonia, impaired 
respiratory function and evidence of an inflammation syndrome with a significant risk of the 
development of ARDS requiring prolonged mechanical ventilation and ICU stay to maintain 
life. Currently, apart from supportive medical care that is of limited benefit in this population, 
there are no approved therapeutics targeting the underlying inflammatory process to improve 
oxygenation, reverse respiratory failure and reduce the complications of SARS-CoV-2 infection 
to improve the overall clinical outcome.
4.6.2
Potential risks to study participants
The risk to participants in this trial will be minimized by adherence to the eligibility criteria, 
close clinical monitoring, frequent follow-up, minimal duration of the study, stopping rules and 
periodic review of safety data by an independent DMC.
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4.6.2.1
Potential risk of Infection
As with any immune-modulating compound, there is a theoretical risk of immune system 
impairment which might increase risk of infection in treated patients. However, MAS825 is not 
expected to elicit broad immune suppression, rather selectively neutralize the pro inflammatory 
IL-1and free/bioactive IL-18 that are extremely elevated in COVID-19 patients, with 
simultaneous neutralization of both cytokines limited to the duration of the proposed post-study 
follow up. To mitigate potential risks of immune modulation and infection in this study, 
exclusion criteria include other immune suppressive treatments administered proximal to 
randomization, or concurrent use thereof. Patients are also excluded with known or suspected 
immunodeficiency state or evidence of active, serious bacterial, fungal or viral infections (other 
than SARS-CoV2).
4.6.2.2
Potential risk of acute infusion and/or hypersensitivity reactions
As with most biologic compounds, administration of MAS825 carries the risk of anaphylaxis
and/or hypersensitivity-type reactions (see Section 16.1). MAS825 is administered as infusion 
over 
 to allow investigators discontinue treatment. In the event of such a reaction,
Investigators should consider study-specific criteria for treatment discontinuation
(Section 9.1.1); and the patient should be treated with supportive care.
Recommendations regarding evaluation and treatment of adverse events are provided in
Section 6.6.2 and IB section 7.
4.6.2.3
Potential risk to women of child-bearing potential
At this stage of development, MAS825 has not yet been assessed in reproductive toxicology 
studies, and all women of childbearing potential (WOCBP) must be informed that exposure to 
MAS825 may involve unknown risks to the fetus if pregnancy were to occur. 
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4.7
Overall risk benefit
 Therefore, the risks 
to COVID-19 patients in this trial will be minimized by adherence to the eligibility criteria, 
close clinical monitoring, frequent follow up, minimal duration of the study, stopping rule and 
periodic review of safety data by an independent DMC.
4.8
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period 
of 127 days, from each participant as part of the study. Approximately 190 mL blood will be 
collected over the first 15 days during which patients are hospitalized. For hospitalization of 
29 days a total blood volume of approximately 250 mL will be collected. If safety follow-up 
visits occur at Day 45 and Day 127, an additional 25 ml of blood will be collected.
Sample volume may vary according to local laboratory standard. Additional samples may be 
required for safety monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1).
See the Section 8.5.6.1 on the potential use of residual samples.
5
Study Population
The study population includes adult male and female SARS-CoV-2 infected patients who are 
hospitalized and diagnosed with COVID-19 pneumonia and impaired respiratory function.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male and female patients aged ≥18 years at screening
2. Signed Informed Consent Form (ICF) by patient capable of giving consent, or, when the
patient is not capable of giving consent, by his or her legal/authorized representative (if
allowed according to local requirements)
3. Clinically diagnosed with the SARS-CoV-2 virus by polymerase chain reaction (PCR) or
by other approved diagnostic methodology within 7 days prior to randomization
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4. Hospitalized with COVID-19-induced pneumonia evidenced by chest x-ray, computed
tomography scan (CT scan) or magnetic resonance scan (MR scan) (taken within 5 days
prior to randomization)
5. Impaired respiratory function, defined as peripheral oxygen saturation (SpO2) ≤93% on
room air or partial pressure of oxygen (PaO2) / fraction of inspired oxygen (FiO2)
<300 millimeter of mercury (mmHg) at time of screening For cities located at altitudes
greater than 2500 m above sea level, these will be substituted with SpO2 <90% and
PaO2/FiO2 <250 mmHg
6. Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score of ≥10
at time of screening
7. CRP ≥20 mg/L or ferritin level ≥600 μg/L at screening
8. Body weight between 45 kg and 145 kg, inclusive, at screening
9. Ability to comply with the study protocol, in the investigator's judgment
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. History of hypersensitivity to the investigational treatment or their excipients or to drugs of
similar chemical classes
2. Suspected active or chronic bacterial (including Mycobacterium tuberculosis), fungal, viral,
or other infection (besides SARS-CoV-2)
3. In the opinion of the investigator, progression to death is imminent and inevitable within
the next 24 hours, irrespective of the provision of treatment
4. Intubated prior to randomization
5. Patients who have explicitly expressed the wish not to receive intensive care support when
this would be indicated based on their condition
6. Previous treatment with anti-rejection and immunomodulatory drugs within the past 2
weeks, or within the past 30 days or 5 half-lives (whichever is the longer) for
immunomodulatory therapeutic antibodies or prohibited drugs (see Section 6.2.1.1), with
the exception of anti-viral therapies or corticosteroids:

For COVID-19 infection, ongoing corticosteroid treatment is permitted at doses as per
local SoC

For non-COVID-19 disorders, ongoing corticosteroid treatment is permitted at doses
up to and including prednisolone 10 mg daily or equivalent (see Section 6.2.1
Concomitant therapy)
7. Serum alanine transaminase (ALT) or aspartate transaminase (AST) >5 times upper limit
of normal detected within 24 hours at screening/baseline (according to local laboratory
reference ranges) or other evidence of severe hepatic impairment (Child-Pugh Class C, see
Appendix 5)
8. Absolute peripheral blood neutrophil count of ≤1000/mm3
9. Estimated GFR (eGFR) ≤30 mL/min/1.73m2 (based on CKD-EPI formula)
10. Pregnant or breastfeeding, or positive urine or serum pregnancy test in a pre-dose
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11. Any serious medical condition or abnormality of clinical laboratory tests that, in the
investigator’s judgment, precludes the patient’s safe participation in and completion of the
study
12. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they agree to abstain from any sexual intercourse for a total of
29 days after randomization (the 14-day treatment period plus a 14-day follow-up period).
During the safety follow up (from day 29 onwards), WOCBP should practice highly
effective contraception for 4 months following treatment with MAS825, when it is predicted
that IL-18 and IL-1will not be neutralized by MAS825.
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 bilateral tubal ligation at least six
weeks prior to randomization. In the case of oophorectomy alone, only when the
reproductive status of the women has been confirmed by follow up hormone level
assessment is she considered not of child bearing potential.
13. Current participation in any other investigational trials, with the exception of (not yet)
approved COVID-19 therapies that are considered (local) standard of care (also see
Section 6.2.1.1. for Prohibited drugs).
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to
be followed for prescribing/dispensing, and administering study treatment are outlined in the 
pharmacy manual.
6.1.1
Investigational and control drugs
The investigational drug, MAS825 and the matching placebo will be prepared by Novartis and 
supplied as open labeled bulk medication to the unblinded site pharmacist (Table 6-1).
An unblinded pharmacist or authorized designee is required to dispense the study drug. 
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
MAS825 
Intravenous use
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Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
Matching Placebo
Concentrate for 
solution for 
infusion
Intravenous use
Open label bulk 
supply; vials
Sponsor (global)
6.1.2
Additional study treatments
Patients assigned to the MAS825 arm will receive single dose of MAS825 
 i.v. in 
addition to SoC, and patients assigned to the control arm will receive matching placebo in 
addition to SoC. Administered SoC in addition to study treatment will be supplied by the 
investigational site. No other investigational treatment beyond MAS825 is included in this study.
6.1.3
Treatment arms/group
Participants will be assigned at randomization to one of the following treatment arms/groups in 
a ratio of 1:1:

MAS825
i.v.

Matching placebo i.v.
6.2
Other treatment(s)
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 Case Report Forms (CRF).
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.
If participants are discharged from hospital prior to Day 15, they must be told to notify the 
treating physician about any new medications he / she takes after receiving MAS825 treatment.
During the course of the study and also prior to screening, participants may receive anti-viral 
therapies (e.g., hydroxychloroquine, chloroquine, remdesivir, faripivavir, ritonavir, lopinavir
convalescent plasma containing high titres of anti SARS-CoV-2 antibodies), intravenous, oral 
or inhaled corticosteroids (e.g. prednisolone, dexamethasone, methylprednisolone), antibiotics, 
anti-coagulants and other agents/treatments where these form part of SoC for the treatment of 
COVID-19 at their participating center (per medical judgement).
Patients are permitted to receive low-dose corticosteroids (up to a maximum of 10 mg/day 
prednisolone equivalent) for the treatment of non-COVID-19 disorders. Immunomodulatory 
(topical or inhaled) use for asthma and atopic dermatitis or corticosteroid use (per medical 
judgement) are not restricted.
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Whilst the protocol defines experimental immunomodulatory treatments including but not 
limited to anti-IL-6 monoclonal antibodies as prohibited (Section 6.2.1.1), patients with 
significantly deteriorating clinical status after MAS825 or placebo may still receive such 
therapies in rescue situations where their treating physician is of the opinion that the potential 
benefit of such therapy outweighs the risks. However, patients having received experimental 
immunomodulatory therapies as rescue therapy after treatment with MAS825 or placebo should 
remain in the study and the Investigator should continue collecting data on outcomes through 
the study visit schedule.
6.2.1.1
Prohibited drugs
The following medications are prohibited: 
Experimental immunomodulatory therapies for the treatment of COVID-19, including, but not 
limited to canakinumab, anakinra and other anti-IL-1 antibodies, tocilizumab, sarilumab and 
other anti-IL-6 antibodies, ruxolitinib and other JAK inhibitors, eculizumab and other 
complement inhibitors (investigational or marketed).
Concomitant use of biologics including abatacept, rilonacept, rituximab and any other biologics 
(investigational or marketed) and TNF inhibitors including etanercept, adalimumab, infliximab 
and/or other TNF inhibitors (investigational or marketed).
All investigational medications being used in an investigational trial.
6.2.1.2
Permitted concomitant therapy requiring caution and/or action
Use of oral, injected or implanted hormonal methods of contraception are allowed while on 
MAS825.
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. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. 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 entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.
6.3.2
Treatment assignment, randomization
At 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 
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will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm.
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. A randomization 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 treatment arms to randomization 
numbers in the specified ratio.
Randomization will be stratified by:

age (≤65years, >65years)

administration of any anti-viral therapy (e.g., hydroxychloroquine, chloroquine,
convalescent plasma, remdesivir, faripivavir, ritonavir, lopinavir) as SoC (yes / no)

presence of ≥1 of the following comorbidities: diabetes, hypertension, cardiovascular
disease, chronic lung disease (yes / no)
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
This is a blinded study. Participants and investigators will remain blinded to study treatment 
throughout the study, except where indicated below.
Participants, investigator staff, persons performing the assessments, and the clinical trial team 
(CTT) will remain blind to the identity of the treatment from the time of randomization until 
end of study visit applying the following rules:

Randomization data are kept strictly confidential until the time of unblinding.

Unblinding will occur in the case of participant emergencies and at the conclusion of the
study.

Unblinding of the CTT members may occur for the purpose of periodic review of the
safety data.

