Clinical trial NCT04362813
Conditions: Cytokine Release Syndrome (CRS) in Patients With COVID-19-induced Pneumonia
Keywords: COVID-19 cytokine release syndrome SARS-CoV-2 canakinumab COVID coronavirus CAN-COVID pneumonia CRS
Sponsor: Novartis Pharmaceuticals
Start date: 2020-04-30; Completion date: 2020-12-22
Enrollment: 454 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of canakinumab plus standard-of-care (SOC) compared with placebo plus SOC in patients with COVID-19-induced pneumonia and cytokine release syndrome (CRS).

Detailed description:
This was a Phase III, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of canakinumab in patients with COVID-19-induced pneumonia and cytokine release syndrome (CRS). The study enrolled patients to canakinumab or placebo, in addition to standard of care (SOC) per local practice, which may have included anti-viral treatment, corticosteroids and/or supportive care.

Patients who met the inclusion/exclusion criteria were randomized in a 1:1 ratio to either canakinumab + SOC or placebo + SOC and were dosed immediately after ensuring that the patient met all eligibility criteria. Patients in the canakinumab arm were dosed on Day 1 with canakinumab 450 mg for body weight of 40-\<60 kg, 600 mg for 60-80 kg or 750 mg for \>80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Patients in the placebo arm were administered with 250 mL of 5% dextrose infused IV over 2 hours.

The study included:

* Screening period of 0-1 day
* Study period from initial dose on Day 1 to Day 29 or hospital discharge
* Follow-up to Day 127 The primary objective was to demonstrate the benefit of canakinumab + SOC in increasing the chance of survival without ever requiring invasive mechanical ventilation among patients with COVID-19-induced pneumonia and CRS.

Arms: arm 1: Canakinumab 450 mg for body weight 40-\<60 kg, 600 mg for 60-80 kg or 750 mg for \>80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1. arm 2: 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
Interventions: intervention 1: Canakinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Canakinumab 450 mg for body weight 40-\<60 kg, 600 mg for 60-80 kg or 750 mg for \>80 kg in 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1. intervention 2: 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.

Protocol documents:
Prot_000.pdf: 


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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.................................................................................................................9
Amendment 1 (29-May-2020)...........................................................................................11
Protocol summary..............................................................................................................13
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................20
2
Objectives and endpoints...................................................................................................21
2.1
Primary estimands .................................................................................................22
2.2
Secondary estimands .............................................................................................23
3
Study design ......................................................................................................................24
4
Rationale............................................................................................................................25
4.1
Rationale for study design .....................................................................................25
4.2
Rationale for dose/regimen and duration of treatment ..........................................25
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................26
4.4
Purpose and timing of interim analyses/design adaptations..................................26
4.5
Risks and benefits..................................................................................................26
5
Study Population ...............................................................................................................30
5.1
Inclusion criteria ....................................................................................................30
5.2
Exclusion criteria...................................................................................................30
6
Treatment...........................................................................................................................31
6.1
Study treatment......................................................................................................31
6.1.1
Investigational and control drugs..........................................................31
6.1.2
Additional study treatments ..................................................................31
6.1.3
Supply of study treatment .....................................................................31
6.1.4
Treatment arms/group ...........................................................................32
6.2
Other treatment(s)..................................................................................................32
6.2.1
Concomitant therapy.............................................................................32
6.2.2
Prohibited medication ...........................................................................32
6.3
Participant numbering, treatment assignment, randomization ..............................33
6.3.1
Participant numbering...........................................................................33
6.3.2
Treatment assignment, randomization ..................................................33


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6.4
Treatment blinding.................................................................................................33
6.5
Dose escalation and dose modification..................................................................34
6.6
Additional treatment guidance...............................................................................34
6.6.1
Treatment compliance...........................................................................34
6.6.2
Recommended treatment of adverse events..........................................34
6.6.3
Emergency breaking of assigned treatment code..................................34
6.7
Preparation and dispensation.................................................................................35
6.7.1
Handling of study treatment..................................................................35
6.7.2
Instruction for prescribing and taking study treatment .........................36
7
Informed consent procedures ............................................................................................36
8
Visit schedule and assessments .........................................................................................37
8.1
Screening ...............................................................................................................41
8.1.1
Information to be collected on screening failures.................................41
8.2
Participant demographics/other baseline characteristics .......................................41
8.2.1
Demographic/baseline characteristics information...............................41
8.2.2
Prior and concomitant medications.......................................................41
8.3
Efficacy..................................................................................................................42
8.3.1
Clinical status (9-point ordinal scale) ...................................................42
8.3.2
Vital signs and oxygen saturation and use ............................................42
43
43
8.3.5
Appropriateness of efficacy assessments..............................................43
8.4
Safety.....................................................................................................................43
8.4.1
Laboratory evaluations..........................................................................44
8.4.2
Physical exam........................................................................................44
8.4.3
Height, weight.......................................................................................45
8.4.4
Electrocardiogram (ECG) .....................................................................45
8.4.5
Pregnancy and assessments of fertility .................................................45
8.4.6
Chest x-ray or CT scan..........................................................................45
8.4.7
Appropriateness of safety measurements..............................................45
8.5
Additional assessments..........................................................................................46
8.5.1
SARS-CoV-2 nasopharyngeal samples.................................................46
46
46
46
46


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47
47
9
Study discontinuation and completion ..............................................................................47
9.1
Discontinuation and completion............................................................................47
9.1.1
Study treatment discontinuation and study discontinuation..................47
9.1.2
Withdrawal of informed consent...........................................................48
9.1.3
Lost to follow-up...................................................................................49
9.1.4
Early study termination by the sponsor.................................................49
9.2
Study completion and post-study treatment ..........................................................49
10 Safety monitoring and reporting........................................................................................50
10.1
Definition of adverse events and reporting requirements......................................50
10.1.1
Adverse events ......................................................................................50
10.1.2
Serious adverse events ..........................................................................51
10.1.3
SAE reporting........................................................................................52
10.1.4
Pregnancy reporting ..............................................................................53
10.1.5
Reporting of study treatment errors including misuse/abuse................53
10.2
Additional Safety Monitoring................................................................................54
10.2.1
Liver safety monitoring.........................................................................54
10.2.2
Data Monitoring Committee .................................................................54
11 Data Collection and Database management......................................................................55
11.1
Data collection.......................................................................................................55
11.2
Database management and quality control............................................................55
11.3
Site monitoring ......................................................................................................56
12 Data analysis and statistical methods ................................................................................56
12.1
Analysis sets ..........................................................................................................57
12.2
Participant demographics and other baseline characteristics.................................57
12.3
Treatments .............................................................................................................57
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................57
12.4.1
Definition of primary endpoint(s)/estimand(s) .....................................57
12.4.2
Statistical model, hypothesis, and method of analysis..........................58
12.4.3
Handling of remaining intercurrent events of primary estimand..........58
12.4.4
Handling of missing values not related to intercurrent event ...............58
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................58
12.4.6
Supplementary analysis.........................................................................58
12.4.7
Supportive analyses...............................................................................58
12.5
Analysis of secondary endpoints/estimands..........................................................59


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12.5.1
Key secondary endpoint........................................................................59
12.5.2
Other Secondary objectives and endpoints ...........................................59
12.5.3
Safety endpoints....................................................................................59
60
60
61
12.6
Interim analyses.....................................................................................................61
12.7
Sample size calculation..........................................................................................61
12.7.1
Primary endpoint(s)...............................................................................61
12.7.2
Secondary endpoint(s)...........................................................................62
13 Ethical considerations and administrative procedures ......................................................63
13.1
Regulatory and ethical compliance........................................................................63
13.2
Responsibilities of the investigator and IRB/IEC..................................................63
13.3
Publication of study protocol and results...............................................................63
13.4
Quality Control and Quality Assurance.................................................................63
14 Protocol adherence ............................................................................................................64
14.1
Protocol amendments.............................................................................................64
15 References .........................................................................................................................65
16 Appendices ........................................................................................................................70
16.1
Appendix 1: Ordinal Scale Determination ............................................................70
70
16.3
Appendix 3: Liver event and laboratory trigger definitions & follow-up 
requirements ..........................................................................................................71


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................21
Table 6-1
Canakinumab dose by body weight ......................................................31
Table 6-2
Investigational and control drug............................................................31
Table 8-1
Assessment and Procedures Schedule (Baseline to 18-week safety 
follow up)13 ...........................................................................................38
Table 8-2
Clinical status (9-point ordinal scale) ...................................................42
47
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................54
Table 12-1
Power for primary analysis under varying assumptions (sample 
size = 450).............................................................................................62
Table 12-2
Power for key secondary analysis (sample size = 450).........................62
Table 16-1
Liver event and laboratory trigger definitions ......................................71
Table 16-2
Follow up requirements for liver laboratory triggers............................72
List of figures
Figure 3-1
Study design..........................................................................................25


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List of abbreviations
AE
Adverse Event
ACE2
Angiotensin-converting enzyme 2
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute neutrophil count
ARDS
Acute respiratory distress syndrome
AST
Aspartate Aminotransferase
ASTCT
American society for transplantation and cellular therapy
BUN
Blood Urea Nitrogen
CFR
Case fatality rate
CMO&PS
Chief Medical Office and Patient Safety
CoV
Coronaviruses
COVID-19
Coronavirus disease 2019
CRF
Case Report/Record Form (paper or electronic)
CRP
C-reactive protein
CRS
Cytokine release syndrome
CT Scan
Computed tomography scan
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECMO
Extracorporeal membrane oxygenation
EDC
Electronic Data Capture
EMA
European medicines agency
EOI
End of Infusion
FAS
Full analysis set
FDA
Food and Drug Administration
FiO2
Fraction of inspired oxygen
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
hr
Hour
i.v./IV
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 Committee
IL
Interleukin
IL-1R
IL-1 receptor


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IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to treat
LLOQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
PaO2
Partial pressure of oxygen
PBO
Placebo
PCR
Polymerase chain reaction
RRT
Renal replacement therapy
s.c.
subcutaneous
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus-2
SOC
Standard of care
SpO2
Peripheral capillary oxygen saturation
SUSAR
Suspected Unexpected Serious Adverse Reaction
ULN
upper limit of normal
WHO
World Health Organization
WoC
Withdrawal of Consent


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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. any background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant
Cohort
A specific group of participants fulfilling certain criteria and generally treated at the same 
time
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or at a later 
point in time as defined by the protocol
Enrollment
Point/time of participant entry into the study at which informed consent must be obtained 
Estimand
A precise description of the treatment effect reflecting the clinical question posed by the 
trial objective. It summarizes at a population-level what the outcomes would be in the 
same patients under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as well 
as the specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable.
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 into the study 
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.


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Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all study drug administration 
is discontinued and no further assessments are planned
Randomization 
number
A unique identifier assigned to each randomized participant
Screen Failure
A participant who did not meet one or more criteria that were required for participation in 
the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data.
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant
Study treatment
Any drug or combination of drugs or intervention administered to the study participants 
as part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also be 
the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination and may 
consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment.
Variable
(or endpoint)
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event.
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant does not want to 
participate in the study any longer and does not allow any further collection of personal 
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Protocol summary
Protocol number
CACZ885D2310
Full Title
Phase 3 multicenter, randomized, double-blind, placebo-controlled study to 
assess the efficacy and safety of canakinumab on cytokine release 
syndrome in patients with COVID-19-induced pneumonia (CAN-COVID)
Brief title
Study of efficacy and safety of canakinumab treatment for CRS in 
participants with COVID-19-induced pneumonia
Sponsor and
Clinical Phase
Novartis
Phase III
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the efficacy and safety of 
canakinumab for the treatment of cytokine release syndrome (CRS) in 
patients with COVID-19-induced pneumonia.
As of March 28, 2020, coronavirus disease 2019 (COVID-19) has been 
confirmed in 629,355 people worldwide. The mortality rate has been 
reported to be approximately 3.7%, compared with a mortality rate of less 
than 1% from influenza (Mehta et al 2020). There is an urgent need for 
effective treatment.
Accumulating evidence suggests that patients develop severe acute 
pneumonia due to COVID-19 with cytokine release syndrome (CRS). 
Currently, there is no clinical experience with canakinumab in the treatment 
of CRS, pneumonia or SARS-CoV-2 infection. However, the cytokine 
profiling of patients with severe COVID-19 that includes elevated levels of 
interleukin (IL)-2, IL-7, IL-6, IL-1, granulocyte-colony stimulating factor, 
interferon-γ inducible protein 10, monocyte chemoattractant protein 1, 
macrophage inflammatory protein 1-α, tumor necrosis factor-α and other 
pro-inflammatory cytokines suggests that canakinumab could improve 
patient outcomes (Mehta et al 2020; Zhou et al 2020).
Primary Objective 
To demonstrate the benefit of canakinumab + SOC in increasing the chance 
of survival without ever requiring invasive mechanical ventilation among 
patients with COVID-19-induced pneumonia and CRS
Secondary 
Objectives

To demonstrate the benefit of canakinumab in reducing 4-week case 
fatality rate (CFR) among patients with COVID-19-induced pneumonia and 
CRS regardless of other subsequent clinical interventions

To evaluate change from baseline in clinical serologic measurements 
related to CRS in COVID-19 patients with pneumonia

To evaluate safety of canakinumab in patients with COVID-19-induced 
pneumonia and CRS 
Study design
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled 
study to assess the efficacy and safety of canakinumab in patients with 
COVID-19-induced pneumonia and CRS. The study will enroll patients to 
canakinumab or placebo, in addition to standard of care per local practice, 
which may include anti-viral treatment, corticosteroids and/or supportive 
care. The total trial duration will be 126 days after the canakinumab or 
placebo dose. Safety will be closely monitored with an internal Novartis 
DMC during the study.