Unblinded results from the planned interim analysis after all participants have completed
the Day 29 visit can be shared with the participants and site staff, if deemed appropriate.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.
Unblinding a single participant at site for safety reasons (necessary for participant management) 
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Drug product will be supplied in bulk, so an unblinded pharmacist who is independent of the 
study team will be required in order to maintain the blind. This unblinded pharmacist at the site 
will be notified by the IRT system that a participants randomized and to which treatment arm, 
which will then enable them to prepare the study drug. Appropriate measures must be taken by 
the unblinded pharmacist to ensure that the treatment assignments are concealed from the rest 
of the site staff.
Sponsor staff
The following unblinded sponsor roles are required for this study amend as appropriate:

Unblinded field monitor(s)

Unblinded clinical staff managing drug re-supply to site

Unblinded sample analyst(s)
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be unblinded 
through review of source documentation compiled by the unblinded pharmacist, which details 
treatment allocation to individual participants. 
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly, but may be 
unblinded through communication of drug re-supply needs via the unblinded site pharmacists.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-2. For example, unblinded summaries and 
unblinded individual data can be shared with the team for all interim analyses.
Study programmers and other personnel involved in study data analysis 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project at the 
time of interim analyses while the study is ongoing. The results from the planned interim 
analysis after all participants have completed their Day 29 visit (or discontinued from the study 
earlier) can be shared more broadly including with participants and site staff, if deemed 
appropriate. If this occurs, then all roles should be considered unblinded from this time points 
onwards. Otherwise, following final database lock all roles may be considered unblinded.
All unblinded personnel will otherwise keep randomization data or information that could 
unblind other study team members confidential and secure except as described above.
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Table 6-2
Blinding and unblinding plan 
Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single participant 
unblinded)
Interim analysis
Participants
B
B
UI
B*
Site staff
B
B
UI
B*
Unblinded site staff e.g. 
pharmacy staff (specify)
UI
UI
UI
UI
Global Clinical Supply 
and Randomization 
Office
UI
UI
UI
UI
Unblinded sponsor staff 
e.g. for study treatment
re-supply, unblinded
monitor(s), sample
analyst(s)
UI
UI
UI
UI
Unblinded 
Pharmacovigilance 
sponsor staff
UI
UI
UI
UI
Statistician/statistical 
programmer/ data 
analysts (e.g. 
)
B
B
UI
UI
Independent 
committees used for 
assessing interim 
results, if required (e.g. 
DMC)
B
B
UI
UI
All other sponsor staff 
not identified above 
(i.e. trial team, project 
team, management & 
decision boards, 
support functions)
B
B
UI
UI
UI: Allowed to be unblinded on individual participant level
B: Remains blinded
NA: Not applicable to this study
* Unblinded results from the planned interim analysis after all subjects have completed their Day 29 visit (or
discontinued earlier) can be shared with participants and site staff, if deemed appropriate. Results from any other
interim analysis prior to the Day 29 visit should not be shared with participants and site staff.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
As dosing will be completed at the study site, assessment of compliance is not applicable. 
All study treatment administered will be recorded on the Study Treatment eCRF. Serum levels 
of MAS825 will be determined at pre-specified timepoints as measures of treatment compliance.  
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in all participants treated with MAS825, as detailed in “Assessment Schedule” in 
Table 8-1
6.6.2
Recommended treatment of adverse events
Medication used to treat AEs must be recorded on the appropriate CRF.
Treatment of infection
In the event of an infection, Investigators should consider early treatment with specific 
antimicrobial therapy based on clinical diagnosis or suspicion thereof (e.g., anti-viral treatment 
for herpes simplex or zoster) in consultation with infectious disease experts, as appropriate.
Treatment of acute infusion and/or hypersensitivity reactions
As with most biologic compounds, 
 administration of MAS825 carries the risk of
anaphylaxis and/or hypersensitivity-type reactions (see Section 16.1). In the event of such a
reaction, Investigators should consider study-specific criteria for treatment discontinuation
(Section 9.1.1), and the patient should be treated with antihistamines and glucocorticoids.
Depending on severity, subjects may also require supplemental oxygen, volume expansion,
catecholamines and transfer to an intensive care setting. Plasmapheresis to decrease the
systemic concentration of MAS825 may be considered dependent on the patient’s condition.
Subjects should be observed for at least four hours after resolution of signs and symptoms, and
those who have experienced severe infusion reactions should be closely observed for 24 hours
after resolution because of the risk for a biphasic episode.
Treatment of overdose
There is no clinical experience with MAS825 overdose. Should an overdose occur, the subject 
or patient should be carefully monitored for any potential symptoms, and if necessary, 
appropriate supportive care should be provided until the subject has recovered. The use of 
plasmapheresis may be considered to facilitate more rapid elimination of MAS825 from the 
peripheral circulation in the case of overdose.
At present there is insufficient information to provide specific recommendations regarding 
treatment of other potential adverse events (AEs) in this patient population. Acute kidney injury 
is common in patients with severe COVID-19. Treatment is supportive, with the institution of 
renal replacement therapy where this is indicated.
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.
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6.6.3
Emergency breaking of assigned treatment code
Emergency breaking of the assigned treatment code must only be undertaken when it is essential 
to treat the participant safely and efficaciously.
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. 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 at any time in case of emergency. The investigator will provide:

protocol number

name (if available)

participant number
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 and placebo in packaging as described under 
investigational and control drugs Section 6.1.1.
Details on preparation of study medication by unblinded pharmacist and dispensation are 
provided in Pharmacy Manual.
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 select as applicable on the labels
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (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 
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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. 
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.
6.7.1.2
Handling of additional treatment
Not applicable
6.7.2
Instruction for prescribing and taking study treatment
Please refer to Pharmacy Manual. 
Table 6-3
Dose and treatment schedule
Investigational / Control Drug
(Name and Strength)
Dose
Frequency and/or Regimen
MAS825 
Day 1 by i.v. infusion
Placebo
Day 1 by i.v. infusion
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB) / Independent Ethics 
Committee (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 or becomes capable of doing so, 
he/she must indicate agreement by personally signing and dating the written informed consent 
document. The consenting process for all study participants will be performed according to the 
applicable local regulations and described in the ICF.
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.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
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Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the 
participant informed consent and should be discussed with the participant during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant.
The following informed consents are included in this study:

Main study consent, which also includes:

As applicable, Pregnancy Outcomes Reporting Consent for female participants who took
study treatment


As applicable, an optional Home Nursing visit consent for all participants to allow for 
home nursing visit if a site visit is not possible
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
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8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all assessments when they are performed. All data obtained from these assessments must be 
supported in the participant’s source documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule (Table 8-1) or as close to the designated day/time 
as possible. Missed or rescheduled visits should not lead to automatic discontinuation. Participants who prematurely discontinue the study for 
any reason should be scheduled for a visit as soon as possible, at which time all of the assessments listed for the final visit will be performed. 
If participant is prematurely discontinued from the study at any visit before Day 15, then assessments of Day 15 visit should be performed,
and if participant is prematurely discontinued at any visit after Day 15 and before Day 127, then assessments of Day 127 visit should be 
performed. 
Table 8-1
Assessment schedule 
Period
Screening / 
Baseline / 
Treatment
Treatment2
Post-Treatment Follow-up
EOS
Visit Name
Screening / 
Baseline / 
Treatment14
Observation
Discharge3
Follow-up4
(if hospitalized 
assessments performed at 
site every 2 days; 
if discharged only telephone 
call on Day 29)
Safety 
follow-
up4
EOS/Safety 
Follow up4
Days
-1 to 1
2
4
6
8
10
12
14
15
17, 19, 21, 23, 
25, 27
29 
(-1/+3 
days)
455
(+/-7
days)
127 (+/- 7
days)5
Domiciled (as required)
X
X
X
X
X
X
X
X
X
X
X
Inclusion / Exclusion criteria
X
Demography
X
Medical history/current medical conditions
X
Presence SARS-CoV-2 virus / viral load5
X
Chest X-ray (CXR), CT or MR scan per local SoC5
X
X12
Randomization (IRT)
X
Physical examination13
S
S
S
S
S
S
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
X
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Period
Screening / 
Baseline / 
Treatment
Treatment2
Post-Treatment Follow-up
EOS
Visit Name
Screening / 
Baseline / 
Treatment14
Observation
Discharge3
Follow-up4
(if hospitalized 
assessments performed at 
site every 2 days; 
if discharged only telephone 
call on Day 29)
Safety 
follow-
up4
EOS/Safety 
Follow up4
Days
-1 to 1
2
4
6
8
10
12
14
15
17, 19, 21, 23, 
25, 27
29 
(-1/+3 
days)
455
(+/-7
days)
127 (+/- 7
days)5
Respiratory status (spont. breathing, FiO2, ventilator 
parameters, ECMO), fluid balance, need for CRRT
X
X
X
X
X
X
X
X
X
X
X
X
X
APACHE II, 
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Status Evaluation with 9-category ordinal scale
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and Height7
X
X
X
ECG evaluation (local)14
X
X
Pregnancy test – urine/serum (local lab)9
X
X
X
Blood chemistry including CRP, Ferritin, LDH, ANC, D-
dimer, troponin and BNP (local lab)8
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology (local lab)8
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation Panel8
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug administration record11
X 
Concomitant medications/Therapies including inotropic 
support
X
Adverse events/serious adverse events
X
Safety Follow up Call
X
X
X
X
Study completion information
X
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
1.
Informed consent must be signed prior to any study-related procedure. 
2.
Study treatment may start immediately after obtaining the screening/baseline measurements and confirming eligibility.  Day 15 visit should be performed for all patients.
3.
If patient is discharged prior to Day 15 (early discharge), then assessments on the day of discharge should be performed according to the schedule listed under Day 15 and patient should return to the site for the 
Day 15 assessment, with a time window of +2 days (if hospital visit is not possible, then home nursing is allowed on day 15 (with a time window of +2 days) that should include all possible assessments including 
oxygen saturation with portable monitors). In case, home nursing is not possible, patients will be contacted by phone on day 15 (with a time window of +2 days), where respiratory history, performance status, 
adverse events, concomitant medication and medical and surgical history will be obtained). No time window for Day 15 is allowed if the patient is not discharged prior to day 15.
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Period
Screening / 
Baseline / 
Treatment
Treatment2
Post-Treatment Follow-up
EOS
Visit Name
Screening / 
Baseline / 
Treatment14
Observation
Discharge3
Follow-up4
(if hospitalized 
assessments performed at 
site every 2 days; 
if discharged only telephone 
call on Day 29)
Safety 
follow-
up4
EOS/Safety 
Follow up4
Days
-1 to 1
2
4
6
8
10
12
14
15
17, 19, 21, 23, 
25, 27
29 
(-1/+3 
days)
455
(+/-7
days)
127 (+/- 7
days)5
4.
f patient is discharged after Day 15 and prior to Day 127 (discharge), then assessments on the day of discharge should be performed according to the schedule listed under Day 127. Furthermore, visits at Days 29, 
45 and 127 should be conducted via phone for patients who were discharged prior to the visit (see footnote 3 for assessments to be obtained on the phone). Visits between day of discharge and Day 127 can be 
omitted. If the patient remains hospitalized, however, all assessments noted in the table should be conducted on the visit day noted.
5.
Results confirming positive SARS-CoV-2 virus by PCR or by other approved diagnostic methodology available within 7 days and chest X-ray, CT or MRI scan within 5 days prior to randomization may be used for 
eligibility. 
6.
Vital signs include heart rate, respiratory rate (if not on mechanical ventilation), systolic and diastolic blood pressure and body temperature. If possible, vital signs should be recorded at the same time at every visit
for a patient (i.e. morning, afternoon or evening) and upon significant clinical changes. Oxygen saturation (if not on mechanical ventilation) or PaO2/FiO2 should be measured at the same time as the vital signs
measurements.If patient is receiving supplemental oxygen (not on invasive ventilation) then oxygen flow rate and/or FiO2 and oxygen saturation to be collected.
7.
If not possible to measure height, it can be reported by the patient. Height will be measured only at screening/baseline/treatment visit.
8.
Hematology, blood chemistry and coagulation panel including CRP, Ferritin, LDH, ANC, D-dimer, troponin and BNP should be measured by the local laboratory. 
9.
Pregnancy test applicable only for females of childbearing potential; serum pregnancy test (serum hCG) will be performed by local laboratory. For enrollment a negative urine test is sufficient
10.
11. For the treatment day, all assessments should be performed pre-dose.
12. Chest X-ray, CT or MRI scan at Day 15 will be performed and reported only if available and performed according to SoC. The same method should be used at Day 15 (or on day of discharge if prior to Day 15) as 
was used at screening.
13. A complete physical examination will be performed at baseline. For the remaining time points, a targeted physical examination, as per investigator discretion, may be performed.
14. All procedures performed as part of local standard of care during this hospitalization, may be used for screening/baseline assessments provided that they were performed up to 24 hours prior to ICF signature. ECG
examination conducted during this 24h window will be accepted as long as the same diagnostic method is used throughout the study.
15. Urine output to be measured as per local SoC.
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8.1
Screening
It is permissible to re-screen a participant once if s/he fails the initial screening.
In the case where a safety laboratory assessment at screening/ baseline is outside of the range 
specified in the exclusion criteria, the assessment may be repeated once prior to randomization. 
If the repeat value remains outside of the specified ranges, the participant must be excluded 
from the study.
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 CRF. 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 CRF.
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 HA
8.2.1
Demographic information
Demographic data to be collected at screening on all participants include: year of birth or age, 
gender, race, ethnicity and child-bearing potential (for females only).
Any relevant medical history including date of onset of COVID-19 disease symptoms, date of 
diagnosis of COVID-19 disease protocol solicited medical history, and/or current medical 
conditions before obtaining informed consent will be recorded in the Medical History CRF. 
Significant findings that are observed after the participant has provided informed consent and 
that meet the definition of an AE must also be recorded in the AE CRF. Whenever possible, 
diagnoses and not symptoms will be recorded.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.