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Study population
Approximately 450 patients with diagnosed COVID-19-induced pneumonia 
and CRS will be randomized to canakinumab or placebo in a 1:1 ratio
Key Inclusion 
criteria
1. Male or female
2. Adults ≥ 18 years old (for US only: patients ≥ 12 years old)
3. Body weight ≥40 kg
4. Informed consent must be obtained prior to participation in this study. For 
US patients 12 - < 18 years old; parent/guardian consent must be obtained 
and assent if applicable.
5. Clinically diagnosed with SARS-CoV-2 virus by PCR or by other 
approved diagnostic methodology within 7 days prior to randomization
6. Hospitalized with COVID-19-induced pneumonia evidenced by chest x-
ray or CT scan (taken within 5 days prior to randomization) with pulmonary 
infiltrates
7. SpO2 ≤ 93% on room air, or arterial oxygen partial pressure (PaO2)/ 
fraction of inspired oxygen (FiO2) < 300mmHg (1mmHg=0.133kPa) 
(corrective formulation should be used for higher altitude regions (over 
1000m))
8. C-reactive protein ≥20 mg/L or ferritin level ≥600 µg/L
Key Exclusion 
criteria
1. History of hypersensitivity to canakinumab or to biologic drugs
2. Intubated and on mechanical ventilation (invasive) at time of 
randomization
3. Treatment with immunomodulators or immunosuppressant drugs, 
including but not limited to tocilizumab, TNF inhibitors and anti-IL-17 agents 
within 5 half-lives or 30 days (whichever is longer) prior to randomization 
with the exception of anakinra which is excluded within 5 half-lives only. 
Note: Immunomodulators (topical or inhaled) for asthma and atopic 
dermatitis and corticosteroids (any route of administration) are permitted
4. Suspected or known untreated active bacterial, fungal, viral, or parasitic 
infection with the exception of COVID-19
5. Neutropenia with ANC <1000/mm3
6. 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
7. In the opinion of the investigator, progression to death is imminent and 
highly likely within the next 24 hours, irrespective of the provision of 
treatments
8. Current participation in any other investigational trials
Study treatment
Arm 1: Canakinumab 450 mg for body weight 40-<60 kg, 600 mg for 60-80
kg, or 750 mg for >80 kg in 250 mL of 5% dextrose infused IV over 2 hours
Arm 2: 250 mL of 5% dextrose infused IV over 2 hours
Canakinumab or placebo infusions will be prepared and blinded by an 
unblinded pharmacist or designated staff member.
Treatment of 
interest
Randomized canakinumab or placebo as described above. In addition, all 
patients will receive SOC per local practice for the treatment of COVID-19-
induced pneumonia. The SOC may include anti-viral treatment, 
corticosteroids and/or supportive care.






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1
Introduction
1.1
Background
Coronavirus disease 2019 (COVID-19) is a global pandemic (Gorbalenya et al 2020, WHO 
2020a). What started as an epidemic of COVID-19 cases with unexplained lower respiratory 
tract infections first detected in Wuhan, the largest metropolitan area in China's Hubei province, 
and reported to the World Health Organization (WHO) Country Office in China on December 
31, 2019 has now spread globally with 629,355 confirmed cases worldwide and 28,963 deaths 
reported (March 28, 2020; Worldometers 2020). As of March 12, 2020, the mortality rate was 
calculated at approximately 3.7%, compared with a mortality rate of less than 1% from 
influenza. Currently, there are no approved treatments nor vaccines, and so there is an urgent 
need for effective treatment (Mehta et al 2020).
COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-
2) and belongs to family coronoviridae (Ahn et al 2019, Gorbalenya et al 2020, WHO 2020a).
Coronaviruses (CoV) are positive-stranded RNA viruses with a crown-like appearance under 
an electron microscope due to the presence of spike glycoproteins on the viral envelope. They 
are a large family of viruses that cause illness ranging from the common cold to more severe 
diseases, such as the severe acute respiratory syndrome coronavirus (SARS-CoV) from 2002 
and the Middle East respiratory syndrome coronavirus (MERS-CoV) from 2012 (MERS). Like 
SARS-CoV and MERS-CoV, it is believed that SARS-CoV-2 moved from bats to an 
intermediate host (possibly a Malayan Pangolin, which shares 91% nucleotide identity) and 
then to humans (Ahn et al 2019, Gorbalenya et al 2020).
Patients infected with SARS-CoV-2 present with a wide range of clinical severity varying from 
asymptomatic to a severe form of interstitial pneumonia, which may progress towards acute 
respiratory distress syndrome (ARDS) and/or multi organ failure and death. The clinical 
symptoms of COVID-19 patients include fever, cough, fatigue, loss of smell, and shortness of 
breath within 2-14 days after exposure (CDC 2020). SARS-CoV-2 uses the same receptor as 
SARS-CoV, angiotensin-converting enzyme 2 (ACE2) and mainly spreads through the 
respiratory tract (Hoffmann et al 2020, Xu H et al 2020, Zhao D et al 2020). Although currently, 
the pathogenesis of the pulmonary manifestations of COVID-19 remains poorly defined and 
knowledge of factors affecting disease severity is limited, underlying illnesses such as diabetes, 
cardiovascular diseases, hypertension, cancer and older age are associated with poorer outcome 
(Huang et al 2020, Chen et al 2020, Guan et al 2020). Cytokine profiling of patients with severe 
COVID-19 includes elevated levels of interleukin (IL)-2, IL-7, IL-6, IL-1, granulocyte-colony 
stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, 
macrophage inflammatory protein 1-α and tumor necrosis factor-α (Wang et al 2020, Mehta et 
al 2020, Wan et al 2020, Liu et al 2020, Zhou et al 2020, Diao et al 2020).
COVID-19 associated pneumonia and ARDS have raised questions about the possible role of a 
cytokine storm in pathogenesis of SARS-CoV-2. Profound lung injury, in particular that of type 
II alveolar epithelial cells that express the viral entry receptor, ACE2, has the potential to 
activate intracellular pathogen sensing platforms called inflammasomes (Chen et al 2019, Xu 
H et al 2020, Zhao and Zhao 2020). Activated inflammasomes initiate cleavage of pro-IL-1β to 
active IL-1β, resulting in a robust pro-inflammatory response with activation and subsequent 
recruitment of neutrophils and macrophages with the normal physiological role of controlling 


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viral infection (Bauernfeind et al 2011, Zhao and Zhao 2020). An overexuberant inflammatory 
response as the result of accumulation of innate immune cells results in vascular leakage, 
pulmonary edema, hypoxia culminating in ARDS (Leff et al 1994, Olman et al 2004, Ganter et 
al 2008). Furthermore, severe COVID-19 patients are reported to exhibit increased circulating 
levels of IL-1β and IL-6 that appears to negatively impact T cell numbers while also increasing 
the expression of checkpoint inhibitor programmed death 1 on T cells (Diao et al 2020, Zheng 
et al 2020). In contrast, non-severe patients that recover show decreased IL-6, IL-10 and 
interferon-γ in circulation, suggesting resolving inflammation and the recruitment of antibody-
secreting B cells, TFH cells and activated CD4+ and CD8+ T cells, together with IgM and IgG 
SARS-CoV-2-binding antibodies, in the patient’s blood before the resolution of symptoms 
(Thevarajan et al 2020). This strongly suggests that lack of resolution of inflammation is a 
hallmark of severe COVID-19 patients and given that IL-1β is a key regulator of inflammation 
in a variety of chronic conditions such as cardiovascular disease, autoinflammatory diseases, 
and cancer (Toldo et al 2014, Fang et al 2018, Mantovani et al 2018), it strongly suggests a role 
of IL-1β in non-resolving inflammation following SARS-CoV-2 in severe COVID-19 patients 
with pneumonia and ARDS.
Numerous clinical and preclinical studies demonstrate that inflammasome-derived IL-1β plays
a critical role in the development of sterile inflammation during ARDS and contributes to acute 
lung injury (Patton et al 1995, Kolb et al 2001, Ganter et al 2008). IL-1β is significantly elevated 
in bronchoalveolar fluid and plasma in patients with ARDS compared to healthy controls and 
is associated with poor clinical outcomes (Meduri et al 1995, Park et al 2001, Bouros et al 2005).
Patients with ARDS following infection with other coronaviruses such as MERS-CoV and 
SARS-CoV exhibit a high IL-1β signature that includes downstream mediators, IL-6 and IL-8 
(He et al 2007, Lau et al 2013, Min et al 2016, Alosaimi et al 2020), strongly indicating that 
inflammation-driven ARDS in severe COVID-19 patients might be driven by IL-1β.
The Spanish influenza pandemic of 1918 and seasonal outbreaks of influenza sub-strains have 
both been documented to cause ARDS in mice and primates with an acute pulmonary 
inflammatory response that includes neutrophils and macrophages and high levels of IL-1β in 
bronchoalveolar lavage and plasma (Meduri et al 1995, Park et al 2001, Beigel et al 2005,
Bouros et al 2005, Tumpey et al 2005, Kobasa et al 2007, Perrone et al 2008). In mice that lack 
IL-1R, the AIM-2 inflammasome - the acute pathological granulocytic response - is markedly 
reduced, and attenuated lung injury and significant improvement in survival against influenza 
A viruses are observed, while viral burden in the lung is not altered (Schmitz et al 2005, Zhang 
et al 2017). Blockade of IL-1β either via administration of recombinant IL-1R antagonist or 
blocking antibody prevented an influenza-driven inflammatory response, reducing the 
development of pulmonary fibrosis and acute lung damage (Gasse et al 2007, Kim et al 2015). 
These data strongly indicate that IL-1β is a key cytokine orchestrating acute lung injury and 
inflammatory response (Kim et al 2015) contributing to ARDS following infection with 
respiratory viruses other than SARS-CoV-2.
CAR-T cell therapy is a highly specific and effective therapy for a subset of B cell malignancies 
(Porter et al 2015, Schuster et al 2017). However, broader use of this powerful approach is 
limited by potentially lethal toxicities, such as the induction of severe cytokine release 
syndrome (CRS) and neurotoxicity. Characteristics of CRS include fever, fatigue, headache, 
encephalopathy, hypotension, tachycardia, coagulopathy, nausea, capillary leak, and multi-


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organ dysfunction (Porter et al 2018) and is graded using the ASTCT CRS grading criteria 
(Appendix 2). The reported incidence of CRS after CAR-T cell therapy ranges from 50% to 
100%, with 13% to 48% of patients experiencing the severe or life-threatening form. Serum 
levels of inflammatory cytokines are elevated, particularly IL-6, and IL-6R blockade using 
tocilizumab has been approved for the treatment of severe or life-threatening CAR-T cell-
induced CRS (Le et al 2018, Kotch et al 2019). Given the increased levels of IL-6 in COVID-
19 patients and the role of IL-6 in SARS-associated ARDS (Wang et al 2020, Mehta et al 2020,
Wan et al 2020, Liu et al 2020, Zhou et al 2020, Diao et al 2020), twenty-one patients with 
severe or critical COVID-19 pneumonia were treated recently with tocilizumab IV (400 mg) 
plus SOC that consisted of lopinavir, methylprednisolone, other symptom relievers, and oxygen 
therapy as recommended by the Diagnosis and Treatment Protocol for Novel Coronavirus 
Pneumonia (Sixth Edition) (Xu X et al 2020). No deaths were reported, and after tocilizumab 
treatment, 75% of patients exhibited lowered O2 intake, 90% of patients showed significant 
improvement in lung opacities and 85% of patients showed significant decrease in C-reactive 
protein (CRP) levels (Xu X et al 2020). Recently, it has been shown that monocyte-derived IL-
1β and IL-6 (downstream of IL-1β) differentially regulate CRS and neurotoxicity associated 
with CAR-T therapy, with the IL-1 receptor antagonist anakinra abolishing both CRS and 
neurotoxicity, resulting in substantially extended leukemia-free survival (Giavridis et al 2018,
Norelli et al 2018). The IL-6R blockade with tocilizumab in alleviating COVID-19 symptoms 
together with the role of IL-1β, upstream of IL-6, in the pathophysiology of CAR-T-induced 
CRS strongly suggests that IL-b blockade might alleviate the cytokine storm following COVID-
19 that promotes pneumonia, ARDS and worse outcome.
Canakinumab is a high-affinity human monoclonal anti-human IL-1β antibody of the IgG1/k 
isotype which is marketed and under ongoing development for the treatment of IL-1β driven 
inflammatory and oncologic diseases. By binding specifically to human IL-1β, canakinumab 
blocks the interaction of IL-1β with the IL-1 receptor (IL-1R), leading to inhibition of its 
downstream targets, thereby preventing IL-1β-induced gene activation and the production of 
downstream inflammatory mediators such as IL-6 and CRP. Canakinumab, first registered for 
the treatment of cryopyrin-associated auto inflammatory syndrome (CAPS) in the United States 
on 17 Jun 2009, ameliorates IL-1β -mediated inflammation and was shown recently in the Phase 
3 CANTOS trial to significantly reduce major adverse cardiovascular events and lung cancer 
incidence and mortality (Ridker et al 2017).
Taken together, evidence including: (1) the central role of IL-1β and IL-1β-driven inflammation 
in the pathophysiology of ARDS; (2) the increased morbidity and mortality of COVID-19
patients with chronic underlying inflammatory conditions (cardiovascular disease, diabetes) 
who develop pneumonia; (3) the CANTOS-trial data in cardiovascular disease and lung cancer; 
and (4) the excellent safety profile of canakinumab, supports the urgent need to evaluate 
canakinumab in COVID-19 patients with pneumonia and cytokine release syndrome in the 
setting of SARS-CoV-2 infection.
Based on recent observations in severe and non-severe COVID-19 patients and historical data 
(Meduri et al 1995, Park et al 2001, Beigel et al 2005, Bouros et al 2005, Tumpey et al 2005,
He et al 2007, Kobasa et al 2007, Perrone et al 2008, Lau et al 2013, Min et al 2016, Alosaimi 
et al 2020, Thevarajan et al 2020) with other infectious pathogens that cause respiratory distress, 
 




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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective
To demonstrate the benefit of canakinumab + 
standard of care (SOC) in increasing chance of 
survival without ever requiring invasive 
mechanical ventilation among patients with 
COVID-19-induced pneumonia and CRS
Endpoint for primary objective:
Clinical response, defined as survival without 
ever requiring invasive mechanical ventilation 
from Day 3 (inclusive) up to Day 29 (inclusive).
Secondary Objective(s)
To demonstrate the benefit of canakinumab in 
reducing 4-week case fatality rate (CFR) among 
patients with COVID-19-induced pneumonia and 
CRS regardless of other subsequent clinical 
interventions
Endpoint(s) for secondary objective(s):
COVID-19-related death during the 4-week
period after study treatment
To evaluate change in clinical serologic 
measurements related to CRS in COVID-19 
patients with pneumonia

Adjusted geometric mean ratio to baseline
overtime up to Day 29 in the following clinical 
chemistry measurements:

CRP

Serum ferritin

D-dimer
To evaluate safety of canakinumab in patients 
with COVID-19-induced pneumonia and CRS
Number of participants with Adverse Event (AE), 
serious adverse events (SAE), 
clinically significant changes in laboratory 
measures, and vital signs


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Objective(s)
Endpoint(s)
2.1
Primary estimands
The primary clinical question of interest is: Does canakinumab + SOC increase the chance of 
survival without ever requiring invasive mechanical ventilation among patients with COVID-
19-induced pneumonia and CRS after start of treatment, regardless of other subsequent clinical 
interventions?
The justification for this primary estimand is that it captures the clinical outcome of most 
interest after canakinumab administration, which reflects also any effects of additional 
subsequent interventions potentially due to such clinical decision. In the ongoing COVID-19 
pandemic with evolving treatment guidelines and healthcare system burdens, this primary 
estimand is deemed better to reflect actual clinical practices. In addition, the IV delivery of 
canakinumab is expected to result in a fast decrease in pharmacologically active IL-1β and to 
reduce L-1β signaling to marginal levels within hours. However, clinical signs or symptoms 
within the 24 hours after treatment may not necessarily reflect such pharmacological effect yet. 
Therefore, only clinical status starting from Day 3 will be considered for the primary endpoint.
The primary estimand includes the following components:
Population: Patients with COVID-19-induced pneumonia and CRS.
Endpoint: Clinical response, defined as survival without ever requiring invasive mechanical 
ventilation from Day 3(inclusive) up to day 29(inclusive). A patient will be defined as a non-
responder if the worst clinical status at any time from Day3 (inclusive) up to Day 29 (inclusive) 
is requiring invasive mechanical ventilation or death (category 6, 7 or 8 on the WHO 9-point
ordinary scale of clinical status).


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Treatment of interest: The randomized study treatment (canakinumab or placebo) added onto 
SOC with or without additional subsequent clinical interventions.
Handling of intercurrent events:
The treatment policy strategy will be adopted for primary analysis.

Clinical interventions (e.g. mechanical ventilator, oxygen, intubation) newly administered 
as escalated SOCs corresponding to the progression of disease are integrated in efficacy 
evaluation based on the 9-category ordinal scale of clinical status.

Other new or change in strength of concomitant interventions will not be adjusted for 
primary analysis.

Early discontinuation from study or lost to follow up before Day 29: A patient will be 
considered as responder if did not require invasive mechanical ventilation any time on or 
after Day 3 and meets at least one of the following two criteria:
1. The patient was discharged from hospital with clinical status of 0 or 1
2. The last clinical status was on Day 15 or later and better than baseline
Patient will otherwise be considered as non-responder.
Summary measure: Difference and Odds-ratio comparing response rates in the canakinumab 
and placebo groups.
2.2
Secondary estimands
The key secondary clinical question of interest in this study is: Does the administration of 
canakinumab reduce 4-week mortality among patients with COVID-19-induced pneumonia and 
CRS, regardless of other subsequent clinical interventions?
The justification for this secondary estimand is that mortality currently represents the main 
epidemiological and clinical concern for COVID-19 patients and accumulating evidences 
suggest coexistence of CRS with severe COVID-19-induced pneumonia. Subsequent clinical 
interventions, including intensive cares when a patient become terminally ill, reflect actual 
clinical practices, whose needs, scope and effectiveness could potentially be related to the 
earlier decision of canakinumab administration.
The key secondary estimand includes the following components:
Population: Patients with COVID-19-induced pneumonia and CRS.
Endpoint: COVID-19-related death during the 4-week period after study treatment
Treatment of interest: The randomized study treatment (canakinumab or placebo) added onto 
SOC with or without additional subsequent clinical interventions.
Handling of remaining intercurrent events:
The treatment policy strategy will be adopted for this key secondary analysis.

Effect of other subsequent clinical interventions will not be adjusted

Early study discontinuation or lost to follow-up before Day 29: A patient will be 
considered as survivor if discharged from hospital with clinical status of 0 or 1
Otherwise, the patient will not be included in this key secondary analysis.


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Summary measure: Difference and Odds-ratio comparing 4-week CFR in the canakinumab 
and control groups.
3
Study design
This is a multicenter, double-blind, randomized, placebo-controlled study to assess the efficacy 
and safety of canakinumab plus SOC compared with placebo plus SOC in adult patients (for 
US only: patients ≥ 12 years old) with COVID-19-induced pneumonia and CRS (Figure 3-1).
The study aims to randomize approximately 450 patients worldwide. Enrollment will stop as 
soon as the target number of randomized patients is reached. Based on the evolving landscape 
in the treatment of COVID-19, additional arms may be added to this protocol in the future.
Patients who meet the inclusion/exclusion criteria will be randomized in a 1:1 ratio to either 
canakinumab + SOC or placebo + SOC and can be dosed immediately after ensuring that the 
patient has met all eligibility criteria. Patients in the canakinumab arm will be dosed on Day 1 
with canakinumab 450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg or 750 mg for 
>80 kg) in 250 mL of 5% dextrose infused IV over 2 hours. Patients in the placebo arm will be 
treated with 250 mL of 5% dextrose infused IV over 2 hours.
An informed consent (for US patients 12 - <18 years old; parent/guardian consent must be 
obtained and assent if applicable) will be obtained from patients before assessments solely 
required for the study are performed. Thereafter, eligibility criteria will be reviewed by study 
personnel. All patients with signed informed consent must be registered in the Interactive 
Response Technology (IRT) system.
 Then
additional safety assessments will be performed approximately every other day during 
hospitalization as described in Table 8-1. Additional follow-up visits will occur on Days 15, 29, 
57 and 127 either by phone, if previously discharged, or in the hospital, if still hospitalized. If 
a patient is hospitalized for longer than Day 29, all invasive protocol assessments will be 
discontinued except at Days 57 and 127, if still hospitalized. If the patient has been discharged, 
the patient should be phoned for follow-up and data collected as in Table 8-1. In addition, 
unscheduled visits are permitted after discharge, as needed.
If patient discontinues the study prior to Day 29, then Day 29 assessments should be conducted 
on the day of discontinuation. If patient discontinues the study after Day 29, then Day 127 
assessments should be conducted on the day of discontinuation.
Analyses for safety will be conducted at regular intervals using an internal Novartis data 
monitoring committee (DMC). Deaths and SAEs will be monitored in real time with routine 
pharmacovigilance and by the internal, independent DMC in order to detect any unexpected 
safety signal. The DMC will function independently of all other individuals associated with the 
conduct of this clinical trial.
Patients who do not meet the criteria for participation in this study (screen failures) will not be 
re-screened.


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Figure 3-1
Study design
4
Rationale
4.1
Rationale for study design
This randomized, double-blind, placebo-controlled design supports the rigorous assessment of 
efficacy as well as safety of canakinumab + SOC therapy for patients with COVID-19-induced
pneumonia and CRS.
Screening Period
The screening period allows for assessment of patient entry criteria to ensure suitable patients 
are entered into the study, while allowing flexibility to dose the same day after ensuring 
eligibility criteria are met.
Study Period
On Day 1, canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg or 750 
mg for >80 kg) versus placebo in 250 mL of 5% dextrose administered intravenously. The 
blinding will be performed by an unblinded pharmacist or designated person.
Due to the extended half-life of canakinumab, patients will be followed until Day 127. The 
endpoints included in this study measure clinical status, clinical and in-hospital outcomes, and 
laboratory values during the Study Period.
4.2
Rationale for dose/regimen and duration of treatment
The IV delivery of a single high dose of canakinumab, which is supported by available safety 
data, ensures a fast decrease in pharmacologically active IL-1β levels and is expected to reduce 
IL-1β signaling to low levels within hours. Adaptation of the dose to body weight using 3 weight 
ranges/dose levels (450, 600 and 750 mg) minimizes complexity in the dosing procedure while 
taking the patient’s weight into consideration. The dose levels were selected based on the 
following considerations and will be added to standard-of-care therapy:


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
In COVID-19-induced pneumonia patients, there seems to be a stage at which CRS may 
become a predominant factor in outcomes. The amount of released cytokines may be 
estimated to be about 30-60 fold above baseline values requiring a high dose. Many 
cytokines have been assayed and showed increased concentrations.

Registered canakinumab doses in currently marketed indications vary from 2 to 8 mg/kg 
in children and from 150 to 600 mg by subcutaneous (s.c.) route in adults. The doses of 10 
mg/kg or 600 mg iv canakinumab have been previously investigated in 288 patients or 
healthy volunteers (including children >3 years of age) as single or repeated doses in 
autoinflammatory conditions, gouty arthritis, asthma, type 2 diabetes mellitus, and ocular 
conditions in the development program. Canakinumab was safe and well tolerated in all 
studies, with no safety concern identified by analysis of AE, laboratory or vital signs.

The 450 mg for body weight of 40-<60kg, 600 mg for 60-80 kg and 750 mg for >80kg
dosing regimen was selected in order to reach the maximal and safe highest exposure to 
canakinumab of approximately 10 mg/kg. The intravenous (IV) route will give higher 
exposure as compared to s.c. shortly after dosing which is considered critical for treatment 
of CRS especially given the rapid decrease in clinical outcomes observed in some patients 
with COVID-19 pneumonia.

A relatively high dose is proposed:

To take into account the possibility of lower drug concentrations in CRS 
patients (as is seen with tocilizumab, Le et al 2018)

To take into account the unknown diffusion in inflamed lung tissues
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Currently, no approved treatment for COVID-19 induced pneumonia and CRS is available. A 
placebo-controlled study should mitigate the potential biases associated with the clinical setting 
and the endpoints related to the study objectives and allow for an objective assessment of 
canakinumab value in this indication.
4.4
Purpose and timing of interim analyses/design adaptations
Not Applicable.
4.5
Risks and benefits
Potential patient benefits
As of March 28, 2020, COVID-19 has been confirmed in 629,355 people worldwide with 
28,963 deaths reported (Worldometers 2020). As of March 12, 2020, the mortality rate was 
calculated at approximately 3.7%, compared with a mortality rate of less than 1% from 
influenza. Currently, there are no approved treatments nor vaccines, and so there is an urgent 
need for effective treatment (Mehta et al 2020).
SARS-CoV-2 is characterized by a spherical morphology with 36 spike projections on the 
surface and is similar to the β-coronaviruses generally seen in bats (Ahn et al 2019). The novel 
coronavirus, SARS-CoV-2 uses the same receptor, ACE2 as that for SARS-CoV (cause of 


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previous corona virus epidemic), and mainly spreads through the respiratory tract. The clinical 
symptoms of COVID-19 patients include fever, cough, fatigue, loss of smell, and shortness of 
breath within 2-14 days after exposure (CDC 2020). The current SARS-CoV-2 pandemic is 
resulting in 10-20% of infected patients developing severe illness. The severe clinical course 
includes interstitial pneumonia that can abruptly evolve within a few days to ARDS and multi-
organ failure. Severe infection is also associated with high elevation of acute-phase reactants, 
including CRP. This clinical picture of increased cytokines and multi-organ failure is consistent 
with CRS. Canakinumab is an IL-1β inhibitor which could improve the outcomes of patients 
with COVID-19-induced pneumonia and CRS based on its effect on the inflammasome 
pathway.
Hyper-activated innate immune responses drive tissue injury during viral infections, and 
increased IL-1β production via the NLRP3 inflammasome has been shown to accelerate lung 
pathology and fibrosis in the context of sterile inflammation or viral infection. Coronaviruses 
can specifically activate the NLRP3 inflammasome, and by promoting bronchial epithelial cell 
death, can further exacerbate inflammasome-driven IL-1β production. Bats, which act as an 
asymptomatic reservoir for coronaviruses, have reduced NLRP3 inflammasome activity, 
linking IL-1β to the organ-specific manifestations seen in humans. Increased levels of IL-1β 
and/or its downstream effector IL-6 have been detected in SARS-CoV and in COVID-19 
patients and correlate with severity of clinical symptoms. Neutralization of IL-1β and/or its 
downstream cytokine IL-6 has shown benefit in preclinical models of CRS and in the clinic 
with patients undergoing CAR-T therapy. Furthermore, case studies using the IL-6R 
neutralizing antibody tocilizumab have shown benefit in treating COVID-19 patients. 
Neutralization of IL-1β upstream of IL-6 could address some of the additional pleiotropic 
tissue-destructive effects of IL-1β in the lung, and canakinumab and other IL-1 antagonists have 
a lower risk of infection than IL-6-targeting agents such as tocilizumab.
Accumulating evidence suggests that patients develop CRS with severe acute pneumonia due 
to COVID-19. Currently, there is no clinical experience with canakinumab in the treatment of 
SARS-CoV-2 pneumonia nor cytokine release syndrome per se. However, the cytokine 
profiling of patients with severe COVID-19 which is associated with elevated levels of IL-1, 
IL-2, IL-7, IL-6, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, 
monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α and tumor necrosis 
factor-α suggests that canakinumab could improve patient outcomes (Mehta et al 2020, Zhou et 
al 2020).
Based on these findings, canakinumab may have a role in reducing the inflammatory response 
in patients with COVID-19-induced pneumonia and CRS.
Potential risks due to study medication
The risk to patients in this trial will be minimized by adherence to the eligibility criteria and 
close clinical monitoring, including by an internal DMC. Over 2,600 patients including 
approximately 480 children (aged 2 to 17 years) have been treated with canakinumab in 
interventional studies in Periodic fever syndromes, Still’s disease, gouty arthritis, or other IL-1 
beta mediated diseases, and healthy volunteers. The most frequently reported adverse drug 
reactions were infections, predominantly of the upper respiratory tract. The majority of the 
events were mild to moderate although serious infections were observed. No impact on the type 