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8.2.2
Prior and concomitant medications
Relevant prior and concomitant medications will be captured at the screening visit. Any changes 
to the ongoing medications or any new concomitant medications will be recorded in CRF on an 
ongoing basis throughout study participation.
8.3
Efficacy
Samples will be collected at the timepoints defined in the Assessment Schedule (Table 8-1) and 
will be obtained and evaluated in all participants. 
8.3.1
Vital signs and oxygen saturation and use
Vital sign measurements include respiratory rate, pulse rate, systolic and diastolic blood 
pressure, and body temperature. If possible, vital signs should be recorded at the same time at 
every visit for a patient (i.e. morning, afternoon or evening) and upon significant clinical 
changes.
Peripheral oxygen saturation on room air should also be measured at the same time as the vitals, 
if not on supplemental oxygen. If patient is receiving supplemental oxygen (not on invasive 
ventilation), then oxygen flow rate (L/min) and/or fraction of inspired oxygen (FiO2) and 
oxygen saturation should be recorded. PaO2/FiO2 should be recorded as needed (see Appendix
5 for guidance on estimation of PaO2/FiO2).
8.3.2
APACHE II severity of disease score
APACHE II (Acute Physiology And Chronic Health Evaluation) records various parameters 
grouped in vital signs, oxygenation, chemistry and hematology; in addition age and Glasgow 
Coma score is part of the APACHE II score (Knaus et al 1985) (Appendix 4). The worst value 
for each parameter in the last 24 hours will be entered in the CRF, with parameters recorded, if 
possible, at the same time at every visit for a patient (i.e. morning, afternoon or evening) and 
upon significant clinical changes. Parameters for APACHE II will be recorded at 
screening/baseline, Day 2 and then every other day until Day 29 for hospitalized participants 
irrespective of ICU submission. The score will be recorded only for the screening/baseline visit 
in the CRF.
Mean arterial pressure (MAP) may either be directly measured or calculated from the diastolic 
and systolic blood pressure (per medical judgement). 
For oxygenation variables, where patients have an arterial line sited an arterial blood sample 
should be used. In patients, without an arterial line sited should have either an arterial, or 
equivalent measurement (eg capillary blood gas). In the case, where an arterial sample is not 
indicated or feasible clinically, a venous blood gas sample scan be used and the PaO2 estimated
(per medical judgement, see Table 16-4 for guidance on estimation of PaO2). For a given patient
the same methodology to obtain the APACHE II parameters should utilized throughout the 
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8.3.3
Clinical status (9-point ordinal scale)
Assessment of clinical status using a 9-point ordinal scale (WHO 2020) will be recorded at 
baseline, Day 2 and then every other day until Day 29 for hospitalized patients (Appendix 2).  
If a patient is discharged from the hospital, the assessment will be made by phone on the visit 
dates noted in Table 8-1. Each day, the patient’s status from the previous calendar day is 
reviewed; the ordinal score is assigned based on the patient’s worst status from the previous 
day. This score (based on the review of the previous day) will be recorded (i.e. on Day 3, the 
Day 2 score is determined from review of all data recorded on Day 2, and the worst score is 
recorded as the score for Day 2). In addition, on Day 127 or the Day of discharge, clinical status 
on Day 127 or the Day of discharge should be recorded.
8.3.4
CRP and Ferritin
Blood samples will be collected according to the Assessment Schedule (Table 8-1), performed 
locally and recorded in the CRF.
8.3.5
Appropriateness of efficacy assessments
The efficacy endpoints selected for this study are clinically relevant and in keeping with those 
employed in other studies of patients with COVID-19 pneumonia (WHO 2020).


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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 AE Section 10.1.1.
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the 
appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse 
Event must be recorded as an adverse event.
Vital signs
Vital signs will include the collection of rectal, otic or oral body 
temperature (recorded in °C), blood pressure (BP) and pulse 
measurements.
Peripheral oxygen saturation on room air should also be measured at 
the same time as the vitals. For participants requiring supplemental 
oxygen, the oxygen flow rate (L/min) and/or FiO2 should be recorded.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured as specified 
in Table 8-1.
If height cannot be measured, the value reported by the patient will be 
entered in the CRF.
8.4.1
Laboratory evaluations
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
Safety laboratory evaluations will be performed by the local laboratory.


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Special clinical laboratory evaluations
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant.
Safety clinical laboratory tests will be performed locally (see Table 8-2) and recorded in the 
CRF.
Table 8-2
Clinical laboratory tests (local)
Clinically notable laboratory findings are defined in Appendix 3.
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential 
(Basophils, 
Eosinophils, 
Lymphocytes, 
Monocytes, 
Neutrophils, Bands
Chemistry
Albumin (ALB), Alkaline phosphatase, ALT , AST , Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), Bicarbonate, 
Calcium, Magnesium, Phosphorus, Chloride, Sodium, Potassium, 
Creatinine, Creatine kinase, Total Bilirubin (TBL), Total Protein, 
Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, 
Lipase, Glucose (non-fasting), CRP, Ferritin, D-dimer, Troponin, Brain 
Natriuretic Peptide (BNP)
Coagulation*
Prothrombin time (PT), International normalized ratio [INR]), Partial 
thromboplastin time (PTT), Activated partial thromboplastin time (APTT)
Pregnancy Test
Serum / Urine pregnancy test (refer to 'Pregnancy and assessments of 
fertility' Section 8.4.5)
*Coagulation assessment should include only those tests routinely performed according to local
standard of care.
8.4.2
Physical examination
A complete physical examination will be performed according to the Assessment Schedule 
(Table 8-1).
8.4.3
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured as specified in Table 8-1.
If height cannot be measured, the value reported by the participant will be entered in the CRF.
8.4.4
Electrocardiogram (ECG)
ECG assessments will be taken locally. 
ECGs must be recorded after 10 minutes of rest in the supine position to ensure a stable baseline.
In the case of a series of assessments, ECG should be first assessment obtained while participant 
is at rest.
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Single ECGs are to be collected with ECG machines available at the site. Single ECGs are 
collected, and results are entered into the appropriate eCRF page. The original ECGs on non-
heat-sensitive paper, appropriately signed, must be collected and archived at the study site.
ECG examination conducted within the 24h time window prior to screening will be accepted as 
long as the same diagnostic method is used throughout the study.
Each ECG tracing must be labeled with study number, participant initials, participant number, 
date and time, and filed in the study site source documents. 
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate. If necessary, a cardiologist may 
be consulted.
8.4.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have urine or serum pregnancy 
testing at screening and Day 15 and Day 29 if hospitalized. Additional pregnancy testing might 
be performed if requested by local requirements. Pregnancy tests will be conducted at the local 
laboratory. If discharged from hospital, WOCBP should carry out a home pregnancy test on 
Day 15, Day 29, monthly thereafter until end of study, and should inform study site/investigator
if they become pregnant. 
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
8.4.6
Other safety evaluations
Chest X-ray
A standard chest X-ray (CXR) or chest CT or MR scan, will be performed as per local standard 
practice to diagnose pneumonia; except for those who have had a valid test done within 5 days
of randomization. The radiological examination performed at Day 15 (or on day of discharge 
if prior to Day 15) will be collected only if performed according to local SoC and if visit at the 
hospital is possible. The same method should be used at Day 15 (or on day of discharge if prior 
to Day 15) as was used at screening.
Additional assessments may be performed, as needed.
Results from chest X-ray, CT scan or MR scan will be recorded in the CRF.
8.4.7
Appropriateness of safety measurements
The safety assessments selected are appropriate for this protocol which utilizes a compound 
which has not previously been used in a patient population and where the safety profile has not 


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therefore been established. The assessments are relevant to the critical care setting and will 
enable determination of both safety and therapeutic response in this setting.
8.5
Additional assessments
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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
This study involves single i.v. infusion of an approximate duration of 
, and therefore 
the infusion can be interrupted if necessary. In case the clinical setting requires it (e.g. long i.v. 
line),
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the participant or the investigator. 
Study treatment must be discontinued under the following circumstances: 

Participant/guardian decision - participants may choose to discontinue study treatment for
any reason at any time. The investigator believes that continuation would negatively
impact the safety of the participant or the risk/benefit ratio of trial participation

Moderate or severe hypersensitivity reaction occurs, including any of the following:
anaphylaxis (Section 16.1), fever, chills, urticaria, dyspnea, headache, myalgia,
hypotension. Immediate discontinuation of study treatment and initiation of appropriate
medical treatment is required in such cases.

Moderate or severe infusion-related reaction to study drug.

Any protocol deviation or situation that results in a significant risk to the participant’s
safety.
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The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any participant whose treatment code has been broken 
inadvertently for any reason. 
If discontinuation of study treatment occurs, investigator must determine the primary reason for 
the participant’s premature discontinuation of study treatment and record this information on 
the Dosage Administration CRF. 
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 9.1.2). 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, and letter) should be 
made to contact the participant/pre-designated contact as specified in 'Lost to follow-up' 
Section 9.1.3. 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.
9.1.2
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 (e.g. telephone, e-mail, letter) 
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.


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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/Sponsor will continue to retain and use all research results (data) that have already 
been collected for the study evaluation.
9.1.3
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.
9.1.4
Study stopping rules
An independent Data Monitoring Committee will regularly review study data, including 
mortality and SAEs. Enrollment in the study will be placed on hold if any of the following 
occurs:

There is a mortality rate which is 25% greater in the MAS825 arm than in the placebo arm 
(assessed after the first 30, 60 and 90 participants are enrolled).

The DMC or Sponsor consider that the number and/or severity of AEs, abnormal safety 
monitoring tests, or abnormal laboratory findings justify putting the study on hold.
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination (if applicable, insert additional study-specific criteria or modify 
the following criteria as per the study set up):

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 (provide 
instruction for contacting the participant, when the participant should stop taking drug, when 
the participant should come in for a final visit) 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. 


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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 and post-study treatment
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).
Randomized and/or treated participants will have a follow-up visit or call conducted at Days 29, 
45 & 127. All SAEs reported during this time period must be reported as described in 
Section 10.1.3. Documentation of attempts to contact the participant should be recorded in the 
source documentation.
Continuing care should be provided by the investigator and/or referring physician based on 
participant availability for follow-up.    
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 10.1.2):
1. Severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities


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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 10.1.2 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:
1. Dose not changed
2. Dose Reduced/increased
3. 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.
Adverse event monitoring should be continued until the end of study. 
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 IB.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:
1) they induce clinical signs or symptoms
2) they are considered clinically significant
3) they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.


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10.1.2
Serious Adverse Events
A Serious Adverse Event (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:
Article I.
fatal
Article II.
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 met and the malignant neoplasm is not a disease progression of the 
study indication.
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 
immediately, without undue delay, under no circumstances later than 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.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, under no circumstances later than 24 hours of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval 
or otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.
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 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
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 immediately, without undue delay, 
under no circumstances later than24 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.
The newborn will be followed up for a minimum of 1 month after delivery.


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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 (European Medicines Agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
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 CRF 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 
CRF (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 Section 10.1.1, Section 10.1.2 and Section 10.1.3.
10.2
Additional safety monitoring
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 Table 16-1 in Appendix 3 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, every liver event defined in Table 16-2 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. 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.

Hospitalization of the participant if appropriate

Causality assessment of the liver event


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
Thorough follow-up of the liver event should 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 
CRF.
10.2.2
Data Monitoring Committee
This study will include a 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. The committee will include Novartis employees 
and at least one external medical expert. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify, or terminate a trial.
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 that is established between the sponsor and the DMC
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 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 electronic data capture (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 CRFs) (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.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated Clinical Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 


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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 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical (ATC) 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Screenings, randomizations, exit statuses, as well as randomization codes and data about all 
treatment arms assigned to the participant will be tracked using an Interactive Response 
Technology (IRT). 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked 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 a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource Direct Data 
Entry (DDE) 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 site’s 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 GCP, 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 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis clinical research associate organization. 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 CRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original ICF signed by the participant 
(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.