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or frequency of adverse drug reactions was seen with longer-term treatment. Hypersensitivity 
reactions and opportunistic infections have been reported in patients treated with canakinumab. 
Neutropenia and leukopenia has also been observed with IL-1 inhibitors including canakinumab, 
with transient decreases to <1x109 /L observed during clinical trials with canakinumab.
In addition to experience in approved indications, over 10,000 patients were enrolled in the
CANTOS study evaluating canakinumab for the prevention of recurrent cardiovascular events 
among stable post-myocardial infarction patients with elevated CRP, with a cumulative 
exposure of 32662.6 patient-years (21745.1 patient-years for total canakinumab and 10917.5 
patient-years total for placebo).
No clinically meaningful differences between canakinumab and placebo were observed for 
most safety topics of interest, apart from an increase in serious infections and of fatal 
infections/sepsis; however, the overall incidence was low. The pattern of infections was stable 
over time, with very few confirmed opportunistic infections distributed evenly across the 
treatment groups. There was no evidence of tuberculosis reactivation in canakinumab-treated 
patients.
The overall incidences of investigator-reported infection AEs and discontinuations due to 
infection AEs were comparable across the treatment groups. For investigator-reported infection 
SAEs, there were numerical differences of 1-2% in the overall incidence for the canakinumab 
300 mg and 150 mg groups compared with placebo. Similarly, a slightly higher percentage of 
patients discontinued due to an infection SAE in the canakinumab 300 mg and 150 mg groups 
than in the placebo group. The majority of infection AEs consisted of non-serious upper 
respiratory tract infections which showed no clinically meaningful differences across the 
treatment groups. Increases in the order of 1% with canakinumab relative to placebo in the 
overall population were seen for certain infection events, i.e., sepsis, cellulitis, infectious 
pneumonias. The increase in cellulitis was seen predominately in patients with type-2 diabetes 
mellitus, and that of infectious pneumonias in patients with a history of asthma/chronic 
obstructive pulmonary disease. There was no meaningful difference between canakinumab 150 
mg and 300 mg in the risk of cellulitis or infectious pneumonias; however, a higher risk of 
sepsis AEs with canakinumab 300 mg was observed.
Laboratory data showed an increase with canakinumab 300 mg only in mild neutrophil and 
platelet count abnormalities (Grade 1), with no imbalances in larger declines (Grades 2-4) in 
neutrophil and platelet counts, or in triglyceride levels, between 300 mg and 150 mg.
All-cause mortality was numerically lower across the three canakinumab treatment groups 
compared to placebo, with both fewer cardiovascular deaths and non-cardiovascular deaths. 
There was an increased incidence of deaths due to infection/sepsis for canakinumab 150 mg vs. 
placebo, although the numbers of related deaths were low overall.
The main adverse drug reaction was infection, of which the most common included viral upper 
respiratory tract infection, influenza, and pneumonia.
Overall, the safety and tolerability profile of canakinumab in post myocardial infarction patients 
was consistent with the known safety profile in the approved indications.
Known risks of canakinumab pertinent to short term use include the risks of infection (including 
opportunistic infection), interaction with live vaccines and the use in combination with other 


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immunosuppressant’s (including TNF inhibitors) due to increased risk of serious infections. 
Taking into account the individual risks as outlined above, the expected risk profile of 
canakinumab from its mechanism of action is expected to be similar to that previously observed. 
Based on overall risk-benefit assessment, the very high unmet medical need and the 
implemented controlled setting, the current trial with canakinumab is justified.
There is a limited amount of data from literature and post-marketing reports on the use of 
canakinumab in pregnant women. Animal studies do not indicate direct or indirect harmful 
effects with respect to reproductive toxicity. The risk for the fetus/mother is unknown. 
Monoclonal antibodies such as canakinumab actively cross the placenta and are detectable in 
the fetus, predominantly in the second and third trimesters of pregnancy. Based on limited 
human data, canakinumab levels were detected in cord and neonatal blood. The clinical impact 
of this is unknown. However, administration of live vaccines to newborn infants exposed to 
canakinumab in utero is not recommended for 16 weeks following the mother's last dose of 
canakinumab before childbirth.
It is not known whether canakinumab is transferred into breast milk. There are no data on the 
effects of canakinumab on the breastfed child or the effects of canakinumab on milk production. 
Animal studies have shown that a murine anti-murine IL-1 beta antibody had no undesirable 
effects on development in nursing mouse pups.
For a comprehensive assessment of the risks of canakinumab, refer to the Investigator’s 
Brochure (IB).
Study specific risks
Protocol-mandated invasive procedures performed during this study include blood sampling for 
the collection of safety laboratory parameters, 
.
Chest radiograph or CT scan are required for the diagnosis of COVID-19-induced pneumonia 
prior to study entry and during follow-up. Radiation exposure occurs during each procedure. 
The radiation received during one x-ray is the same as 1 to 2 weeks of normal radiation received 
in everyday life. The radiation received during one CT exam is the same as 2 - 10 years of 
normal radiation received in everyday life, depending on the body parts included. Some people 
may experience claustrophobia while inside the CT machine.
Oversight committees
An internal DMC will be established comprising of an independent (of the study) group of 
individuals from Novartis who have experience and expertise in the management of patients 
within this disease area, experience in statistical methods, safety monitoring and in the 
monitoring of randomized clinical trials who will review safety data provided by the study team 
at regular intervals, to ensure the safety of patients enrolled in this new disease area.


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5
Study Population
The study population includes adult (for US only: patients ≥ 12 years old) male and female 
patients who are hospitalized and diagnosed with COVID-19-induced pneumonia and CRS.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Male or female
2. Adults ≥ 18 years old (for US only: patients ≥ 12 years old)
3. Body weight ≥ 40 kg
4. Informed consent must be obtained prior to participation in this study. For US patients 12 
- <18 years old; parent/guardian consent must be obtained and assent if applicable.
5. Clinically diagnosed with the SARS-CoV-2 virus by PCR or by other approved diagnostic 
methodology within 7 days prior to randomization.
6. Hospitalized with COVID-19-induced pneumonia evidenced by chest x-ray or CT scan
(taken within 5 days prior to randomization) with pulmonary infiltrate.
7. SpO2 ≤ 93% on room air, or arterial oxygen partial pressure (PaO2)/fraction of inspired 
oxygen (FiO2) < 300mmHg (1mmHg=0.133kPa) (corrective formulation should be used 
for higher altitude regions (over 1000m)).
8. C-reactive protein ≥20 mg/L or ferritin level ≥600 μg/L.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. History of hypersensitivity to canakinumab or to biologic drugs.
2. Intubated and on mechanical ventilation (invasive) at time of randomization
3. Treatment with immunomodulators or immunosuppressant drugs, including but not 
limited to tocilizumab, TNF inhibitors and anti-IL-17 agents within 5 half-lives or 30 days 
(whichever is longer) prior to randomization with the exception of anakinra which is 
excluded within 5 half-lives only. Note: Immunomodulators (topical or inhaled) for 
asthma and atopic dermatitis and corticosteroids (any route of administration) are 
permitted
4. Suspected or known untreated active bacterial, fungal, viral, or parasitic infection with the 
exception of COVID-19
5. Neutropenia with ANC <1000/mm3
6. 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
7. In the opinion of the investigator, progression to death is imminent and highly likely 
within the next 24 hours, irrespective of the provision of treatments
8. Current participation in any other investigational trials


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6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
The study will enroll patients who require hospitalization and will receive, in addition to the 
local SOC, canakinumab or placebo. The total duration of treatment will be approximately 2 
hours (Table 6-1).
Investigational treatment:
Canakinumab dose as per Table 6-1 in 250 mL of 5% dextrose infused IV over 2 hours.
Placebo:
250 mL of 5% dextrose infused IV over 2 hours
Table 6-1
Canakinumab dose by body weight
Patient's weight (kg)
Dose of canakinumab
Volume of 150 mg/mL
> 80
750 mg
5.0 mL
60 to 80
600 mg
4.0 mL
40 to < 60
450 mg
3.0 mL
Canakinumab or placebo will be prepared by the unblinded pharmacist. Details on the 
requirements for storage and management of study treatment, and instructions to be followed 
for participant numbering, prescribing/dispensing, and taking study treatment are outlined in 
the Pharmacy Manual.
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Supply of study treatment
Investigational and control drugs will be provided as described in Table 6-2.
Table 6-2
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of
Administration
Supply Type
Sponsor
(global or local)
ACZ885 
150mg/1ml
Concentrate for 
solution for 
infusion
Intravenous use
Open label bulk 
supply; vials
Sponsor (global)
Dextrose 5% will be used at the site to dilute investigational drug or as placebo.


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6.1.4
Treatment arms/group
Participants will be assigned at randomization at 1:1 ratio to one of the following treatment 
arms/groups:

Investigational treatment: Canakinumab dose as per Table 6-1 in 250 mL of 5% 
dextrose infused IV over 2 hours.

Reference treatment: 250 mL of 5% dextrose infused IV over 2 hours.
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.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study.
The patient must be told to notify the Treating Physician about any new medications that he/she 
takes after the start of canakinumab.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Patients in this study will be enrolled to canakinumab or placebo, in addition to SOC per local 
practice, which may include anti-viral treatment, corticosteroids and supportive care.
Immunomodulator (topical or inhaled) use for asthma and atopic dermatitis or corticosteroid 
use (per medical judgement) are not restricted.
Use of oral, injected or implanted hormonal methods of contraception are allowed while on 
canakinumab.
6.2.2
Prohibited medication
The following medications are prohibited:

Up to Day 29, concomitant use of biologics including anakinra, tocilizumab, 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.
For additional information, please refer to the IB.


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6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigative site) with a sequential participant 
number suffixed to it, so that each participant’s participation is numbered uniquely across the 
entire database. Upon signing the informed consent (ICF) form, the participant is assigned to 
the next sequential Participant No. available.
6.3.2
Treatment assignment, randomization
At Randomization visit, all eligible patients will be randomized via IRT to one of the treatment 
arms. A designated site staff member (preferably the pharmacist conducting the blinding) other 
than the investigator or study staff involved in safety and efficacy assessments or eCRF 
completion will contact the IRT after confirming that the patient fulfills all the 
inclusion/exclusion criteria. The IRT will assign a randomization number to the participant, 
which will be used to link the participant to a treatment arm.
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, or by a delegate under 
Novartis supervision, 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.
If a patient discontinues before Randomization, the IRT should be notified within two days and 
the reason for not being randomized should be recorded on the appropriate Case Report Forms.
Randomization will be stratified by country to ensure a balanced allocation of patients to 
treatment groups within the strata.
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
This is a double-blind randomized treatment trial. Participants, all site staff (including study 
investigator and study nurse), persons performing the assessments, and clinical trial team will
remain blind to the identity of the treatment from the time of randomization until database lock
for primary analysis.
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site.
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 will 
receive the treatment arm assigned by the IRT system during the randomization transaction. 




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information and confirm the necessity to break the treatment code for the participant. The 
investigator will then receive details of the investigational drug treatment for the specified 
participant and a fax or email confirming this information. The system will automatically 
inform the Novartis monitor for the site and the study team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

participant number
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
Study drug will be packed and labeled as ACZ885 and supplied as open label bulk supplies.
Each box will contain multiple vials of ACZ885 150mg/1ml. The box can be used for treatment 
of multiple patients. However, each vial intended for one patient should not be used for another 
patient.
Preparation of the investigational drug must be done in a separate space/room where study 
personnel have no access during time of preparation.
6.7.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the designated site personnel 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified in the IB.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
The pharmacist or other qualified site personnel must maintain an accurate record of the 
shipment and dispensing of study treatment in a drug accountability log which will be kept in a 
Pharmacy File in a secured location to which no blinded site staff would have access to.
Study treatment will be prepared by an independent pharmacist or qualified site personnel in 
order to ensure treatment blinding as described in Section 6.1.
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 




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8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation.
Participants should be seen or phoned 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. At the day of discharge from the hospital, 
all assessments should be conducted per Table 8-1. In addition, contact information for the 
patient and/or legal representatives should be obtained for the follow-up visits.
Screening assessments are to be taken as indicated in Table 8-1 prior to randomization and are 
considered baseline measurements. Patients who meet the inclusion/exclusion criteria may be 
dosed immediately after obtaining the baseline measurements.


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Table 8-1
Assessment and Procedures Schedule (Baseline to 18-week safety follow up)13
Visit Day
-1 (0-24 hrs 
prior to 
randomization)1
1
2
Every day during 
hospitalization until 
Day 29 or discharge 
(whichever is earlier)
152
29 or Day of 
Discharge2
Day 572
(±7 days)
1272
(±7 days)/ 
End of Study
Informed consent (including optional genetic 
ICF and assent if applicable)3
x
Inclusion/Exclusion criteria
x
x4
Demographics / medical history
x
SARS-CoV-2 virus testing (local labs)
x8
Record all testing, if obtained
SARS-CoV-2 nasopharyngeal samples 
(central lab)
x
x
Vital signs:
Heart rate, Respiratory rate, Oxygen 
saturation or PaO2/FiO2, Systolic/diastolic 
blood pressure, Body temperature5
x
x4
x
x
x
x
Height, weight
x
Physical exam6
S4
S
S
S
S
Clinical status evaluation with 9-point ordinal 
scale (e.g. oxygen requirement, 
invasive/non-invasive mechanical 
ventilation, additional organ support)
x4
x
x
x
x
x
x
Hematology (local labs)
x
x
x (every other day e.g., 
Days 3, 5, 7, etc.)
x
x
x
Clinical chemistry, CRP, ferritin, d-dimer
(local labs)
x
x
x (every other day e.g., 
Days 3, 5, 7, etc.)
x
x
x
Pregnancy test7 (local labs)
s
s
s
s
Chest x-ray or CT scan8
x
Record all pulmonary imaging if obtained
ECG (local)
s
s
s
Adverse events
x
x4
x
x
x
x
x
x
Prior/concomitant medications/non-drug 
therapy (i.e. oxygen)
x
x4
x
x
x
x
x
x






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8.1
Screening
No rescreening will be permitted.
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 SAE section 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 CRF.
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 Health Authorities.
8.2.1
Demographic/baseline characteristics 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.
8.2.2
Prior and concomitant medications
Relevant prior and concomitant medications will be captured at the screening visit, and updated 
at the baseline visit. Any changes to the ongoing medications or any new concomitant 
medications will be recorded in CRF on an ongoing basis throughout study participation.


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8.3
Efficacy
8.3.1
Clinical status (9-point ordinal scale)
Assessment of clinical status using a 9-point ordinal scale (WHO 2020b) will be recorded at 
baseline on Day 1 before the start of the study treatment and then again once per day through 
Day 29 of the Study Period, if hospitalized (Appendix 1). 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 the 
previous day’s data, and the worst score is recorded as the score for Day 2). In addition, on Day 
29 or the Day of discharge, clinical status on Day 29 or the Day of discharge should be recorded.
Table 8-2
Clinical status (9-point ordinal scale)
Patient State
Descriptor
Scor
e
Uninfected
No Clinical or 
virological evidence of 
infection
0
Ambulatory (not in hospital or in hospital and ready for 
discharge)
No limitation of 
activities
1
Limitation of activities
2
Hospitalized
Mild disease
Hospitalized, no oxygen 
therapy (defined as 
SpO2 ≥ 94% on room 
air)
3
Oxygen by mask or
nasal prongs
4
Hospitalized
Severe disease
Non-invasive ventilation 
or high-flow oxygen
5
Intubation and 
mechanical ventilation
6
Ventilation + additional 
organ support -
pressors, RRT (renal 
replacement therapy), 
ECMO (extracorporeal 
membrane 
oxygenation)
7
Dead
Death
8
8.3.2
Vital signs and oxygen saturation and use
Vital sign measurements include respiratory rate, pulse rate, systolic and diastolic blood 
pressure, and body temperature. Vitals signs should be recorded at a consistent time once each 
day for a patient (i.e. morning, afternoon or evening) and upon significant clinical changes.




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8.4.1
Laboratory evaluations
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
8.4.1.1
SARS-CoV-2 virus testing
For the Screening inclusion criterion, SARS-CoV-2 virus should be measured by PCR or by 
other approved diagnostic methodology ≤ 7 days prior to randomization by local lab.
Documentation of the method used should be available in the source notes.
If additional testing is conducted locally, results should be recorded in the CRF.
8.4.1.2
Laboratory evaluations
Laboratory evaluations will be performed by the local lab.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured according to the assessment schedule in Table 8-1.
Chemistry
BUN/urea, creatinine, total bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transpeptidase, lactate 
dehydrogenase, sodium, potassium, chloride, calcium, bicarbonate, phosphorus, total protein, 
albumin, glucose, uric acid will be measured according to the assessment schedule in Table 8-
1. If a given test is not available locally, this should be documented on the eCRF.
Additional markers of inflammation: CRP, ferritin, and d-dimer should be collected in 
accordance with Table 8-1.
In the case where a laboratory range is not specified by the protocol, but a value is outside the 
reference range for the laboratory at screening and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the Investigator (in 
consultation with the sponsor) and shall be based, in part, upon the nature and degree of the 
observed abnormality. In all cases, the Investigator must document in the source documents, 
the clinical considerations (i.e., result was/was not clinically significant and/or medically 
relevant) in allowing or disallowing the participant to continue in the study.
All patients with laboratory tests containing clinically significant abnormalities should be 
followed until the values return to within the normal ranges or until a clinical explanation is 
identified, even after study medication has discontinued.
8.4.2
Physical exam
A complete physical examination will be performed for baseline measurement at the time point 
defined in Table 8-1. It will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 


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extremities, vascular and neurological. Then, for remaining time points, targeted physical 
examination, per investigator discretion, may be performed.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to informed consent being granted must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
eCRF. Significant findings made after informed consent is given which meet the definition of 
an Adverse Event must be recorded on the Adverse Event screen of the patient’s eCRF.
8.4.3
Height, weight
Height in centimeters will be measured at the Screening visit as specified in the table of 
assessments (Table 8-1).
Body weight (to the nearest 0.1 kilogram in indoor clothing, but without shoes) will be 
measured at the Screening visit as specified in the table of assessments (Table 8-1).
8.4.4
Electrocardiogram (ECG)
An ECG will be taken locally as specified in the Table 8-1
The ECG should be recorded after 10 minutes of rest in the supine position to ensure a stable 
baseline.
Each ECG tracing should be labeled with study number, patient initials patient number, date 
and time, and filed in the study site source documents.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF /eCRF page as appropriate. If necessary, a 
cardiologist may be consulted.
8.4.5
Pregnancy and assessments of fertility
All women of child-bearing potential (except if already confirmed pregnant) will have a serum 
pregnancy test at Screening and urine or serum pregnancy test at subsequent designated visits 
(Table 8-1), if hospitalized. Pregnancy tests will be conducted at the local lab and documented 
in the source documents.
8.4.6
Chest x-ray or CT scan
Standard chest x-ray or CT scan will be performed for eligibility except for those who have had 
a valid x-ray or CT scan done within 5 days prior to randomization. The results must be known 
prior to randomization to determine the patient’s eligibility for the study. Additional chest x-
rays (or CT scan) will be performed, as needed.
Chest x-ray or CT scan results 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 marketed 
compound where the safety profile has been established. The assessments are relevant to the 
critical care setting and will enable determination of therapeutic response in this setting.


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8.5
Additional assessments
8.5.1
SARS-CoV-2 nasopharyngeal samples
Viral load may be measured by assessment of nasopharyngeal swabs sent to the central lab at 
time points designated in the assessment schedule (Table 8-1). Nasopharyngeal swabs should 
be taken in both nostrils or in the same nostril throughout the trial (whenever possible).
Laboratory Manuals will be provided with detailed information on sample collection, handling, 
and shipment


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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances

Participant/guardian decision

Use of prohibited treatment as per recommendations in the prohibited treatment section

Any situation in which study participation might result in a safety risk to the participant

Following emergency unblinding


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
Emergence of adverse events that in the judgment of the investigator, taking into account 
the participant’s overall status, prevent the participant from continuing participation in the 
study

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study

Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, 
fever, chills, urticaria, dyspnea, headache, myalgia, hypotension. Immediate interruption 
of the infusion to administer study treatment is required in such cases.
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the participant/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section.
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 (WoC) 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


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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.
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
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 time point of his/her scheduled last study 
visit has passed.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:
Unexpected, significant, or unacceptable safety risk to participants enrolled in the study
Decision based on recommendations from the internal data monitoring committee (DMC) after 
review of safety and efficacy data
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion 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.


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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 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
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.


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All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. Its outcome (i.e. recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued to the end of study visit.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
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.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect


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
requires in-patient 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.
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. SAE reporting
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until the last study visit must be reported to Novartis safety 
within 24 hours of learning of its occurrence. Detailed instructions regarding the submission 
process and requirements are to be found in the investigator folder provided to each site.
Screen Failures (e.g. a participant who is screened but is not treated or randomized): SAEs 
occurring after the participant has provided informed consent until the time the participant is 
deemed a Screen Failure must be reported to Novartis.
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 
within 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.


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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, an associate from the Chief 
Medical Office and Patient Safety (CMO&PS) Department may urgently require further 
information from the investigator for health authority reporting. Novartis may need to issue an 
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, or is enrolled while pregnant, 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, if a pregnant patient is enrolled or a patient becomes 
pregnant after signing the informed consent, this must be reported to Novartis within 24 hours 
of learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to CMO&PS. Pregnancy follow-
up should be recorded on the same form and should include an assessment of the possible 
relationship to the study treatment any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
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.


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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 sections.
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 16-1 should 
be followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-2. Repeat 
liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and GGT) 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

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 an internal data monitoring committee (DMC) which will function 
independently of all other individuals associated with the conduct of this clinical trial, including 
the site investigators participating in the study. 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.


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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 with 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 and defined in the 
Assessment Schedule (Table 8-1) into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs, 
allow modification and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on eCRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes will be tracked using an Interactive Response Technology (IRT). The 
system will be supplied by the Novartis IRT, who will also manage the database. The data will 
be sent electronically to Novartis) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 


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and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at an initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements with the investigators and 
their staff. During the study, Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will check the 
completeness of participant records, the accuracy of data capture / data entry, the adherence to 
the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor in conducting these activities. Continuous 
monitoring of each site’s data will be performed throughout the conduct of the study.
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis clinical teams to assist with trial 
oversight.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to the respective source 
documents. The investigator must also keep the original informed consent form signed by the 
participant and/or legal representative (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Source data verification may be done on-
site, if possible, or remotely, if the field monitor does not have access or have limited access to 
the site due to the current COVID-19 pandemic. Different approaches can be used depending 
on site medical records, and some of them could include sharing the information through 
electronic systems or platforms provided by a third party. In all cases, investigator and sponsor 
must adhere to the recommendations established by the applicable Health Authorities.
Novartis monitoring standards require verification for the presence of all informed consents, 
adherence to the inclusion/exclusion criteria, documentation of SAEs, and of data that will be 
used for all primary variables. Additional checks of the consistency of the source data with the 
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
The primary analysis of the study will be performed after all patients finished day 29 assessment 
or discontinued early from study before Day 29. The final analysis will happen after all patients 
complete the study.
Safety summaries will be produced for regular DMC safety monitoring according to the 
schedule of DMC meetings.


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Unless if otherwise clarified, descriptive summaries for categorical data will include 
frequencies and percentages, and continuous data will be presented with mean, standard 
deviation, median, minimum, and maximum. For selected parameters, 25th and 75th percentiles 
may also be presented.
Differences, relative risks (RR) and odds ratios (OR) for the comparisons between the two 
treatment arms will be presented with 2-sided 95% confidence interval (CI). P-values will be 
presented if formal hypothesis test is performed.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all participant to whom study treatment has been 
assigned by randomization. According to the intent to treat (ITT) principle, participants will be 
analyzed according to the treatment they have been assigned to during the randomization 
procedure. Efficacy analyses will be performed on the FAS.
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized/assigned treatment if the participant took at least one dose 
of that treatment or the first treatment received if the randomized/assigned treatment was never 
received. The Safety Set will be used in the analysis of all safety variables.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS. Detailed list of demographic and 
baseline characteristic parameters will be included in SAP.
12.3
Treatments
Analyses on treatment and exposure will be on safety set.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary analysis for this study will be conducted on the FAS using treatment policy strategy.
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary estimand, including primary endpoints, are defined in Section 2.1 of this protocol. 
The primary endpoint will be derived based on the 9-point ordinal scale of clinical status
(Appendix 1).
Additional details on primary endpoint derivation will be included in SAP.




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12.5
Analysis of secondary endpoints/estimands
12.5.1
Key secondary endpoint
The key secondary endpoint is the COVID-19 related death during the 4-week period after study 
treatment. Hypothesis test for the key secondary analysis will be performed if and only if the 
null hypothesis for the primary analysis is rejected.
The null hypothesis for the key secondary analysis is that there is no difference in the COVID-
19 related death rate (i.e. CFR) in patients treated with canakinumab compared to patients on 
placebo. The test of the hypothesis will be based on a logistic regression model adjusted for 
treatment, region and the baseline clinical status. The null hypothesis will be rejected if the 
observed p-value for treatment comparison (based on the CFR ratio) is less than the significance 
level of 0.05. Model-based estimates of the CFR and their 95% confidence intervals (CIs), 
estimate of the CFR ratio and 95% CI, and p-value for comparing canakinumab vs. placebo will 
be provided.
The number and percent of patients with COVID-19 related death during the 4-week period 
will also be provided by treatment arms.
The key secondary efficacy analysis is based on FAS. Patients who are lost to follow-up or 
discontinue early from study before Day 29 will be deemed as survivor if the latest clinical 
status is 0 or 1 on the 9-point ordinal scale. Otherwise, the patient will not be included in the 
analysis.
A sensitivity analysis will be provided by considering all patients who lost to follow-up or 
discontinue early from study before Day 29 as survivors.
12.5.2
Other Secondary objectives and 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 variables that of the categorical type.
12.5.3
Safety endpoints
All safety analyses will be based on the safety set including all data collected on or after the 
first dose date.
Adverse events
The number (and percentage) of patients with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind 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.

by treatment, Standardized MedDRA Query (SMQ) and preferred term.
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.


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Similar summaries will be provided for study medication related adverse events, death, serious 
adverse events.
The number (and proportion) of participants with adverse events of special interest/related to 
identified and potential risks (i.e. Infections, Opportunistic infections, Drug induced liver injury, 
Immunosuppressants combination therapy toxicity, Interactions with vaccines, Macrophage 
activation syndrome) will be summarized by treatment.
Deaths, serious AEs, and study medication related AEs will be listed separately.
Vital signs
Vital signs data will be summarized by treatment and visit.
Clinical laboratory evaluations
Laboratory data will be summarized by treatment and visit.
12.5.4
Biomarkers
Adjusted geometric mean ratio to baseline in serum ferritin, CRP and D-dimer will be reported
by treatment arm and visit.


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12.6
Interim analyses
Summaries of safety data will be produced for DMC safety monitoring when needed.
12.7
Sample size calculation
12.7.1
Primary endpoint(s)
Approximately 450 patients will be randomized to canakinumab + SOC or placebo + SOC in a 
1:1 ratio.
Patients infected with COVID-19 exhibit a wide range of clinical severity. With recent initial 
outbreak and evolving pandemic situations, limited data is available to precisely estimate the 
rate of disease progression after hospital admission for the population of interest under SOC. 
The CDC reported 31.4% hospitalizations and 11.5% ICU admissions (among patients with 
known hospitalization and ICU admission status) in the United States between February 12 and 
March 16, 2020 (CDC COVID Response Team 2020). An earlier summary (Wu and McGoogan 
2020) of 72314 diagnosed cases in China estimated about 81% mild cases, 14% severe cases, 
5% critical case and an overall case-fatality rate of 2.3%. A worldwide tally by WHO as of 
March 12th, 2020 estimated a mortality rate of 3.7% with 125,048 confirmed cases. A study by 
Zhou et al (2020) based on complete follow-up of 191 in-hospital patients during the early 
outbreak of COVID-19 in China reported an in-hospital CFR as high as 28%, while other studies 
reported much smaller CFR with incomplete follow-up data. Detailed summaries of disease 
progression time course during hospitalization or by disease status based on large samples, 
however, were not found.
With this study enrolling only hospitalized patients with COVID-19 induced pneumonia and 
CRS, and assuming that more than half of this patient population will likely require invasive 
mechanical ventilation, the true response rate for the control arm of this study is considered 
most likely in the range from 20% - 50%, while the CFR is not likely to be more than 25%.
Invasive mechanical ventilation is a radical departure from the physiology of breathing 
spontaneously, which put patients under risks of various immediate and long-term 
complications (Soni and Williams 2008) regardless of the survival outcome. The benefits of 
canakinumab for COVID-19 patients is considered clinically meaningful if it leads to an 
absolute increase of 15% patients who survived without ever requiring invasive mechanical 


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ventilation. A 4-week CFR reduction by half (i.e. relative risk=0.5) is also considered 
meaningful clinical benefit outweighing the known risks of canakinumab.
Assuming the true response rate for the control arm lies within the range of 20% - 50%, a total 
sample size of 450 and 1:1 randomization ratio will provide at least 89% power to detect the 
minimum clinically meaningful benefit of interest.
Table 12-1
Power for primary analysis under varying assumptions (sample size = 
450)
Response Rate (%)
Clinically meaningful benefits
Power (2-side 
α=0.05)
Control
ACZ885
difference
OR
RR
50
65
15
1.86
1.3
89%
40
55
15
1.83
1.38
89%
30
45
15
1.91
1.5
90%
20
35
15
2.15
1.75
94%
Early discontinuation from study before patient recovery is considered unlikely in this study, 
hence the sample size is not adjusted for attrition. Blinded sample size reevaluation may be 
performed to confirm the assumptions for the sample size calculation, based on which the 
sample size may be updated without inflation of type I error.
12.7.2
Secondary endpoint(s)
Using a hierarchical testing procedure for familywise 2-sided type I error control at 0.05, the 
hypothesis test in key secondary analysis on 4-week CFR will be performed if and only if null 
hypothesis in primary analysis is rejected. The conditional power for detecting a 50% drop of 
4-week CFR are evaluated under different assumptions on control arm 4-week CFR.
Table 12-2
Power for key secondary analysis (sample size = 450)
CFR (%)
Clinically meaningful benefits
Power (2-side 
α=0.05)
Control
ACZ885
difference
OR
RR
25
12.5
-12.5
0.43
0.5
92%
20
10
-10
0.44
0.5
83%
15
7.5
-7.5
0.46
0.5
70%
Cases of lost to follow up before patient’s recovery (clinical status = 0 or 1 on the 9-point ordinal 
scale) and before Day 29 is expected to be minimal. Sample size adjustment for key secondary 
analysis is not planned.
There is no formal hypothesis test or power consideration for other secondary analysis.