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Novartis monitoring standards require full verification for the presence of informed consent, 
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 
CRFs 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. The analysis will be conducted on all participant data at the 
time the trial ends.
12.1
Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment(s) 
randomized. 
The Safety analysis set will include all randomized participants that have received any study 
drug.
The PD analysis set will include all randomized participants with no protocol deviations with 
relevant impact on PD data.
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. Categorical data will be presented as frequencies 
and percentages. For continuous data, mean, standard deviation, median, minimum, and 
maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be listed and 
summarized by system organ class and preferred term by treatment group.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The dates and times of MAS825 dosing will be listed.
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.
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12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary aim of the study is to evaluate the effect of MAS825 compared with placebo on 
the APACHE II score. A decrease in the score is considered a favourable outcome.
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary estimand, including the primary endpoint is defined in Section 2.1 of this protocol. 
It is based on the APACHE-II score.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint will be evaluated by an analysis of covariance model including treatment 
group and the three stratification factors as factors and baseline APACHE-II score as a covariate. 
The analysis will be performed on the safety analysis set. The mean differences of MAS825 vs 
placebo will be reported with 90% confidence intervals (CIs). The 1-sided p-value for the 
overall treatment factor will be reported.
The primary objective will be achieved if the null hypothesis that MAS825 is not different to 
placebo is rejected using a one side alpha of 10%. 
12.4.3
Handling of remaining intercurrent events of primary estimand
As described in Section 2.1, discontinuation of study treatment for any reason will be ignored. 
12.4.4
Handling of missing values not related to intercurrent event
Handling of missing APACHE II scores or components of APACHE II scores at Day 15 or on 
day of discharge will be specified in the SAP.
12.4.5
Sensitivity analyses for primary endpoint/estimand
If there are imbalances in demographic or baseline characteristics between the two treatment 
groups, then an ANCOVA model similar to the primary analysis model with the additional 
inclusion of these demographic or baseline characteristics as covariates may be fitted.
12.4.6
Supplementary analysis
Not applicable
12.4.7
Supportive analyses
Not applicable.
12.5
Analysis of secondary endpoints/estimands
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Descriptive statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for variables that are of the numeric or continuous type, while frequency distributions 
(with number and percent) will be provided for categorical variables.


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Analyses of the hospital outcomes will be fully specified in the SAP.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
.
12.5.2.1 Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of randomized 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events and other significant adverse events leading to discontinuation.
12.5.2.2 Vital signs
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. 
Summary statistics will be provided by treatment and visit/time.
12.5.2.3 ECGs
PR, QRS, QT, QTcF, and RR intervals will be obtained from ECGs for each participant during 
the study. ECG data will be read and interpreted locally.
Categorical analysis of QT/QTcF interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTcF intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced by treatment group.
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.


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12.5.2.4 Clinical laboratory evaluations
All laboratory data will be listed by treatment group, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time. 
Serum CRP levels will be analyzed on a log-scale fitting a repeated measures mixed model 
including treatment group, study day, the three stratification factors and log transformed 
baseline CRP as a covariate. Interactions between study day and each of the terms in the model 
will also be included. The back-transformed ratios of MAS825 vs placebo will be reported with 
90% CIs. The 1-sided p-value for the overall treatment factor will be reported. Ferritin levels 
will also be analyzed in the same manner.
12.5.2.5 Other safety evaluations 
The proportion of participants who have a positive SARS-CoV-2 test will be summarized by 
treatment group and visit.
12.6
Analysis of exploratory endpoints
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12.9
Sample size calculation
12.9.1
Primary endpoint(s)
The sample size is limited to maximum of 60 participants to be treated with a single i.v.dose of 
MAS825 due to limitations in the available drug supply at this point in time.To establish clinical 
efficacy based on APACHE II score a sample size of 60 participants per treatment group 
provides 80% power when testing on an 10% 1-sided alpha level under the assumption that 
MAS825 reduces the APACHE II score by 3.6 points more than placebo (assumed standard 
deviation of 9.2 based on Yang et al 2020).
12.9.2
Secondary endpoint(s)
For the analysis of CRP a sample size of 60 participants per treatment group provides 80% 
power when testing on a 1% 1-sided alpha level under the assumption that MAS825 reduces 
CRP by 44% more than placebo (assumed CV of 130% based on the range of variability 
observed in Chen et al 2020 and previous studies with canakinumab).
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 (GCP), 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.
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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 ICF, 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. 
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, 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.
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.


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14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.
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
References are available upon request
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19 Pneumonia (COVACTA) https://clinicaltrials.gov/ct2/show/NCT04320615 (accessed 22nd 
April 2020)
Abdel Fattah E, Bhattacharya A, Herron A, et al (2015) Critical role for IL-18 in spontaneous 
lung inflammation caused by autophagy deficiency. J Immunol 194: 5407-5416.
Afonina IS, Muller C, Martin SJ, et al (2015) Proteolytic Processing of Interleukin-1 Family 
Cytokines: Variations on a Common Theme. Immunity 42: 991-1004.
Ascierto PA, Fox B, Urba W, et al (2020) Insights from immuno-oncology: the Society for 
Immunotherapy of Cancer Statement on access to IL-6-targeting therapies for COVID-19. J 
Immunother Cancer 8.
Belkaya SE, Michailidis CB, Korol M, et al (2019) Inherited IL-18BP deficiency in human 
fulminant viral hepatitis. J Exp Med 216: 1777-1790. 
Cameron LA, Taha RA, Tsicopoulos A, et al (1999) Airway epithelium expresses interleukin-
18. Eur Respir J 14: 553-559. 
Canna SW, Girard C, Malle L,
et al (2017)
Life-threatening NLRC4-associated
hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol 139: 
1698-1701.
Cao Y, Li Q, Chen J, et al (2020) Hospital Emergency Management Plan During the COVID-
19 Epidemic. Acad Emerg Med 27: 309-311.
Chakraborty A, Tannenbaum S, Rordorf C, et al (2012) Pharmacokinetic and pharmacodynamic 
properties of canakinumab, a human anti-interleukin-1β monoclonal antibody. Clin 
Pharmacokin 51: e1-e18.
Chen N, Zhou M, Dong X, et al (2020) Epidemiological and clinical characteristics of 99 cases 
of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet; 
395(10223):507-13.
Coates BM, Staricha KL, Ravindran N, et al (2017) Inhibition of the NOD-Like Receptor 
Protein 3 Inflammasome Is Protective in Juvenile Influenza A Virus Infection. Front Immunol 
8: 782. 
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CD73 in innate protection during acute lung injury. J Immunol 178: 8127- 8137.
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function: study design, data analysis, and impact on dosing and labeling. Rockville, MD: Food 
and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for 
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Franchi L, Eigenbrod T, Munoz-Planillo R, et al (2014) Cytosolic double-stranded RNA 
activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ 
efflux. J Immunol 193: 4214-4222. 
Hasan D, Blankman P, and Nieman GF (2017) Purinergic signalling links mechanical breath 
profile and alveolar mechanics with the pro-inflammatory innate immune response causing 
ventilation-induced lung injury. Purinergic Signal 13: 363-386.
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danger signals by the inflammasomes. Immunol Rev 243: 119-135.
Huang KJ, Su IJ, Theron M, et al (2005) An interferon-gamma-related cytokine storm in SARS 
patients. J Med Virol 75: 185-194.
Huang C, Wang Y, Li X, et al (2020) Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. The Lancet, 395: 497-506.
Ichinohe T, Lee HK, Ogura Y, et al (2009) Inflammasome recognition of influenza virus is 
essential for adaptive immune responses. J Exp Med 206: 79-87.
Jia X, Liu B, Bao L, et al (2018) Delayed oseltamivir plus sirolimus treatment attenuates H1N1 
virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation 
and inflammatory cell infiltration. PLoS Pathog 14: e1007428.
Kang MJ, Choi JM, Kim BH, et al (2012) IL-18 induces emphysema and airway and vascular 
remodeling via IFN-gamma, IL-17A, and IL-13. Am J Respir Crit Care Med 185: 1205-1217.
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diseases. J Interferon Cytokine Res 32: 443-449.
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classification system. Crit Care Med 13: 818-829.
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lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest 107: 1529-1536.
Kuipers MT, Aslami H, Janczy JR, et al (2012) Ventilator induced lung injury is mediated by 
the NLRP3 inflammasome. Anesthesiology 116: 1104-1115.
Liu H, Gu C, Liu M, et al (2019) Ventilator-induced lung injury is alleviated by inhibiting 
NLRP3 inflammasome activation. Mol Immunol 111: 1-10.
Lv Z, Wang Y, Liu YJ, et al (2018) NLRP3 Inflammasome Activation Contributes to 
Mechanical Stretch-Induced Endothelial-Mesenchymal Transition and Pulmonary Fibrosis. 
Crit Care Med 46: e49-e58.
Matsuyama H, Amaya F, Hashimoto S, et al (2008) Acute lung inflammation and ventilator-
induced lung injury caused by ATP via the P2Y receptors: an experimental study. Respir Res 
9: 79.
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McAuley JL, Tate MD, MacKenzie-Kludas CJ, et al (2013) Activation of the NLRP3 
inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and 
disease. PLoS Pathog 9: e1003392.
Mehta P, McAuley DF, Brown M, et al (2020) COVID-19: consider cytokine storm syndromes 
and immunosuppression. Lancet 395:1033–4.
Moghaddas F, Zeng P, Zhang Y, et al (2018) Autoinflammatory mutation in NLRC4 reveals a 
leucine-rich repeat (LRR)-LRR oligomerization interface. J Allergy Clin Immunol 142: 1956-
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lung injury stimulates fibroblast proliferation through IL-1 beta-induced IL-6 expression. J 
Immunol 172: 2668-2677.
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lavage fluids from patients with ARDS, a prominent role for interleukin-1. Am J Respir Crit 
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inflammation in the mammalian host via the NLRP3-caspase-1 inflammasome. Sci Rep 7: 7625.
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blockade in PBMC.
Tate MD, Ong JDH, Dowling JK, et al (2016) Reassessing the role of the NLRP3 
inflammasome during pathogenic influenza A virus infection via temporal inhibition. Sci Rep 
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Practical Scale. The Lancet. Volume 304, Issue 7872, Pages 81-84.
Vanden Berghe T, Demon D, Bogaert P, et al (2014) Simultaneous targeting of IL-1 and IL-18 
is required for protection against inflammatory and septic shock. Am J Respir Crit Care Med 
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Blueprint, Feb 18 2020.
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Wu J, Yan Z, Schwartz DE, et al (2013) Activation of NLRP3 inflammasome in alveolar 
macrophages contributes to mechanical stretch-induced lung inflammation and injury. 
J Immunol 190: 3590-3599.
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drug disposition model for two drugs competing for the same receptor.
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Yang X, Yu Y, Xu J, et al (2020) Clinical course and outcomes of critically ill patients with 
SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational 
study. Lancet Respir Med.
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respiratory syndrome. Infect Immun 72: 4410-4415. 
Zhang X, Song K, Tong F, et al (2020) First case of COVID-19 in a patient with multiple 
myeloma successfully treated with tocilizumab. Blood Adv 4: 1307-1310.
Zhang LM, Zhang Y, Fei C, et al (2019) Neutralization of IL-18 by IL-18 binding protein 
ameliorates bleomycin-induced pulmonary fibrosis via inhibition of epithelial-mesenchymal 
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Zhou F, Yu T, Du R, et al (2020) Clinical course and risk factors for mortality of adult inpatients 
with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet.


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16
Appendices
16.1
Appendix 1: Anaphylaxis
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from baseline.