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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit)
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System 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
Available upon request
Ahn M, Anderson DE, Zhang Q, et al (2019) Dampened NLRP3-mediated inflammation in 
bats and implications for a special viral reservoir host. Nature Microbiology; 4:789-99.
Alosaimi B, Hamad ME, Naeem A, et al (2020) MERS-CoV infection is associated with 
downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated 
inflammatory innate immune response in the lower respiratory tract. Cytokine; 126:154895.
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open questions. Cell Mol Life Sci; 68:765-83.
Beigel JH, Farrar J, Han AM, et al on behalf of the Writing Committee of the WHO 
Consultation on Human Influenza A/H5 (2005) Avian influenza A (H5N1) infection in 
humans. NEJM; 353:1374-85.
Bouros D, Alexandrakis MG, Antoniou KM, et al (2005) The clinical significance of serum 
and bronchoalveolar lavage inflammatory cytokines in patients at risk for acute respiratory 
distress syndrome. BMC Pulm Med; 4(6); doi: https://doi.org/10.1186/1471-2466-4-6.
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https://.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html (Accessed 02 April 
2020).
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Disease 2019 (COVID-19) - United States, February 12–March 16, 2020. Morb Mortal Wkly 
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coronavirus viroporin 3a activates the NLRP3 inflammasome. Front Microbiol; 10:50.
Chen T, Wu D, Chen H, et al (2020) Clinical characteristics of 113 deceased patients with 
coronavirus disease 2019: retrospective study. BMJ; 368:m1091.
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patients with coronavirus disease 2019 (COVID-19). medRxiv; doi: 
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myocardial infarction risk: A meta-analysis. Medicine; 97(30):e11645.
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αvβ5 and αvβ6 integrin-dependent mechanisms. Molecular Med; 102:804-12.
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essential in pulmonary inflammation and fibrosis in mice. J Clin Invest; 117(12):3786-99.
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syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med; 24:731-8.
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International Committee on Taxonomy of Viruses (2020) The species severe acute respiratory 




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Mehta P, McAuley DF, Brown M, et al (2020) COVID-19: consider cytokine storm 
syndromes and immunosuppression. Lancet; 395:1033-4.
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and immunological responses in MERS patients representing a broad spectrum of disease 
severity. Sci Rep; 6:25359.
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differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. 
Nature Medicine; 24:739-48.
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early lung injury stimulates fibroblast proliferation through IL-1 beta-induced IL-6 
expression. J Immunol; 172(4):2668-77.
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with acute respiratory distress syndrome. Am J Respir Crit Care Med; 164:1896-903.
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virus infection results in early and excessive infiltration of macrophages and neutrophils in the 
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induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl 
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with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol; 11(1):35.
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ventricular systolic/diastolic function and restores contractility reserve in severe ischemic 
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Tocilizumab. chinaXiv:202003.00026v1.
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lung injury and mortality. J Immunol; 198(11):4383-93.
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19 patients. Cell Mol Immunol; doi: 10.1038/s41423-020-0401-3.


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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; doi: 
https://doi.org/10.1016/S0140-6736(20)30566-3.


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16
Appendices
16.1
Appendix 1: 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
(WHO 2020b)


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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)

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 is 
higher)
*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 Bilirubin (isolated)
>1.5 – 3.0 ULN

Repeat LFTs within 48-72 
hours
Monitor LFTs weekly until 
resolutiona 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 
resolutiona (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
a Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) 
stable values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated 
level after a maximum of 6 months, (4) liver transplantation, and (5) death.
*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
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.

SAP_001.pdf: 








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Table of contents
Table of contents .................................................................................................................5
List of abbreviations............................................................................................................8
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
Figure 1-1
Study design..........................................................................................10
1.2
Study objectives and endpoints .............................................................................10
Table 1-1
Objectives and related endpoints .........................................................10
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................12
Table 2-1
Canakinumab dose by body weight ......................................................12
2.2
Analysis sets ..........................................................................................................14
2.2.1
Subgroup of interest ..............................................................................15
2.3
Patient disposition, demographics and other baseline characteristics ...................16
2.3.1
Patient disposition.................................................................................16
2.3.2
Demographic characteristics.................................................................16
2.3.3
Baseline disease characteristics.............................................................16
2.3.4
Medical history......................................................................................17
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................17
2.4.1
Study treatment / compliance................................................................17
2.4.2
Prior, concomitant and post therapies...................................................17
2.5
Analysis of the primary estimand..........................................................................18
2.5.1
Primary estimand ..................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................19
2.5.3
Handling of missing values/censoring/discontinuations.......................20
2.5.4
Sensitivity analysis................................................................................20
2.5.5
Supplementary analysis.........................................................................20
2.5.6
Supportive analysis ...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................21
2.6.1
Key secondary estimand .......................................................................21
2.6.2
Statistical hypothesis, model, and method of analysis..........................21
2.6.3
Handling of missing values/censoring/discontinuations.......................22
2.6.4
Sensitivity analysis................................................................................22
2.6.5
Supplementary analysis.........................................................................22
2.7
Analysis of secondary efficacy objective(s)..........................................................22


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2.7.1
Secondary endpoints .............................................................................22
2.7.2
Statistical hypothesis, model, and method of analysis..........................23
2.7.3
Handling of missing values/censoring/discontinuations.......................23
2.8
Safety analyses.......................................................................................................23
2.8.1
Adverse events (AEs)............................................................................23
2.8.2
Laboratory data .....................................................................................25
2.8.3
Other safety data ...................................................................................26
26
26
27
28
28
29
30
31
31
31
31
31
32
32
2.10
Interim analysis......................................................................................................32
3
Sample size calculation .....................................................................................................32
3.1.1
Primary endpoint...................................................................................32
Table 3-1
Power for primary analysis under varying assumptions (sample 
size = 450)..............................................................................................................33
3.1.2
Key secondary endpoint........................................................................33
Table 3-2 
Power for key secondary analysis (sample size = 450).........................33
4
Change to protocol specified analyses ..............................................................................34
5
Appendix ...........................................................................................................................34
5.1
Imputation rules.....................................................................................................34
5.1.1
Study drug.............................................................................................34
5.1.2
AE date imputation ...............................................................................34
5.1.3
Concomitant medication date imputation .............................................36
5.1.4
Concomitant therapies and procedures date imputation .......................37
5.2
AEs coding/grading ...............................................................................................38


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5.3
Statistical models...................................................................................................38
5.3.1
Primary analysis....................................................................................38
5.3.2
Key secondary analysis.........................................................................39
5.4
Rule of exclusion criteria of analysis sets..............................................................39
Table 5-1
Protocol deviations that cause subjects to be excluded.........................39
Table 5-2
Subject Classification............................................................................39
5.5
Clinical status (9-point ordinal scale)....................................................................39
Table 5-3
Clinical status (9-point ordinal scale) ...................................................40
5.6
Type of pulmonary/ventilatory support.................................................................40
Table 5-4
Type of pulmonary/Ventilatory support based on the level of 
oxygen requirement from low to high ...................................................................40
41
41
6
Reference...........................................................................................................................41


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List of abbreviations
AE
Adverse event
AESI
AE of Special Interest
ASTCT
American Society for Transplantation and Cellular Therapy
ATC
Anatomical Therapeutic Classification
CI
Confidence Interval
CFR
Case Fatality Rate
COVID-19
Coronavirus disease 2019
CRP
C Reactive Protein
CRS
Cytokine Release Syndrome
CSR
Clinical Study report
CV
Coefficient of variation
DBL
Database lock
DMC
Data Monitoring Committee 
EoS
End of Study
FAR
First analysis report
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
ICU
Intensive care unit
IV
Intravenous
LDH
Lactate dehydrogenase
LLOQ
lower limit of quantification
LOCF
Last Observation Carry Forward
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MH
Medical History
OR
Odds ratio
PD
Protocol Deviation
PT
Preferred Term
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SD
Standard deviation
SoC
Standard of Care
SOC
System Organ Class
TFL
Table/Figure/Listing
ULOQ
upper limit of quantification
WHO
World Health Organization


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1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of 
statistical analyses for the Day 29 First Interpretable Results (FIR) and First Analysis Report
(FAR) as well as the final report including all the analyses conducted at the Day 29 database 
lock (DBL) and new analyses including safety follow up data in the final DBL at the end of the 
study. The analyses to be conducted for FAR or the primary publications at the time of Day 29 
will be identified on the Table/Figure/Listing (TFL) shell document.
The SAP should be finalized before the Day 29 DBL after all patients either completed Day 29 
assessment or discontinued early from the study before Day 29. Any changes to the SAP after 
approval will be documented. 
The following documents were referenced while writing this SAP:
CACZ885D2310 Clinical Trial Protocol Final version 00 dated 10-April-2020
CACZ885D2310 Clinical Trial Protocol Final version 01 amendment dated on 01-June-2020
Important information is given in the following sections and details are provided, as applicable, 
in Section 5 Appendix.
1.1
Study design
This is a multicenter, double-blind, randomized, placebo-controlled study to assess the efficacy 
and safety of canakinumab plus standard of care (SoC) compared with placebo plus SoC in 
adult patients with SARS-CoV-2 virus-induced pneumonia and CRS (Figure 1-1).
The study aims to randomize approximately 450 patients worldwide. Randomization is 
stratified by country to ensure a balanced allocation of patients to treatment groups within the 
strata. Enrollment will stop as soon as the target number of randomized patients is reached. 
Patients who meet the inclusion/exclusion criteria will be randomized in a 1:1 ratio to either 
canakinumab + SoC or placebo + SoC and can be dosed immediately after ensuring that the 
patient has met all eligibility criteria. Patients in the canakinumab arm will be dosed on Day 1 
with canakinumab 450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg or 750 mg for 
>80 kg) in 250 mL of 5% dextrose infused intravenously (IV) over 2 hours. Patients in the 
placebo arm will be treated with 250 mL of 5% dextrose infused IV over 2 hours. 
Patients who do not meet the criteria for participation in this study (screen failures) will not be 
re-screened.


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Figure 1-1 Study design 
Safety monitoring will be conducted at weekly intervals during the study using a data 
monitoring committee (DMC). The analysis plan for the DMC will be created separately.
1.2
Study objectives and endpoints
Study objectives and related endpoints pre-specified in the protocol are described in Table 1-1
below. 
Table 1-1
Objectives and related endpoints 
Objective(s)
Endpoint(s)
Primary Objective
To demonstrate the benefit of canakinumab + 
standard of care (SOC) in increasing chance of 
survival without ever requiring invasive 
mechanical ventilation among patients with 
COVID-19-induced pneumonia and CRS
Endpoint for primary objective:
Clinical response, defined as survival without 
ever requiring invasive mechanical ventilation 
from Day 3 (inclusive) up to Day 29 (inclusive). 
Secondary Objective(s)
To demonstrate the benefit of canakinumab in 
reducing 4-week case fatality rate (CFR) among 
patients with COVID-19-induced pneumonia and 
CRS regardless of other subsequent clinical 
interventions
Endpoint(s) for secondary objective(s):
COVID-19-related death during the 4-week
period after study treatment
To evaluate change in clinical serologic 
measurements related to CRS in COVID-19 
patients with pneumonia
Adjusted geometric mean ratio to baseline 
overtime up to Day 29 in the following clinical 
chemistry measurements:
o
C Reactive Protein (CRP)
o
Serum ferritin
o
D-dimer
To evaluate safety of canakinumab in patients 
with COVID-19-induced pneumonia and CRS
Number of participants with Adverse Event (AE), 
serious adverse events (SAE), 
clinically significant changes in laboratory 
measures, and vital signs


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Objective(s)
Endpoint(s)


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2
Statistical methods.
2.1
Data analysis general information
For the primary analyses based on Day 29 DBL, efficacy analyses will be based on all data up 
to and including Day 29. The safety analyses will include all data up to the time of data cut (i.e., 
including data after Day 29 for those enrolled early in the study) if not otherwise specified.
At the final DBL, summary of all safety data collected from post treatment until end of study 
will be provided. 
Novartis statistical and programming team will be performing the analyses as planned in this 
document. The Statistical Analysis System (SAS) 9.4 or higher versions will be used. R version 
3.6.1 may also be used as appropriate.
Unless if otherwise clarified, descriptive summaries for categorical data will include 
frequencies and percentages, and continuous data will be presented with mean, standard 
deviation, median, minimum, and maximum. For selected parameters, geometric mean and 
geometric coefficient of variation (CV) may also be presented. 
Rate differences and odds ratios (OR) for the comparisons between the two treatment arms will 
be presented with 2-sided 95% confidence interval (CI). P-values will be presented if formal 
hypothesis test is performed.
The randomization of the study is stratified by country to ensure a balanced allocation of 
patients to treatment groups within the strata. Statistical models will include adjustments for 
regions (North America and Europe) by pooling countries to regions.  The countries are pooled 
by regions as follows:
North America: United States
Europe: Italy, France, Germany, Spain, United Kingdom, Hungary, Russia
2.1.1
General definitions 
Study treatment
This is a one-time treatment study. Study treatment refers to canakinumab (including patients 
on any dose as per Table 2-1) in 250 mL of 5% dextrose infused IV over 2 hours or placebo as 
250 mL of 5% dextrose infused IV over 2 hours. 
Table 2-1
Canakinumab dose by body weight 
Patient's weight (kg)
Dose of canakinumab
Volume of 150 mg/mL
> 80
750 mg
5.0 mL
60 to 80
600 mg
4.0 mL
40 to < 60
450 mg
3.0 mL 
Study day
Day 1 is defined as the date when the study treatment is started. Study day is defined as the 
number of days since the date of study treatment (Day 1). 


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Therefore, for a particular date, study day will be calculated as follows:

for dates on or after Day 1:
Study day = Assessment date – Day 1 + 1;

for dates prior to Day 1:
Study day = Assessment date – Day 1.
If a patient never took any double-blind treatment, the randomization date will be used as Day 
1 .
2.1.1.1
Baseline
The baseline value is defined as the last assessment performed prior to start of study treatment 
at Day 1. 
For patients who are not treated, the baseline is the last assessment scheduled for pre-baseline
visit on or before the randomization date, e.g., a 9-point ordinal scale on Day 1 pre-dose visit is 
considered as baseline.
2.1.1.2
Post-baseline measurement
All data collected after the start of study treatment are defined as post-baseline. For patients 
who are not treated, the post-baseline is any scheduled post-baseline assessments on or after the 
randomization visit, e.g., a 9-point ordinal scale on Day 1 or an assessment for early exit visit 
on the randomization date is considered post-baseline measurement.
The following formula will be used, depending on how the post-baseline endpoint is defined, 
for each scheduled visit and time-point where baseline and post-baseline values are both 
available:
Change from baseline = post-baseline value – baseline value.
Percent change from baseline= (post-baseline value – baseline value)/baseline value*100%.
Ratio to baseline= post-baseline value / baseline value.
AEs will be considered as treatment-emergent if the event is starting after the start of double-
blind treatment or the event is present prior to start of double-blind treatment but increased in 
severity after the start of treatment based on preferred term and up to end of study on Day 127.
Details on calculation of post-baseline values are provided in the latter sections.
2.1.1.3
End of study/end of treatment
The end of study (EoS) date is the date when a patient completes or discontinues the study, i.e., 
the “Disposition Event Date” from the “disposition” CRF form for study disposition.
This is a one-time treatment study and disposition status based on the study treatment is not 
applicable.
For reporting data by visit in outputs, the discontinuation from study visit will be allocated to 
the visit number based on the day of EoS if discontinuation is on or before Day 29.  For the 


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assessments that are scheduled on every other day and EoS visit falls on a day without scheduled 
assessment, the EoS visit will be mapped to next scheduled visit for the corresponding 
assessment.  If the discontinuation from study is after Day 29, the EoS visit will be mapped to 
the next scheduled visit. 
2.1.1.4
Discharge from hospital
Discharge from hospital is not time point specific visit and will be mapped based on the actual 
day since day 1 if the discharge is on or before Day 29.  For the assessments that are scheduled 
on every other day and discharge falls on a day without scheduled assessment, the discharge 
visit will be mapped to next scheduled visit for the corresponding assessment.
2.1.1.5
Unscheduled visits
Data collected at unscheduled visits will not be used for analysis by visit, but will be included 
in analyses based on all post-baseline values such as Last observation carried forward (LOCF) 
imputation or summary of abnormal findings during the study.
2.1.1.6
Nominal visit of discharge/Day 29
To evaluate the treatment effect at the time of discharge up to Day 29, summary at 
discharge/Day 29 may be provided based on assessments from 

early discharge visit for those who are discharged from hospital before Day 29 or 

from last available assessment up to Day 29 if not discharged before Day 29 
2.1.1.7
Missing and imputable dates
The general approach to handling missing dates is described in Section 5.1.
2.1.1.8
Laboratory results meeting limits of quantification
For observations beyond the limits of quantification, a value of the lower limit of quantification 
(LLOQ) or the upper limit of quantification (ULOQ) will be used for analysis if not otherwise 
specified. This rule will be applied to all applicable laboratory values prior to checking against 
the notable criteria as well as computation of any statistics.
2.2
Analysis sets
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. An accidental or premature randomization of a patient without 
providing study medication is considered as a misrandomized patient. Misrandomized patients
will be included in FAS. According to the intent to treat (ITT) principle, participants will be 
analyzed according to the treatment they have been assigned during the randomization 
procedure.
The FAS will be used for the summary of demography and baseline characteristics as well as 
for all efficacy analyses.
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 




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
Use of anti-IL6 treatment (Yes, No)
The subgroups based on the use of prior COVID-19-induced pneumonia treatment medication 
are defined as with/without the given medication that started on or after the onset of the first 
symptom of COVID-19-induced pneumonia and before the study treatment date (or 
randomization date if no study treatment is taken).
2.3
Patient disposition, demographics and other baseline 
characteristics
No inferential testing on the differences in patient disposition, demographics and other baseline 
characteristics between treatment arms will be performed.
2.3.1
Patient disposition
The number and percentage of patients who were screened but not randomized will be 
summarized based on all screened patients. 
The following disposition status will be summarized based on the FAS:

The number and percentage of patients who receive study treatment 

The number and percentage of patients who discontinue from study as well as the 
primary reason for discontinuation on or prior to Day 29  

The number and percentage of patients who discontinue from study as well as the 
primary reason for discontinuation on or prior to the time of data cut for Day 29 DBL 
or EoS (for the final DBL)

The number and percentage of patients who are ongoing up to the time of data cut for 
Day 29 DBL. This is only applicable for the analysis based on Day 29 DBL
The number of patients included in each analysis set will be tabulated. Patients exclusion from 
analysis sets will be listed for all patients with reasons for exclusion (i.e. including both protocol 
and non-protocol deviations). 
2.3.2
Demographic characteristics
Demographic characteristics, including gender, race, ethnicity, age, age categories (<18,  18-
<65, 65-<75 and ≥ 75 years), body weight, body categories (40 to <60 kg, 60 to 80 kg, >80 kg), 
body mass index (BMI), BMI categories (≤ 30.0 kg/m2 and > 30.0 kg/m2), country and region
(North America vs. Europe) will be summarized with descriptive statistics for the FAS by 
treatment and overall.
2.3.3
Baseline disease characteristics
The summary of the following baseline disease characteristics will be provided by treatment 
group using the FAS:
o
Days from the onset of symptom to randomization as continuous variable
o
Days from diagnosis to randomization as continuous variable




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2.4.2.1
Concomitant medication
Records on the Prior and Concomitant Medications eCRF page will be coded using the WHO 
drug dictionary. All medications will be classified as prior or concomitant medication as follows:

Prior medications are defined as drugs taken and stopped prior to start of the study 
medication on Day 1.

Concomitant medications are defined as drugs taken at least once after the start of the 
study medication on Day 1
Medications will be categorized into one (and only one) of the two classes based on recorded 
or imputed start and end dates. When incomplete or missing, dates will be imputed according 
to Novartis standards (Section 5.1.3). 
Medications in one of the two categories will be summarized separately by treatment group, 
ATC code (ATC class level 3, i.e., therapeutic/pharmacological subgroup) and preferred term. 
2.4.2.2
Surgical and medical procedures
Records on the surgical and medical procedures eCRF page will be coded using the MedDRA 
dictionary. All procedures will be classified as prior or concomitant procedure, in the same way 
as done for concomitant medications.  Surgical and medical procedures in one of the two 
categories will be summarized separately by SOC, PT and treatment group.
Imputation rules for start and end dates will follow the same rule as for the concomitant 
medications (section 5.1.4).
2.5
Analysis of the primary estimand
The primary analysis for this study will be conducted on the FAS using treatment policy strategy.
2.5.1
Primary estimand
The primary clinical question of interest is: Does canakinumab + SoC increase the chance of 
survival without ever requiring invasive mechanical ventilation among patients with COVID-
19-induced pneumonia and CRS after start of treatment, regardless of other subsequent clinical 
interventions?
The justification for this primary estimand is that it captures the clinical outcome of most 
interest after the canakinumab administration, which reflects also any effects of additional 
subsequent interventions potentially due to such clinical decision. In the ongoing COVID-19 
pandemic with evolving treatment guidelines and healthcare system burdens, this primary 
estimand is deemed better to reflect actual clinical practices. In addition, the IV delivery of 
canakinumab is expected to result in a fast decrease in pharmacologically active IL-1β and to 
reduce L-1β signaling to marginal levels within hours.  However, clinical signs or symptoms 
within the 24 hours after treatment may not necessarily reflect such pharmacological effect yet. 
Therefore, only clinical status starting from Day 3 will be considered for the primary endpoint.
The primary estimand includes the following components:
Population: Patients with COVID-19-induced pneumonia and CRS. 






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2.6
Analysis of the key secondary objective
The key secondary efficacy analysis is based on FAS. The inferential testing on the key 
secondary endpoint specified in this section will be performed if the null hypothesis of the 
primary endpoint is rejected with a two-sided testing with p-value less than 0.05. This testing 
procedure controls the overall two-sided type-I error rate to less than 0.05 within the study.
2.6.1
Key secondary estimand
The key secondary clinical question of interest in this study is: Does the administration of 
canakinumab reduce 4-week mortality among patients with COVID-19-induced pneumonia and 
CRS, regardless of other subsequent clinical interventions?
The justification for this secondary estimand is that mortality currently represents the main 
epidemiological and clinical concern for COVID-19 patients and accumulating evidences 
suggest coexistence of CRS with severe COVID-19-induced pneumonia. Subsequent clinical 
interventions, including intensive care when a patient become terminally ill, reflect actual 
clinical practices, whose needs, scope and effectiveness could potentially be related to the 
earlier decision of canakinumab administration.
The key secondary estimand includes the following components:
Population: Hospitalized patients with COVID-19-induced pneumonia and CRS. 
Endpoint: All COVID-19-related deaths (i.e., all deaths caused by study indication) during the 
4-week period after study treatment
Treatment of interest: The randomized study treatment (canakinumab or placebo) added onto 
SOC with or without additional subsequent clinical interventions. 
Handling of remaining intercurrent events:
The treatment policy strategy will be adopted for this key secondary analysis. 

Effect of other subsequent clinical interventions will not be adjusted

Early study discontinuation or lost to follow-up before Day 29: a patient will be considered 
as survivor if the last clinical status of 0 or 1; otherwise, the patient will not be included in 
this key secondary analysis (note: this include deaths which are not marked as caused by 
study indication).
Summary measure: Odds-ratio comparing 4-week CFR in the canakinumab and control groups.
2.6.2
Statistical hypothesis, model, and method of analysis
The null hypothesis for the key secondary analysis is that there is no difference in the COVID-
19 related death rate (i.e. CFR) in patients treated with canakinumab compared to patients on 
placebo. The alternative hypothesis is that there is a difference between the two treatment 
groups. 
The superiority of canakinumab over placebo will be concluded if the odds ratio <1 for the 
COVID-19 related death between canakinumab and placebo and the null hypothesis can be 
rejected at the two-sided significance level of 0.05.  


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The test of the hypothesis will be based on a logistic regression model with study treatment, 
region (North America vs. Europe), baseline clinical status based on the 9-point ordinal scale 
(≤4, ≥5) as factors. Model-based estimates of the CFR and their 95% confidence intervals (CIs), 
estimate of the odds ratio and 95% CI, and p-value for comparing canakinumab vs. placebo will 
be provided. In case of model converge problem caused by separability, Firth’s penalized 
maximum likelihood estimation will be performed based on the same logistic regression model. 
The estimated odds ratio, p-values and 95% CI (all computed by penalized profile likelihood) 
will be presented. 
The number and percent of patients with COVID-19 related death during the 4-week period 
will also be summarized by treatment arms. The difference in observed response rates between 
canakinumab and placebo arms will also be presented along with the asymptotic 95% 
confidence interval.
2.6.3
Handling of missing values/censoring/discontinuations
Missing data due to intercurrent events has been address via the handling of intercurrent event 
under the key secondary endpoint estimand definition. 
2.6.4
Sensitivity analysis
As a sensitivity analysis, the between group difference will also be assessed by rate difference 
using the marginal standardization method, for which the rate difference will be derived from 
the predicted rate for every patient as if they had received the study treatment or the placebo 
using a logistic regression model.  The model will be adjusted by treatment, region (North 
America vs. Europe), and baseline clinical status based on the 9-point ordinal scale (≤4, ≥5) as 
factors. The rate within each treatment arm along with the 95% CI, rate difference along with 
the 95% CI and p-value will be presented. 
2.6.5
Supplementary analysis
A supplementary analysis will be implemented, for which all patients who discontinued from 
study or lost to follow up will be considered non-survivors in the analysis. 
The supplementary analysis will apply the same logistic regression model as for the key 
secondary analysis. 
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
The secondary efficacy endpoints include the clinical serologic measurements on markers of 
inflammation related to CRS in COVID-19 patients with pneumonia:
o
ratio to baseline overtime up to Day 29 in CRP
o
ratio to baseline overtime up to Day 29 in Serum ferritin
o
ratio to baseline overtime up to Day 29 in D-dimer
The ratio to baseline and post baseline value will be summarized by mean, SD, median, Q1, Q3, 
and geometric statistics (geometric mean, geometric CV, 95% CI of the geometric mean) by 
treatment arm and visit. The summary is based on data with last observation carry forward 




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Summaries by primary system organ class and preferred term will be provided for serious 
adverse events. 
In addition, AE (and SAE) suspected to be related to study medication, AE requiring additional 
therapy, AE requiring discontinuation of study treatment will be summarized by treatment, 
primary system organ class and preferred term
Serious AEs and study medication related AEs will be listed separately
2.8.1.1
Adverse events of special interest / grouping of AEs
The number (and proportion) of patients with the adverse events that fulfill the risk search terms 
(listed below as defined in the case retrieval sheet) will be summarized by risk name, PT, and 
treatment: 
o
Infections
o
Interactions with vaccines
o
Opportunistic infections 
o
Drug induced liver injury 
o
Immunosuppressants combination therapy toxicity
o
Macrophage activation syndrome
In the summary table, risk names will be sorted alphabetically and, within each risk name, the 
PTs will be sorted in descending order of frequency in the canakinumab arm. If a patient 
reported more than one adverse event with the same PT, the AE will be counted only once. If a 
patient reported more than one AE within the same risk, the patient will be counted only once 
at that risk.
SAEs of special interest, AEs of special interest suspected to be related to study treatment, and 
SAEs of special interest suspected to be related to study treatment, will also be summarized by 
risk name, PT and treatment group.
A list of the risk search terms used for the selection of AE of special interest will be provided.
2.8.1.2
Deaths
Adverse events leading to death will be summarized with number and percentage by treatment 
and primary AE (SOC and PT).  Similar summary on adverse events leading to death that is 
suspected to be related to study treatment will also be provided. Listing of death will also be 
provided. 
2.8.1.3
Adverse events reporting for CT.gov and EudraCT
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
2% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set including 
all data up to EoS based on the final DBL.