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16.2
Appendix 2: 9-point ordinal scale determination
The ordinal scale is an assessment of the clinical status at the first assessment of a given study 
day. 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:
Patient State  
Descriptor   
Score
Uninfected
No clinical or virological evidence of infection
0
Ambulatory
No limitation of activities
1
Limitation of activities
2
Hospitalized
Mild disease
Hospitalized, no oxygen therapy
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, 
ECMO
7
Dead
Death
8
Source: (WHO 2020)


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16.3
Appendix 3: 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 > 3x 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
Criteria
Actions required
Follow-up monitoring
Total Biliruin (isolated)
>1.5 – 3.0 ULN

Repeat LFTs within 48-72 
hours
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome)

Repeat LFT within 48-72 
hours

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Monitor LFTs weekly until 
resolutionc 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

Establish causality

Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
Any AE potentially indicative of 
a liver toxicity*

Hospitalization if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab)in 
the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution 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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16.4
Appendix 4: ICU scores 
Table 16-3
APACHE II
Variable
Unit
Age
years
Glasgow Coma Score
Vitals
Body temperature
oC
Mean arterial pressure (MAP)
mmHg
Heart rate 
bpm
Respiratory rate
breaths/m
Oxygenation 
FiO2
%
PaO2
mmHg
Arterial pH
PaCO2
Altitude of site
mmHg
Meters above sea level
Chemistry
Sodium
mEq/L
Potassium 
mEq/L
Creatinine 
mg/dL
Acute Renal Failure
Yes/No
Hematology
Hematocrit 
%
White blood cell (WBC) count
x109/L
Severe organ system 
insufficiency or is 
immunocompromised
Yes/No
Source: (Knaus et al 1985)


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Table 16-4
Estimating PaO2 from a given SpO2
SpO2 (%) PaO2 (mmHg)
PaO2 (mmHg)
80
44
81
45
82
46
83
47
84
49
85
50
86
52
87
53
88
55
89
57
90
60
91
62
92
65
93
69
94
73
95
79
96
86
97
96
98
112
99
145
Source : (Vincent et al 2009)


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Table 16-5
Estimating FiO2
Method
O2 flow (l/min)
Estimated FiO2 (%)*
Nasal cannula
1
24
2
28
3
32
4
36
5
40
6
44
Nasopharyngeal catheter
4
40
5
50
6
60
Face mask
5
40
6-7
50
7-8
60
Face mask with reservoir
6
60
7
70
8
80
9
90
10
95
Source : (Vincent et al 2009)
* If patient is breathing air then estimated Fi02 is 21%


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Table 16-8
GLASGOW COMA SCORE
Eye Opening
Criterion
Rating
Score
Open before stimulus
Spontaneous
4
After spoken or shouted 
request
To sound
3
After finger tip stimulus
To pressure
2
No opening at any time, no 
interfering factor
None
1
Closed by local factor
Non testable
NT
Verbal Response
Criterion
Rating
Score
Correctly gives name, place 
and date
Orientated
5
Not orientated but 
communication coherently
Confused
4
Intelligible single words
Words
3
Only moans/groans
Sounds
2
No audible response, no 
interfering factor
None
1
Factor interfering with 
communication
Non testable
NT
Best motor response
Criterion
Rating
Score
Obey 2-part request
Obeys commands
6
Brings hand above clavicle to 
stimulus on head neck
Localising 
5
Bends arm at elbow rapidly, but 
features not predominantly 
abnormal
Normal flexion
4
Bends arm at elbow, features 
clearly predominantly abnormal
Abnormal flexion
3
Extends arm at elbow
Extension 
2
No movement in arms/legs, no  
interfering factor
None
1
Paralysed or other limiting 
factor
Non testable
NT
Source: (Teasdal and Jennett 1974)


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16.5
Appendix 5: Severity of hepatic impairment (Child-Pugh)
Points scored for observed 
findings
1 point
2 points
3 points
Encephalopathy grade*
Absent
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum bilirubin(µmol/L)
<34.2
34.2 – 51.3
>51.3
Serum albumin (g/L)
>35
28 – 35
<28
Prothrombin time (INR)
<1.16
1.16 – 1.56
>1.56
Classification
Child-Pugh grade
Child-Pugh A
Child-Pugh B
Child-Pugh C
Points required
5 – 6
7 – 9
10 – 15
*Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity
Source: (FDA 2003)

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
CMAS825
CMAS825F12201 / NCT04382651
MAS825: A Phase 2, randomized, placebo-controlled, 
participant and investigator blinded, multi-center study to 
assess efficacy and safety of MAS825 for the treatment of 
SARS-CoV-2 infected patients with COVID-19 pneumonia 
and impaired respiratory function
Statistical Analysis Plan (SAP)
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Author(s):
Document type:
SAP Documentation – NIBR
Document status:
Final
Release date:
20-May-2021
Number of pages:
51
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Table of contents
Table of contents..................................................................................................................3
List of tables.........................................................................................................................5
List of figures.......................................................................................................................5
1
Introduction..........................................................................................................................6
1.1
Scope of document...................................................................................................6
1.2
Study reference documentation................................................................................6
1.3
Study objectives.......................................................................................................6
1.4
Study design and treatment......................................................................................7
2
First interpretable results (FIR)............................................................................................8
3
Interim analyses ...................................................................................................................9
4
Statistical methods: Analysis sets........................................................................................9
4.1
Baseline..................................................................................................................10
4.2
Unscheduled visits .................................................................................................10
6
Statistical methods for Pharmacodynamic (PD) parameters .............................................11
6.1
Primary objective...................................................................................................11
6.1.1
Variable .................................................................................................11
6.1.2
Descriptive analyses..............................................................................12
6.1.3
Statistical model, assumptions and hypotheses.....................................12
6.1.4
Sensitivity analysis for primary objective.............................................12
6.1.5
Model checking procedures...................................................................13
6.1.6
Intercurrent events.................................................................................13
6.1.7
Missing data...........................................................................................13
6.1.8
Handling of discharge and death...........................................................13
6.1.9
Derivation of the primary estimand.......................................................13
6.1.10
Supportive analysis................................................................................14
6.2
Secondary objectives..............................................................................................16
6.2.1
Variables................................................................................................16
6.2.2
Descriptive analyses..............................................................................16
6.2.3
Statistical model, assumptions and hypotheses.....................................18
6.2.4
Model checking procedures...................................................................18
6.2.5
Graphical presentation of results...........................................................18
6.3
Exploratory objectives ...........................................................................................19
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7
Statistical methods for safety and tolerability data............................................................22
7.1
Variables ................................................................................................................22
7.2
Descriptive analyses...............................................................................................22
7.2.1
Subject demographics and other baseline characteristics......................22
7.2.2
Treatment...............................................................................................24
7.2.3
Vital signs..............................................................................................27
7.2.4
ECG evaluations....................................................................................27
7.2.5
Clinical laboratory evaluations..............................................................28
7.2.6
Adverse events.......................................................................................28
7.2.7
Graphical presentation...........................................................................29
9
Reference list .....................................................................................................................31
10 Appendix............................................................................................................................31
10.1
Units and conversions............................................................................................31
10.1.1
Conversion for absolute neutrophil counts............................................32
10.2
APACHE II............................................................................................................32
10.2.1
APACHE II Scoring..............................................................................35
10.5
Glasgow Coma Score.............................................................................................48
10.5.1
Glasgow Coma Scoring.........................................................................48
10.6
9-point ordinal scale...............................................................................................49
10.7
Steroid conversion factors......................................................................................49
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List of tables
Table 1-1
Objectives................................................................................................6
Table 4-1
Protocol deviation codes and analysis sets..............................................9
Table 10-1
Conversion of SpO2 to PaO2 ................................................................33
Table 10-2
Steroids conversion factors....................................................................50
List of figures
Figure 1-1
Study design ............................................................................................7
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1
Introduction
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CMAS825F12201”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol to be reported in the CSR as well as any potential IA. The data 
presentation and analyses for the DMC are not part of this analysis plan.
1.2
Study reference documentation
This SAP is based on the protocol amendment v01 for study CMAS825F12201 dated 03-Jul-
2020.
1.3
Study objectives
Table 1-1
Objectives
Objective(s)
Endpoint(s)
Primary Objective(s)

To evaluate the effect of MAS825,
compared with placebo, on the Acute
Physiology and Chronic Health Evaluation II
(APACHE II) score
Endpoint(s) for primary objective(s)

APACHE II severity of disease score on Day
15 or on day of discharge (whichever is
earlier) with worst case imputation for death
Secondary Objective(s)

To evaluate the effect of MAS825,
compared with placebo on inflammatory
status
Endpoint(s) for secondary objective(s)

Serum C-reactive protein (CRP) levels and
ferritin

To evaluate the effect of MAS825,
compared with placebo, on clinical status
Endpoints based on the 9-point ordinal scale:

Survival without the need for invasive
mechanical ventilation at Days 15 and 29

At least one level improvement in clinical
status at Days 15 and 29

Clinical status over time

To evaluate the safety of MAS825,
compared with placebo

Number of participants with Adverse Events
(AE), Serious Adverse Events (SAE),
clinically significant changes in laboratory
measures, and vital signs
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1.4
Study design and treatment
This is a Phase 2, randomized, placebo -controlled, participant and investigator blinded, multi-
center study to assess the efficacy and safety of MAS825 for the treatment of SARS-CoV-2 
infected patients with COVID-19 pneumonia and impaired respiratory function 
(Figure 1-1).
Figure 1-1
Study design 
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The study consists of five parts:
1. Screening / Baseline / Treatment (Day -1 to 1): lasts up to a maximum of 24 hours and
comprises a screening / baseline assessment. This visit will be used to confirm that the study
inclusion and exclusion criteria are met and serves as baseline assessment prior to
randomization. Baseline blood tests will be performed in all patients; those who screen fail
because of study inclusion / exclusion criteria (e.g., serum CRP, liver function tests), will
not undergo randomization.
Eligible patients will receive a single i.v. infusion of 
 MAS825 or placebo on Day
-1 to 1 and will be observed until Day 15. Patients will be randomized as soon as possible,
but within a maximum of 24 hours after screening in a 1:1 ratio to receive either treatment
with MAS825 or placebo in addition to SoC. Randomization will be stratified according to
the following, all of which may influence outcome in COVID-19:

age (≤65years, >65years)

administration of any anti-viral therapy (e.g., hydroxychloroquine, chloroquine,
convalescent plasma, remdesivir, faripivavir, ritonavir, lopinavir) as SoC (yes / no)

presence of ≥1 of the following comorbidities: diabetes, hypertension, cardiovascular
disease, chronic lung disease (yes / no)
2. Treatment period (Day 2-15): Study assessments to be conducted every 2 days for
hospitalized patients. If patients are discharged from the hospital prior to Day 15,
assessments on the day of discharge should be performed according to the schedule listed
under Day 15 and patient should return to the site for the Day 15 assessment (all other visits
between discharge and Day 15 can be omitted). If a hospital visit is not possible at Day 15,
then home nursing services may be used to support this last visit where these are available
in accordance with local guidelines and should include all possible assessments (e.g. oxygen
saturation with portable monitors). In case home nursing is not possible, patients will be
contacted by phone on day 15.
3. Follow-up (Day 16-29): After completion of the treatment period, patients will be observed
until Day 29 or discharged from hospital, whichever is sooner. Study assessments to be
conducted every 2 days for domiciled patients.
If patients are discharged from hospital prior to Day 29, a study visit conducted by telephone
will occur on Day 29 (all other visits between discharge and Day 29 can be omitted).
4. Safety follow-up visit assessment (Day 45): A follow-up visit will be conducted at Day 45
if the patient is hospitalized. If patients are discharged from hospital prior to Day 45, a study
visit will be conducted by telephone on Day 45.
5. End of Study/Safety follow-up visit assessment (Day 127): A follow-up visit for safety
will be conducted at Day 127 if the patient is hospitalized. If patients are discharged from
hospital prior to Day 127, a study visit will be conducted by telephone on Day 127.
2
First interpretable results (FIR)
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3
Interim analyses
4
Statistical methods: Analysis sets
For all analysis sets, participants will be analyzed according to the study treatment(s) 
randomized. 
The Safety analysis set will include all randomized participants that have received any study 
drug.
The PD analysis set will include all randomized participants with no protocol deviations with 
relevant impact on PD data.
The PD analysis set 2 will include all randomized participants with no protocol deviations with 
relevant impact on PD data. The participants that did not meet all the eligibility criteria 
mentioned in study protocol section 5 will be excluded from this set programmatically. Exclude 
participants with APACHE II score less than 10 at baseline programmatically.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category 
   Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from safety analysis in case of these PDs:
Exclude subject from safety 
analysis set
INCL02
Informed consent form not obtained
Yes
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Category 
   Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from safety analysis in case of these PDs:
Exclude subject from safety 
analysis set
INCL02
Informed consent form not obtained
Yes
Subjects are excluded from PD analysis set in case of these PDs:
Exclude subject from PD 
analysis set
INCL06
Patient enrolled but APACHE II score is less 
than 10 at Screening Visit
       Yes
INCL03
Patient randomized but no confirmed 
coronavirus (SARS-CoV)-2 infection
     Yes
INCL02
Informed consent form not obtained
Yes
Subjects are excluded from PD analysis set 2 in case any of the 
inclusion/exclusion criteria related PDs occur
Exclude subject from PD 
analysis set 2
INCLxx, EXCLxx
Yes
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.
4.1
Baseline
The baseline value is defined as the last assessment performed prior to randomization.
4.2
Unscheduled visits
Data collected at unscheduled visits will not be used for analysis by visit, but will used to replace 
missing values if a Last observation carried forward (LOCF) approach is applied (i.e. for the 
mortality scores APACHE II, SAPS II and SOFA as described below).
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6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary aim of the study is to evaluate the effect of MAS825 compared with placebo on 
the APACHE II score. A decrease in the score is considered a favourable outcome.
6.1.1
Variable
The primary clinical question of interest is: What is the effect of MAS825 compared with 
placebo in SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired respiratory 
function on APACHE-II severity of disease score taking into account early discharge from 
hospital or death but regardless of investigational treatment discontinuation?
The justification for the primary estimand is that it will capture the combined effect of 
investigational treatment in participants who remain in hospital for 14 days, the effect on early 
discharge within 14 days and the effect on death rate within 14 days, in a manner than reflects 
clinical practice. In this document the primary estimand will be referred to as the “combined 
APACHE II score”.
The primary estimand is described by the following attributes:

Population: SARS-CoV-2 infected patients with COVID-19 pneumonia and impaired
respiratory function.

Endpoint: APACHE II severity of disease score on Day 15 or on day of discharge
(whichever is earlier) with worst case imputation for death. Participants who die on Day
15 or earlier will be assigned the highest observed APACHE II score of any of the
participants at any time during the trial. Note this imputation for death takes precedence
over the APACHE II score on day of discharge.

Treatment of interest: the randomized treatment (the investigational treatment MAS825
or placebo).

Handling of remaining intercurrent events: Treatment discontinuation for any reason
will be ignored and thus follow a treatment policy strategy i.e. participants who
discontinue treatment will be treated in the same manner as those that continue the
treatment as planned.

Summary measure: The difference in variable means between treatments.
APACHE II scores are on a range between 0 and 71 points, however, in practice it is rare for 
any patient to accumulate more than 55 points. A decrease in the APACHE II score is 
considered a favorable outcome.
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The APACHE II scores are derived from a number of different clinical endpoints according to 
the scoring table as outlined in (Knaus et al., 1985) and listed in the Appendix. The handling of 
missing data is described in Section 6.1.7.
6.1.2
Descriptive analyses
To assess the impact of the replacement with score values at early discharge and the worst case 
imputation for death on the combined APACHE II score the following summary statistics will 
be provided: 

only for the participants with an early discharge (i.e. prior to day 15): if APACHE II 
score values at the early discharge visit and the actual Day 15 visit are available these 
will be summarized separately by visit (“early discharge”, “Day 15”). 

In addition the frequency of worst case imputation for deaths per treatment group will 
be provided. 
Panels of individual spaghetti plots over time for APACHE II scores and their change from 
baseline will be provided by treatment group. The profiles of all participants in the respective 
treatment group will be included in these graphs as grey lines in the background and the 
respective individual participants profile will be plotted with darker color in the foreground. It 
will be indicated by a symbol when a patient was discharged or died (see data handling rules 
below in Section 6.1.8).
The sub-scores contributing to APACHE II scores derivation would be summarized.
6.1.3
Statistical model, assumptions and hypotheses
The combined APACHE II endpoint as described in the estimand above is assumed to follow a 
normal distribution. 
The primary endpoint will be analyzed by an analysis of covariance model including treatment 
group and the three stratification factors as factors and baseline APACHE-II score as a covariate. 
The analysis will be performed on the safety analysis set. The mean differences of MAS825 vs 
placebo will be reported with 90% confidence intervals (CIs). The 1-sided p-value for the 
overall treatment factor will be reported.
The primary objective will be achieved if the null hypothesis that MAS825 is not different to 
placebo is rejected using a one side alpha of 10%.
6.1.4
Sensitivity analysis for primary objective
The combined APACHE II endpoint as described in the estimand above is assumed to follow a 
normal distribution. 
The primary endpoint will be analyzed by an analysis of covariance model including treatment 
group and the three stratification factors as factors and baseline APACHE-II score as a covariate. 
The analysis will be performed on the PD analysis set 2. The mean differences of MAS825 vs 
placebo will be reported with 90% confidence intervals (CIs). The 1-sided p-value for the 
overall treatment factor will be reported.


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6.1.5
Model checking procedures
The appropriateness of the normality assumption of the combined APACHE II score will be 
assessed by graphical means e.g. residual plots.
6.1.6
Intercurrent events
As described in the primary estimand discontinuation of study treatment for any reason will be 
ignored. 
6.1.7
Missing data
Missing data for the APACHE II score will be handled as follows:

Missing values for age at screening will be replaced by using the stratification information 
assigning 3 points to participants up to 65 years (<=65 years) and 5 points to participants 
above 65 years.  

Missing information on acute renal failure status: use Serum Creatinine values without 
renal status information.

Subscores of the Glasgow Coma Score (i.e. responses to Best Eye Response, Motor 
Response, Verbal Response) scored as “untestable”, “unknown” or missing will be 
replaced by the last available actual score. The response “untestable” is selected if the 
patient is unconcious (e.g. through sedation in case of mechanical ventilation). 

Missing values in any of the other parameters required for the derivation of the APACHE 
II score will be replaced by the last available assessment, as long as data is not carried 
forward by more than 4 days.
For a given visit, these missing data rules will only be applied if for at least one of the parameters 
contributing to the APACHE II score a value at this visit was reported.
6.1.8
Handling of discharge and death
For the APACHE II score, 

in case a participant is discharged before Day 29 it will not be derived for any visits after 
the discharge visit (i.e. the last APACHE II score will be derived on the day of discharge). 

In case a participant dies no APACHE II score will be derived starting from the day of 
death.
6.1.9
Derivation of the primary estimand
The primary estimand, referred to as the “combined APACHE II score”, will be derived as 
follows from the APACHE II scores after application of the missing data as well as discharge 
and death handling approaches described above:

For participants hospitalized at Day 15: APACHE II score at Day 15

For participants discharged prior to Day 15: APACHE II score at the discharge visit is 
used


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
For participants that died on Day 15 or earlier: highest observed APACHE II score of
any of the participants at any time during the trial.

Imputation for death takes precedence over the imputation of the APACHE II score on
day of early discharge.
6.1.10
Supportive analysis 
Variable and analysis set
For analysis 1 the combined APACHE II score as for the primary analysis will be used. This 
analysis will be run on the PD analysis set.
For analyses 2-4 mentioned above all available APACHE II scores at all scheduled visits 
(excluding discharge or early discharge visits) up to Day 29 after applying the rules for missing 
data and handling of discharge and death. These analyses will be based on the safety analysis 
set.
For the subgroup analyses the “PD analysis set” is used. In addition only participants in the high 
baseline CRP group are considered. The high baseline CRP group is defined as any subject with 
a baseline CRP value > median baseline CRP value of all participants in this study.
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Model checking procedures
The appropriateness of the normality assumption of the APACHE II scores will be assessed by 
graphical mean e.g. residual plots.
Graphical presentation of results
Estimated mean APACHE II scores +/- SE will be plotted over time by treatment group.
6.2
Secondary objectives
6.2.1
Variables
The following variables and corresponding objectives are classified as secondary  
pharmacodynamic endpoints and will be evaluate for their effect of MAS825 compared with 
placebo,

On inflammatory status: Serum C-reactive protein (CRP) levels and ferritin

On clinical status: Endpoints based on the 9-point ordinal scale:

Survival without the need for invasive mechanical ventilation at Days 15 and 29
defined by a 9-point ordinal scale score of < 6 points at all time points

At least one level improvement in clinical status at Days 15 and 29:
defined as difference of ≥1 in the 9-point ordinal scale score of the screening value
– Day 15 or Day 29 respectively.

Clinical status over time
Missing data
For the clinical status 9-point ordinal scale missing values will be handled as follows:

For participants who died prior to Day 29: The score for death will be imputed for all
visits following the death up to and including Day 29.
For all other participants: LOCF will be applied up to and including Day 127. Following 
discharge or early discharge LOCF will be applied to all intermediate visits. 
6.2.2
Descriptive analyses
CRP and ferritin
Panels of individual spaghetti plots over time for CRP and ferritin will be provided using a 
logscale. The profiles of all participants in the respective treatment group will be included in 
these graphs as grey lines in the background and the respective individual participants profile 
will be plotted with darker color in the foreground. The respective applicable normal ranges 
will be added and it will be indicated by a symbol if a patient died.


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Survival without the need for invasive mechanical ventilation
The numbers and percentages of responders will be calculated up to Day 15 and up to Day 29 
respectively. It will be presented by treatment group together with the difference in response 
rates.
Improvement in clinical status
The numbers and percentages of responders will be calculated up to Day 15 and up to Day 29 
respectively. It will be presented by treatment group together with the difference in response 
rates and a two-sided 90% CI based on Fishers exact test.
In addition a shift table of changes in response status will be provided with weekly time intervals 
(e.g. baseline, week 1, week 2, week 3 and week 4). For this the following response categories 
will be included:

improvement of at least 1 step from baseline, 

no change from baseline

worsening from baseline.
Also a stacked barchart illustrating the percentage of participants in each response categories 
as outlined above will be provided. Treatment groups will be presented next to each other. This 
will be provided for weeks 1, 2, 3 and 4.
For the subgroup analysis a shift table and stacked barchart for subgroup of participants with 
high baseline CRP by high and low corticosteroid dose during week 1 will be provided.
Clinical status over time
The 9-point ordinal scale will be summarized (mean, median, standard deviation, minimum, 
maximum, frequencies and percentages in each category) will be summarized by visit 
(including a time point for data from early discharge) and treatment group.
A stacked barchart illustrating the percentage of participants for each category of the 9-point 
ordinal scale with one bar will be provided. Treatment groups will be presented next to each 
other within one category. This will be provided for Day 8, Day 15, Day 21 and Day 29 
(labeled as weeks 1, 2, 3 and 4). 
The 9-point ordinal scale will also be plotted using a heat map with one row representing one 
patient and the score from baseline up to Day 29 visit will be shown by time using one unique 
color for each level of scale. The heat map will be plotted for each treatment group, within 
which patients will be sorted by the 9-point ordinal scale from high to low and by visit. The 
time when discharged from hospital will also be flagged on the plot. Values imputed by LOCF 
will be indicated by a different pattern (e.g. stripes) but the same color.
In addition a shift table and stacked barchart of changes between the categories of the 9-point 
scale will be provided with weekly time intervals (e.g. baseline, week 1, week 2, week 3 and 
week 4).
For the subgroup analysis a shift table and stacked barchart for subgroup of participants with 
high baseline CRP by high and low corticosteroid dose during week 1 will be provided.


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6.2.3
Statistical model, assumptions and hypotheses
CRP and ferritin
CRP levels are assumed to follow a log-normal distribution. Thus the log-transformed CRP data 
will be analyzed by fitting an MMRM model. Treatment, visit and their interaction as well as 
the three stratification factors will be included as fixed factors and baseline CRP as a covariate. 
Interactions between visit and each of the terms in the model will also be included. To model 
the dependency of observations an unstructured variance-covariance matrix will be fitted.
The analysis will be performed on the PD analysis set. The back-transformed geometric means 
for both treatment groups as well as the geometric mean ratios (MAS825 vs placebo) will be 
reported together with 90% confidence intervals (CIs) for each visit. The 1-sided p-value for 
the overall treatment factor will be reported. Ferritin levels will also be analyzed in the same 
manner.
For the subgroup analysis the same model as for the original MMRM analysis including in 
addition a factor for high vs. low corticosteroid use during week 1 (see Section 7.2.2 for details) 
and its 3-way interaction with treatment and visit. The geometric means (+/-SE) per 
corticosteroid category and treatment group as well as the ratio of geometric mean (90% CI) 
per corticosteroid group are reported for each visit.
6.2.4
Model checking procedures
CRP and ferritin
The appropriateness of the log-normality assumption of CRP and ferritin values will be assessed 
by graphical mean e.g. residual plots.
6.2.5
Graphical presentation of results
CRP and ferritin
Estimated mean CRP +/- SE will be plotted over time by treatment group. The estimated 
geometric mean ratio to baseline in CRP +/- SE will also be presented. Ferritin levels will also 
be presented in the same manner.
For the subgroup analyses the following graphs will be provided:

A line plot of the geometric means (+/-SE) are provided by corticosteroid dose category
and treatment group together with the estimated values of the primary analyses by
treatment group over time.
Side-by-side a second line plot on the treatment ratios (90% CI) per by corticosteroid dose 
category together with the estimated treatment difference (90% CI) of the primary analyses over 
time is given.