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If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2
Laboratory data
Laboratory tests will be conducted by local lab. Clinically significant abnormal results will be 
reported as adverse events and included in the AE summaries; however the following liver 
enzyme testing results will be entered into the clinical database:

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Total bilirubin (TBIL) / Direct bilirubin

Alkaline phosphatase (ALP)
Number (%) of newly occurring liver enzyme abnormalities, as listed below, at any time during 
post-treatment will be provided. A newly occurring event is when a patient not meeting a given 
criterion at baseline but meeting the corresponding criterion during post-baseline. 

ALT or AST > 3.0x, 5.0x, 10.0x, 20.0x ULN  

ALP>1.5xULN                               

TBIL > 1.5x, 2.0x ULN

ALT or AST > 3.0x ULN & TBIL > 1.5x ULN 

ALT or AST > 3.0x ULN & TBIL > 2.0x ULN  
The last two criteria on the list are based on the maximum post-baseline ALT, AST, and TBIL. 
An eDISH plot on the maximum post-baseline ALT value relative to the ULN and TBIL value 
relative to the ULN will also be provided at log-log scale.
Hematology parameters
The hematology parameters include absolute neutrophil count, monocytes, lymphocytes 
measured from local lab. The post baseline value and the percent change from baseline at post 
baseline are summarized by mean, SD, median, Q1, and Q3. The summary is based on the 
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2.8.3
Other safety data
2.8.3.1
SARS-CoV-2 Virus test
The presence of SARS-CoV-2 virus will be tested by central lab based on nasopharyngeal 
samples taken at baseline and at discharge from hospital/Day 29 if not discharged. 
A summary on viral load by sequential quantitative RT-PCR for SARS associate coronavirus 
will be summarized by geometric mean at baseline, at discharge for those who are discharged 
on or before Day 29, at Day 29 for those who are not discharged on or before Day 29. The 
summary will also be provided by the day interval between Day 1 to discharge from hospital: 
Discharge on Day 1 to Day 7, discharge on Day 8 to Day 14, Discharge on Day 15-Day 21, 
Discharge on Day 21 to Day 29. 
In addition, a summary on number (%) of patients with positive (a reading ≥LLOQ) or negative
(<LLOQ) test results will be provided at baseline, at discharge for those who are discharged 
on or before Day 29, at Day 29 for those who are not discharged on or before Day 29, and by 
the discharge day interval.
2.8.3.2
Vital signs
Vital sign measurements include respiratory rate, pulse rate, systolic and diastolic blood 
pressure, and body temperature. Absolute values and change from baseline will be summarized 
for each of the aforementioned vital sign parameters by treatment group, visit and time point 
including the minimum and maximum Post-baseline value. 


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2.10
Interim analysis
Summaries of safety data will be produced for DMC safety monitoring when needed.
3
Sample size calculation
3.1.1
Primary endpoint
Approximately 450 patients will be randomized to canakinumab + SOC or placebo + SOC in a 
1:1 ratio. 
Patients infected with COVID-19 exhibit a wide range of clinical severity. With recent initial 
outbreak and evolving pandemic situations, limited data is available to precisely estimate the 
rate of disease progression after hospital admission for the population of interest under SOC. 
The CDC reported 31.4% hospitalizations and 11.5% ICU admissions (among patients with 
known hospitalization and ICU admission status) in the United States between February 12 and 
March 16, 2020 (CDC COVID Response Team 2020). An earlier summary (Wu and McGoogan 
2020) of 72314 diagnosed cases in China estimated about 81% mild cases, 14% severe cases, 
5% critical case and an overall case-fatality rate of 2.3%. A worldwide tally by WHO as of 
March 12th, 2020 estimated a mortality rate of 3.7% with 125,048 confirmed cases. A study by 
Zhou et al (2020) based on complete follow-up of 191 in-hospital patients during the early 
outbreak of COVID-19 in China reported an in-hospital CFR as high as 28%, while other studies 


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reported much smaller CFR with incomplete follow-up data. Detailed summaries of disease 
progression time course during hospitalization or by disease status based on large samples, 
however, were not found. 
With this study enrolling only hospitalized patients with COVID-19 induced pneumonia and 
CRS, and assuming that more than half of this patient population will likely require invasive 
mechanical ventilation, the true response rate for the control arm of this study is considered 
most likely in the range from 20% - 50%, while the CFR is not likely to be more than 25%.  
Invasive mechanical ventilation is a radical departure from the physiology of breathing 
spontaneously, which put patients under risks of various immediate and long-term 
complications (Soni and Williams 2008) regardless of the survival outcome.  The benefits of 
canakinumab for COVID-19 patients is considered clinically meaningful if it leads to an 
absolute increase of 15% patients who survived without ever requiring invasive mechanical 
ventilation. A 4-week CFR reduction by half (i.e. relative risk=0.5) is also considered 
meaningful clinical benefit outweighing the known risks of canakinumab.
Assuming the true response rate for the control arm lies within the range of 20% - 50%, a total 
sample size of 450 and 1:1 randomization ratio will provide at least 89% power to detect the 
minimum clinically meaningful benefit of interest. 
Table 3-1
Power for primary analysis under varying assumptions 
(sample size = 450)
Response Rate (%)
Clinically meaningful benefits
Power (2-side 
α=0.05) 
Control
ACZ885
difference
OR
RR
50
65
15
1.86
1.3
89%
40
55
15
1.83
1.38
89%
30
45
15
1.91
1.5
90%
20
35
15
2.15
1.75
94%
Early discontinuation from study before patient recovery is considered unlikely in this study, 
hence the sample size is not adjusted for attrition. Blinded sample size reevaluation may be 
performed to confirm the assumptions for the sample size calculation, based on which the 
sample size may be updated without inflation of type I error.
3.1.2
Key secondary endpoint
Using a hierarchical testing procedure for familywise 2-sided type I error control at 0.05, the 
hypothesis test in key secondary analysis on 4-week CFR will be performed if and only if null 
hypothesis in primary analysis is rejected. The conditional power for detecting a 50% drop of 
4-week CFR are evaluated under different assumptions on control arm 4-week CFR.
Table 3-2
Power for key secondary analysis (sample size = 450)
CFR (%)
Clinically meaningful benefits
Power (2-side 
α=0.05) 
Control
ACZ885
Difference
OR
RR
25
12.5
-12.5
0.43
0.5
92%
20
10
-10
0.44
0.5
83%




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4. If the imputed AE end date is less than the existing AE start date then use AE start date as 
AE end date.
5.1.2.2
AE start date imputation
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed.
Day 
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
(1) No convention
(1) No convention
(1) No convention
(1) No convention
YYYY < TRTY
(2.a) Before 
Treatment Date
(2.b) Before 
Treatment Date
(2.b) Before 
Treatment Date
(2.b) Before
Treatment Date
YYYY = TRTY
(4.a) Uncertain
(4.b) Before 
Treatment Date
(4.c) Uncertain
(4.c) After 
Treatment Date
YYYY > TRTY
(3.a) After 
Treatment Date
(3.b) After 
Treatment Date
(3.b) After 
Treatment Date
(3.b) After 
Treatment Date
Before imputing AE start date, find the AE start reference date.
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment
date then AE start reference date = min (informed consent date, earliest visit date).
2. Else AE start reference date = treatment date
Impute AE start date -
1. If the AE start date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set
to NULL.
2. If the AE start date year value is less than the treatment date year value, the AE
started before treatment. Therefore:
a. If AE month is missing, the imputed AE start date is set to the mid-year point
(01JulYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month
point (15MONYYYY).
3. If the AE start date year value is greater than the treatment date year value, the AE
started after treatment date. Therefore:
a. If the AE month is missing, the imputed AE start date is set to the year start point
(01JanYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the later of
(month start point (01MONYYYY), AE start reference date + 1 day).


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4. If the AE start date year value is equal to the treatment date year value:
a. And the AE month is missing the imputed AE start date is set to the AE reference
start date + 1 day.
b. Else if the AE month is less than the treatment month, the imputed AE start
date is set to the mid-month point (15MONYYYY).
c. Else if the AE month is equal to the treatment date month or greater than the
treatment date month, the imputed AE start date is set to the later of (month
start point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.
5.1.3
Concomitant medication date imputation
For the start and end dates of the concomitant medication records, when incomplete or missing, 
dates will be imputed according to Novartis standards as described below. The same data 
imputation rules will be applied for therapies and procedures.
5.1.3.1
Concomitant medication end date imputation
Incomplete or missing end date for prior therapies will be dealt with in the following way
1. If the CM end date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed CM
end date is set to NULL.
2. Else, if the CM end date month is missing, the imputed end date should be set to the
earliest of the (study end date, 31DECYYYY, date of death).
3. If the CM end date day is missing, the imputed end date should be set to the earliest of the 
(study end date, last day of the month, date of death).
If the imputed CM end date is less than the existing CM start date, use the CM start date as the 
imputed CM end date.
5.1.3.2
Concomitant medication start date imputation
In order to classify a medication as prior and prior/concomitant, it may be necessary to impute 
the start date.
Completely missing start dates will be set to one day prior to treatment date. As a conservative 
approach, such treatments will be classified as prior and concomitant (and summarized for each 
output).
Concomitant treatments with partial start dates will have the date or dates imputed.
The following table explains the notation used in the logic matrix
Day 
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Date
Not used
TRTM
TRTY


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The following matrix explains the logic behind the imputation.
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
(1) Uncertain
(1) Uncertain
(1) Uncertain
(1) Uncertain
YYYY < TRTY
(2.a) Before 
Treatment Date
(2.b) Before 
Treatment Date
(2.b) Before 
Treatment Date
(2.b) Before 
Treatment Date
YYYY = TRTY
(4.a) Uncertain
(4.b) Before 
Treatment Date
(4.a) Uncertain
(4.c) After 
Treatment Date
YYYY > TRTY
(3.a) After 
Treatment Date
(3.b) After 
Treatment Date
(3.b) After 
Treatment Date
(3.b) After 
Treatment Date
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior
to Treatment date.
2. If the CM start date year value is less than the Treatment date year value, the CM
started before treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the mid-year point
(01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-month
point (15MONYYYY).
3. If the CM start date year value is greater than the Treatment date year value, the CM
started after treatment. Therefore:
a. If the CM month is missing, the imputed CM start date is set to the year start point
(01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the month
start point (01MONYYYY).
4. If the CM start date year value is equal to the Treatment date year value:
a. And the CM month is missing or the CM month is equal to the Treatment date
month, then the imputed CM start date is set to one day prior to Treatment date.
b. Else if the CM month is less than the Treatment date month, the imputed CM start
date is set to the mid-month point (15MONYYYY).
c. Else if the CM month is greater than the treatment date month, the imputed CM
start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.
5.1.4
Concomitant therapies and procedures date imputation
The missing dates will be imputed using the same rule as for the concomitant medication.






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
one assessment is captured as the worst assessment on the day of early 
discharge/discontinuation visit and entered under the visit of Day X (X=early 
discharge/discontinuation date-Day 1+1)

one assessment is captured as the status by the time of early discharge/discontinuation 
and entered under the visit of early discharge/discontinuation 
In summary by visit, the worse score will be used for the summary on Day X and the score 
reported for early discharge/discontinuation will be used for data imputation with LOCF and 
other analyses based on the latest status by early discharge/discontinuation.
Table 5-3
Clinical status (9-point ordinal scale) 
Patient State  
Descriptor   
Score
Uninfected
No Clinical or virological evidence of infection
0
Ambulatory not in hospital 
or in hospital and ready 
for discharge)
No limitation of activities
1
Limitation of activities
2
Hospitalized
Mild disease
Hospitalized, no oxygen therapy (defined as SpO2 ≥ 
94% on room air)
3
Oxygen by mask or nasal prongs
4
Hospitalized
Severe disease
Non-invasive ventilation or high-flow oxygen
5
Intubation and mechanical ventilation
6
Ventilation + additional organ support - pressors, 
RRT, (renal replacement therapy), ECMO 
(extracorporeal membrane oxygenation)
7
Dead
Death
8
5.6
Type of pulmonary/ventilatory support
The level of Oxygen requirement is assessed based on the type of support specified in the 
table below.
Table 5-4
Type of pulmonary/Ventilatory support based on the level of 
oxygen requirement from low to high
Type of support
Require supplemental oxygen
Require mechanical ventilation
Low flow nasal oxygen
Yes
No
High flow nasal oxygen
Yes
No
Oxygen via face mask
Yes
No
Non-invasive ventilation
Yes
No
Mechanical ventilation
Yes
Yes
Intubation
Yes
Yes
Tracheostomy
Yes
Yes


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Type of support
Require supplemental oxygen
Require mechanical ventilation
ECMO
Yes
Yes
The baseline use of pulmonary ventilatory support is the latest type of Oxygen supply that 
started before the study treatment. There are records with an oxygen supply starting from Day 
1 but there is no time information provided, in which case, it is not possible to tell if such 
procedure started pre-/post-treatment. Here is the summary on how to define baseline when
time information is missing from a procedure that starts/ends on Day 1:

If a patient is on type A oxygen supply from a pre-treatment date and end on Day 1 then 
changed from type A to type B on the same date, type A will be considered as the 
baseline type of oxygen supply.

If a patient has one record on oxygen supply that ends on Day 1 but with one record 
starting on Day 1, the perspective oxygen supply type will be considered as the baseline.
6
Reference
CDC COVID Response Team (2020) Severe Outcomes Among Patients with Coronavirus 
Disease 2019 (COVID-19) - United States, February 12–March 16, 2020. Morb Mortal Wkly 
Rep; 69:343-346. DOI: http://dx.doi.org/10.15585/mmwr.mm6912e2. 
Ge M, Durham LK, and Meyer DR. Covariate-adjusted difference in proportions from clinical 
trials using logistic regression and weighted risk differences. Drug Information Journal 
2011;45:481-493
Soni N and Williams P (2008) Positive pressure ventilation: what is the real cost? British J 
Anaesthesia; 101.4:446-57.


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WHO (2020) Novel Coronavirus(2019-nCoV) Situation Report – 22. (Internet) Available from 
<https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200211-sitrep-22-
ncov.pdf?sfvrsn=fb6d49b1_2> (Accessed 01 April 2020).
Wu Z and McGoogan JM (2020) Characteristics of and important lessons from the coronavirus 
disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the 
Chinese Center for Disease Control and Prevention. JAMA; Published online Feb 24. 
DOI:10.1001/ jama.2020.2648.
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; doi: 
https://doi.org/10.1016/S0140-6736(20)30566-3.
Brock GN, Barnes C, Ramirez JA, Myers J: BMC Medical Research Methodology 2011, 11:144