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Survival without the need for invasive mechanical ventilation
Kaplan-Meier graphs with separate lines by treatment group will be provided for a graphical 
presentation. Participants will be censored discontinuating from the study or not experiencing 
an event.
6.3
Exploratory objectives
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7
Statistical methods for safety and tolerability data
All safety presentations and analyses will be based on the Safety Analysis Set. 
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, respiratory rate, body temperature, 
peripheral oxygen saturation, oxygen flow rate and/or FiO2), ECG intervals, safety laboratory 
measurements, as well as subject demographics, baseline characteristics, and treatment 
information.
7.2
Descriptive analyses
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data, which will also be summarized where appropriate (e.g. change from 
baseline summaries). 
The on-treatment period lasts from the date of administration of study treatment to Day 127.
7.2.1
Subject demographics and other baseline characteristics
Screen failures with SAEs
For screen failed participants in case the participant experienced a serious adverse event during 
the screening phase the following information is captured and listed: demographic information, 
informed consent, as well as information on SAEs. Inclusion/Exclusion criteria will be 
summarized.
Disposition
The following disposition status will be summarized as the number and percentage of 
participants

who were screened but not randomized (percentage based on all screened participants)

who were randomized (percentage based on all screened participants)

who were randomized but not treated (overall and by reason) 

who were discharged prior to day 15 and day 29

who completed the study until day 15, day 29, day 45 as well as day 127 

who discontinued treatment  prior to day 15,

who discontinued from study (overall and by the primary reason for discontinuation).
The number and percentage of participants included in each analysis set will be tabulated by 
treatment group. Participants excluded from an analysis sets will be listed with reasons for 
exclusion (i.e. including both protocol and non-protocol deviations).
Unless otherwise stated any percentages are based on the respective number of randomized 
participants.


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Demographic and Baseline characteristics
Demographic characteristics, including gender, race, ethnicity, age, age categories (<65 and ≥ 
65 years), height, body weight at screening, body categories (40 to <60 kg, 60 to <80 kg, 80 kg 
to <100 kg, 100 kg to <120 kg, >=120 kg), body mass index (BMI), BMI categories (< 30.0 
kg/m2 and 30.0 kg/m2  to 40 kg/m2 , >=40 kg/m2 ) will be summarized with descriptive statistics  
by treatment and overall.
A stacked barchart illustrating gender, race and ethnicity will be done. Boxplots will be done 
for all continuous variables in demographics and baseline characteristics. 
Body weight and BMI will be also summarized by time point.
Body mass index (BMI) will be calculated using the following formula:

BMI = Body weight (kg) / [Height (m)]2
The Screening visit height measurement will be used for BMI calculations throughout the study.
The number of days between the onset of symptoms to start of treatment will be listed.
The summary of the following baseline disease characteristics will be provided by treatment 
group:

Days from the onset of symptom to randomization 

Days from the onset of symptoms to treatment

Days from diagnosis to randomization 

Number of days from hospital admission to randomization

Chest X-ray or CT scan interpretation (Normal/Abnormal/not available)

Clinical status based on the 9-point ordinal scale (Score=0, 1, ...8)

Use of corticosteroid at the time of randomization (based on prednisone equivalent dose see 
Section 10.7)

Use of anti-coagulants at the time of randomization

Use of anti-infectives at the time of randomization

Use of anti-viral treatment at the time of randomization (Yes, No) and by type of anti-viral 
treatment (e.g. hydroxychloroquine, chloroquine, convalescent plasma, remdesivir, 
faripivavir, ritonavir, lopinavir)

Number and presence of the following comorbidities: diabetes, hypertension, 
cardiovascular disease (i.e. chronic heart disease), chronic lung disease (e.g. COPD, 
asthma)Baseline Oxygen use based on the type of pulmonary/ventilatory support (defined 
in Table 6-1) 

Marker for inflammation as continuous variables: CRP, Serum Ferritin, D-Dimer, LDH, 
neutrophil counts, BNP and troponin.

A stacked barchart illustrating the percentage of participants by treatment with the number 
of comorbidities at baseline (0, 1, 2, 3, 4, 5, 6 or more)

A barchart illustrating the number and presence of the following comorbidities: diabetes, 
hypertension, cardiovascular disease (i.e. chronic heart disease), chronic lung disease (e.g. 
COPD, asthma)


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The distribution of the three stratification parameters will be summarized separately by 
treatment group.
For oxygen requirement at baseline the type of support required prior but closest to the day of 
randomization will be reported. 
Protocol deviations will be listed and summarized by treatment group.
All medical history including the comorbidities will be listed.
Randomization information will be listed and summarized by treatment group.
7.2.2
Treatment
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. For corticosteroids ATC-Subclasses 
will be added. Convalescent plasma treatment will included in the anti-viral treatment 
presentations.
For any of the below mentioned three treatment categories, if it started prior to treatment and 
continued during the study, it will be reported under baseline as well as part of SoC during study 
participation.
A graphical presentation of the cumulative use of different concomitant medications at baseline 
over the course of the study by treatment group will be provided. For this the cumulative 
average percentage use will be plotted on the y-axis over the cumulative number of enrolled 
participants on the x-axis. This presentation will be provided for the following medications:

Dexamethasone

Remdesivir

Hydroxchloroquine or Chloroquine

Anti-coagulants (using ATC class as provided)
Corticosteroids use 
The number and percentage of patients will be summarized by treatment group for the following 
parameters:

receiving  any corticosteroids after randomization

receiving Dexamethasone after randomization reporting the highest total daily dose
observed during the study using the following ranges:
<6 mg, 6-<12 mg, >= 12 mg
The following presentations will be based on the prednisone equivalent dose (see Appendix 
for details):

with a change in their corticosteroids dose after randomization (increased/reduced/stable
dose)

receiving corticosteroids after randomization reporting the highest total daily dose
observed during the study using the following ranges:
<7.5 mg, 7.5-<20 mg, >= 20 mg


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For subgroup analyses the participants with a high vs. a low corticosteroid dose during the first 
week following randomization were identified. This was defined as follows:

Considering any corticosteroid mediation selected by ATC class administered between 
randomization and the following 7 days (i.e. start date < day 8 and end date > 0).

Only medication reported with a unit of “mg” was included

Doses are converted into prednisone equivalent doses applying Table 10-2.

The total daily dose is derived based in the administration frequency reported in the CRF:
1.
 “ONCE”, “QD”, “QID”, “Q24H” – factor 1
2.
“BID” – factor 2
3.
“TID”, “Q8H” – factor 3
4.
“Q6H” – factor 4

The total dose administered during the first week is derived based on the actual number of 
days the drug was administered in this period. This is done on a “day” scale, i.e. additional 
details on administration times are not considered.

The sum of the total daily doses during the first week in the study is calculated

The average total daily dose is derived by dividing the sum of the total daily doses by 7.

A dose of zero is added for any participants not receiving corticosteroids during the first 
week.

The average daily prednisone equivalent doses during the first week (dailydose1wk) in mg 
are categorized as follows:

dailydose1wk = 0: “none”

dailydose1wk <= 10 (including zero): “<=10”

10< dailydose1wk <= 20: “>10-20”

20< dailydose1wk <= 50: “>20-50”

50< dailydose1wk <= 100: “>50-100”

100< dailydose1wk <= 200: “>100-200”

200< dailydose1wk: “>200”
A stacked barchart is provided showing the distribution in these dose categories by treatment 
group.

For further subgroup analyses the categories “<=10 mg (Low)” and “>10 mg (High)” are 
used. 
For the medications listed below barcharts on the “counts” use of corticosteroids at baseline by 
treatment group will be given.

Dexamethasone

Methylprednisolone

Prednisone

Other


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
None
Anti-viral medication use 
The number and percentage of patients will be summarized by treatment group for the following 
parameters:

receiving any anti-viral medication after randomization

receiving hydroxychloroquine/chloroquine/remdesivir/faripivavir/ritonavir/lopinavir/
convalescent plasma after randomization receiving a combination of the above anti-viral
medications after randomization tabulated by all combinations actually occurring.
For the medications listed below barcharts on the “counts” use of anti-virals at baseline by 
treatment group will be given.

Azithromycin

Hydroxychloroquine

Remdesivir

Convalescent plasma

Immunoglobulin G human

Other

None
For convalescent plasma and immunoglobulin G human, also consider them as baseline
records if any participant had them administered before screening/baseline visit.
Anti-coagulation therapy
The number and percentage of patients will be summarized by treatment group for the following 
parameters:

receiving any anti-coagulation medication after randomization
The “counts” at baseline will be displayed in a barchart.

Anti-infectives therapy
The number and percentage of patients will be summarized by treatment group for the following 
parameters:

receiving any anti-infectives medication after randomization
The “counts” at baseline will be displayed in a barchart.
Combination of SoC medications
The number and percentage of patients receiving any combination of steroids, anti-viral, anti-
infectives and/or anti-coagulants treatments after randomization will be summarized by 
treatment group. 


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7.2.3
Vital signs
Vital sign measurements include respiratory rate, pulse rate (PR), systolic and diastolic blood 
pressure, mean arterial pressure body temperature, weight and BMI. Peripheral oxygen 
saturation on room air should also be measured at the same time as the vitals. For participants 
requiring supplemental oxygen, the oxygen flow rate (L/min) and/or FiO2 is also recorded.
Summary statistics will be provided by treatment group and visit/time.
The following exploratory MMRM analyses were conducted for body temperature: 
1. Including all participants using the safety analysis set.
2. on the high baseline CRP subgroup and by corticosteriod dose during the first week 
following randomization using the “PD analysis set” is used. 
In addition only participants in the high baseline CRP group are considered. The high baseline 
CRP group is defined as any subject with a baseline CRP value > median baseline CRP value 
of all participants in this study.
For analysis 1. the MMRM model is including treatment, visit and their interaction as well as 
the three stratification factors and their interaction with visit as fixed factors and baseline body 
temperature as a covariate. Interactions between visit and each of the terms in the model will 
also be included. To model the dependency of observations an unstructured variance-covariance 
matrix will be fitted.
The means per treatment group as well as the mean difference (MAS825 vs. Placebo) will be 
reported together with 90% confidence intervals (CIs) for each visit. In addition the 1-sided p-
values for the overall treatment factor will be reported.
Estimated mean body temperatures +/- SE will be plotted over time by treatment group.
For analysis 2. the same model as for the original MMRM analysis including in addition a 
factor for high vs. low corticosteroid use during week 1 (see Section 7.2.2 for details) and its 3-
way interaction with treatment and visit. 
The means (+/-SE) per corticosteroid category and treatment group as well as the mean 
differences (90% CI) per corticosteroid group are reported for each visit. 
A line plot of the means (+/-SE) are provided by corticosteroid dose category and treatment 
group together with the estimated values of the primary analyses by treatment group over time. 
Side-by-side a second line plot on the treatment differences (90% CI) per by corticosteroid dose 
category together with the estimated treatment difference (90% CI) of the primary analyses over 
time is given.
7.2.4
ECG evaluations
Heart rate, PR, QRS, QT, QTcF,  and RR intervals will be obtained from ECGs (12-lead or 5-
lead)  for each participant during the study. ECG data will be read and interpreted locally.
Categorical analysis of QT/QTcF interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTcF intervals or changes from baseline 
will be presented.


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Summary statistics will be provided by treatment group and visit/time.
7.2.5
Clinical laboratory evaluations
Summary statistics will be provided by treatment group and visit/time.
In case for one parameter multiple types of assessments were reported for the same 
visit/assessment the following rules are applied for any analysis e.g. summarizing the results:

In case both absolute counts and percentages (e.g. “bands” or ratios) are provided,
absolute counts are used.

In case both Urea and BUN parameters are provided, Urea is used.

In case for troponin multiple versions are provided (e.g. troponin T, I and/or C), troponin
T is used; if not available troponin I is used.
In addition to the parameters collected the ratio of Urea/creatinine will be reported, where 
both parameters are converted to the same unit e.g. mg/dL (see Section 10.3 for conversion 
details for Urea).
Estimated mean values +/- SE will be plotted over time by treatment group for each of the 
following lab parameters.

Leukocytes, Neutrophils, Eosinophils, and Platelets.
To ensure that lab parameters only have numerical values, censored values will be imputed as 
follows

Values like <xx.x are replaced by xx.x/2.

Values like >xx.x are replaced by xx.x.
7.2.6
Adverse events
All information obtained on adverse events will be listed by treatment and subject.
Summary tables for adverse events (AEs) will summarize only on-treatment events, with a start 
date during the on-treatment period (treatment-emergent AEs).
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. Separate summaries will be provided for 
study medication related adverse events and other significant adverse events leading to 
discontinuation. 
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 until day 29 and 
after day 29. 
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 PT until day 29 and after day 
29. 
A subject with multiple adverse events within a body system is only counted once towards the 
total of this body system and treatment.
For the legal requirements of ClinicalTrials.gov and EudraCT, two tables are required: 


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on treatment emergent adverse events which are not serious adverse events  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 analysis set. 
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 SAEs and deaths by State will be graphically presented in a barchart. Refer to Section 10.8 
for details on the state.
7.2.7
Graphical presentation 
For all vital signs, ECGs and laboratory parameters the following graphical presentations will 
be provided: 
Panels of individual spaghetti plots over time for each parameter and their change from baseline 
will be drawn. The profiles of all participants in the respective treatment group will be included 
in these graphs as grey lines in the background and the respective individual participants profile 
will be plotted with darker color in the foreground. The respective applicable normal ranges 
will be added and it will be indicated by a symbol if a patient died.
Means (+/- SE) will be plotted over time by treatment group
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9
Reference list
Knaus WA, Draper EA, Wagner DP, et al (1985) APACHE II: a severity of disease 
classification system. Crit Care Med; 13(10):818-29.
10
Appendix
10.1
Units and conversions
Special care must be taken with respect to converting lab parameters prior to applying the 
scoring described below to avoid propagation of rounding errors. The following principles will 
be applied: 

If the unit of the original lab assessment from the local lab is equal to the unit used in the
scoring table, this original value is used.

In case the SI unit which is available within the SDTM data sets is equal to the unit used
in the scoring table, the value converted to SI units is used.
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
If neither the original nor the SI unit are matching the unit used in the scoring table then
convert the original value from the local lab to the unit required by the scoring table. Note
that for some parameters there are scoring tables available for different units.

Do convert the value in SI units further.

Do apply rounding to the precision required in the scoring table only after conversion to
the unit used in the scoring table has been done.
10.1.1
Conversion for absolute neutrophil counts
If not reported the absolute neutrophil counts can be derived if  

% of neutrophils

Total WBC
is available via the following formula:
absolute neutrophil count = total WBC * neutrophil percentage.
10.2
APACHE II
The APACHE II score is derived from a number of different clinical endpoints according to the 
scoring table as outlined in (Knaus et al., 1985):
1. Body temperature (°C)
Depending on the collection method selected apply the following correction factors before
scoring:

Core: no correction needed

Axillary: + 1.0 °C

Oral: + 0.5 °C

No method selected: no correction.
2. Mean Arterial Pressure (mmHg)
In case the “method” is reported as “calculated” confirm the calculation by applying the
following formula:  MAP = [SBP + (2x DBP)] / 3. If the reported and recalculated
numbers differ by more than 10% use the recalculated value (i.e. if reported value < 0.9*
recalculated value or reported value >1.1* recalculated value)
3. Heart Rate (beats per minute)
If the participant has a pacemaker any HR <= 109 bpm will be scored to 0.
4. Respiratory Rate (breaths per minute)
5. Oxygenation: depending on the Fraction of inspired Oxygen (FiO2, where FiO2 is a
value between 0 and 1 (i.e. not on % scale)):
a.
If FiO2 < 0.5: use PaO2 (mmHg)
b. If FiO2 >= 0.5: use A-aDO2 (mmHg): where A-aDO2 is calculated as
A-aDO2 = (FiO2  × 713 -  PaCO2/0.8 ) – PaO2)


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       In case PaO2 is not available for a certain visit it can be derived from SPO2 if available 
instead using the following conversion table:
Table 10-1Conversion of SpO2 to PaO2
SpO2 (%)
PaO2 (mmHg)
80
44
81
45
82
46
83
47
84
49
85
50
86
52
87
53
88
55
89
57
90
60
91
62
92
65
93
69
94
73
95
79
96
86
97
96
98
112
99
145
In case PaCO2 is not available for a certain visit it can be derived from HCO3 if available 
instead using the following conversion:
PaCO2 (mmHg) = HCO3(mEq/L)*1.5 + 8
6. Arterial pH: if Arterial pH is not available use Serum HCO3 (venous mMol/L) instead
7. Serum Sodium (mmol/L)
8. Serum Potassium (mmol/L)
9. Serum Creatinine (mg/dL=mg/100mL)
10. Hematocrit (%)


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11. White Blood Count (10^9/L = 1000/mm^3 = 10^3/mm^3)
12. Age at screening (years)
13. Chronic Health Points at Screening: 
Points are assigned only if for this patient “Did the subject experience Severe organ system 
insufficiency or is immunocompromised ?” is selected as “yes”. 

If “Did the subject experience Severe organ system insufficiency or is 
immunocompromised ?”  = “no”, no points are assigned and a record should not be 
created for this question in the SDTM data set.

If  “Did the subject experience Severe organ system insufficiency or is 
immunocompromised ?” is selected as “yes” Chronic Health points will be derived from 
“Admission Classification”:  

Medical(non-operative)

Emergency post-operative

Elective post-operative
If in this scenario none of these conditions is selected the Chronic Health points will be set to 
0.
14. Glasgow Coma Score:  First each sub-score is scored according to the socring table 
below

Best Eye Response

Motor Response

Verbal Response 
Then these three subscores are added up to obtain the scoring of the “Total Glasgow Coma 
Score”. The value included in the APACHE II for Glasgow-Coma-Score is then = 15 – “Total 
Glasgow Coma Score”.
SDTM Mapping strategy
APACHE II specific mapping strategy: It provides guidance on how the result variables 
(RSORRES, RSSTRESC, and RSSTRESN) should be populated for the measure. All original 
results are represented with preferred terminology in RSORRES. This result is then transformed 
into a standard numeric score in RSSTRESN and a character representation of the standard 
numeric score in RSSTRESC.
To obtain the total APACHE II score all 14 derived values of RSSTRESN are then added up. 
If one item is missing the APACHE II score at STDM level for this visit is missing. Missing 
data imputation will be implemented at ADAM level.


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10.2.1
APACHE II Scoring
Temperature (°C)
RSORRES
RSSTRESC
RSSTRESN
>=41
4
4
39-40.9
3
3
38.5-38.9
1
1
36-38.4
0
0
34-35.9
1
1
32-33.9
2
2
30-31.9
3
3
≤29.9
4
4
Mean Arterial Pressure (mmHg)
RSORRES
RSSTRESC
RSSTRESN
>=160
4
4
130-159
3
3
110-129
2
2
70-109
0
0
50-69
2
2
<=49
4
4
Heart rate (BEATS/MIN)
Does the 
participant 
have a 
pacemaker?
RSORRES
RSSTRESC
RSSTRESN
Irrespective
>=180
4
4
Irrespective
140-179
3
3
Irrespective
110-139
2
2
No/unknown
70-109
0
0
No/unknown
55-69
2
2
No/unknown
40-54
3
3
No/unknown
<=39
4
4
Yes
<=109
0
0
Respiratory rate (BREATHS/MIN)
Note: Ventilated or non-ventilated patient scores will be the same as per table below
RSORRES
RSSTRESC
RSSTRESN
>=50
4
4
35-49
3
3
25-34
1
1
12-24
0
0
10-11
1
1


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6-9
2
2
<=5
4
4
Impute the unit for respiratory rate as breaths/min in case it is missing.Oxygenation: 

If FiO2 >= 0.5 then use A-aDO2 (mmHg)
RSORRES
RSSTRESC
RSSTRESN
>=500
4
4
350-499
3
3
200-349
2
2
<200
0
0

If FiO2 < 0.5 then use PaO2 (mmHg)
RSORRES
RSSTRESC
RSSTRESN
>70
0
0
61-70
1
1
55-60
3
3
<55
4
4
If any value for <X, impute the value X in that case.
Arterial pH

Use arterial pH if reported
RSORRES
RSSTRESC
RSSTRESN
>=7.7
4
4
7.6-7.69
3
3
7.5-7.59
1
1
7.33-7.49
0
0
7.25-7.32
2
2
7.15-7.24
3
3
<7.15
4
4

Alternatively use Serum HCO3 (mmol/L)
RSORRES
RSSTRESC
RSSTRESN
>=52
4
4
41-51.9
3
3
32-40.9
1
1
22-31.9
0
0
18-21.9
2
2
15-17.9
3
3
<15
4
4


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Serum sodium (mmol/L)
RSORRES
RSSTRESC
RSSTRESN
>=180
4
4
160-179
3
3
155-159
2
2
150-154
1
1
130-149
0
0
120-129
2
2
111-119
3
3
<=110
4
4
Serum potassium (mmol/L)
RSORRES
RSSTRESC
RSSTRESN
>=7
4
4
6-6.9
3
3
5.5-5.9
1
1
3.5-5.4
0
0
3-3.4
1
1
2.5-2.9
2
2
<2.5
4
4
Serum creatinine (mg/dL)
RSORRES
RSSTRESC
RSSTRESN
>=3.5 and acute renal failure 
=”yes”
8
8
2-3.4 and acute renal failure 
=”yes”
6
6
1.5-1.9 and acute renal 
failure=”yes”
4
4
0.6-1.4 and acute renal 
failure =”yes”
0
0
<0.6 and acute renal failure 
=”yes”
4
4
>=3.5
4
4
2-3.4
3
3
1.5-1.9
2
2
0.6-1.4
0
0
<0.6
2
2
Hematocrit (%)
RSORRES
RSSTRESC
RSSTRESN
>=60
4
4
50-59.9
2
2


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46-49.9
1
1
30-45.9
0
0
20-29.9
2
2
<20
4
4
White Blood Count (10^9/L)
RSORRES
RSSTRESC
RSSTRESN
>=40
4
4
20-39.9
2
2
15-19.9
1
1
3-14.9
0
0
1-2.9
2
2
<1
4
4
Age points (years)
RSORRES
RSSTRESC
RSSTRESN
<=44
0
0
45-54
2
2
55-64
3
3
65-74
5
5
>=75
6
6
Chronic health points
RSORRES
RSSTRESC
RSSTRESN
For non-operative or 
emergency post-operative 
patients
5
5
For elective post-operative 
patients
2
2
None selected
0
0


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10.5
Glasgow Coma Score
10.5.1
Glasgow Coma Scoring

Best eye response
Result
Score (Char)
Score (Num)
No eye opening
1
1
Eye opening to pain
2
2
Eye opening to verbal 
command
3
3
Eyes open spontaneously
4
4
Untestable
Untestable
Unknown
Unknown

Motor response
Result
Score (Char)
Score (Num)
No motor response
1
1
Abnormal extension
2
2
Abnormal flexion
3
3
Flexion withdrawal
4
4
Localizes pain
5
5
Obeys command
6
6
Untestable
Untestable
Unknown
Unknown

Verbal response
Result
Score (Char)
Score (Num)
No verbal response
1
1
Incomprehensible sound
2
2
Inappropriate words
3
3
Confused
4
4
Oriented
5
5
Untestable
Untestable
Unknown
Unknown


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10.6
9-point ordinal scale
Patient State
Descriptor
Score
Abbreviated 
description
Uninfected
No Clinical or virological evidence of 
infection
0
Uninfected
No limitation of activities
1
Amb: No limitations
Ambulatory
Limitation of activities
2
Amb: Limitations
Hospitalized, no oxygen therapy
3
Hosp: No Oxygen
Hospitalized
Mild disease
Oxygen by mask or nasal prongs
4
Hosp: Oxy Mask/ 
Nasal prongs
Non-invasive ventilation or high-flow 
oxygen
5
Hosp: Non-Inv Vent/ 
High flow oxy
Intubation and mechanical 
ventilation
6
Hosp: Intub + Mech 
Vent
Hospitalized
Severe 
disease
Ventilation + additional organ 
support - pressors, RRT, ECMO
7
Hosp: Vent + 
pressors
Dead
Death
8
Dead
10.7
Steroid conversion factors
Steroids will be displayed using prednisone equivalent doses. The doses displayed in the 
following table are considered equivalent. To determine prednisone equivalent doses, doses (in 
unit mg) will be multiplied by the conversion factor shown in Table 10-2. In case multiple 
corticosteriods are used at a certain visit the prednisone equivalent doses will be added up to 
obtain the total prednisone equivalent dose.


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Table 10-2
Steroids conversion factors
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