CAN-COVID: Study of Efficacy and Safety of Canakinumab Treatment for CRS in Participants With COVID-19-induced Pneumonia

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04362813
• Collaborator: (none)
• Enrollment: 454
• Locations: 39
• Arms: 2
• Actual Duration (Months): 7.8
• Patients Per Site: 11.6
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Cytokine Release Syndrome (CRS) in Patients With COVID-19-induced Pneumonia	Drug: Canakinumab; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 454 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official 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)
• Actual Study Start Date: Apr 30, 2020
• Actual Primary Completion Date: Sep 16, 2020
• Actual Study Completion Date: Dec 22, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Canakinumab 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.	Drug: Canakinumab; 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.; Other Names: ACZ885
Placebo Comparator: Placebo 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.	Drug: Placebo; 250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.

Outcome Measures

Primary Outcome Measures

1. Participants Who Survived Without Requiring Invasive Mechanical Ventilation From Day 3 to Day 29, Primary Analysis [Day 3 to Day 29]

   Number of responders who survived without requiring invasive mechanical ventilation from Day 3 to Day 29. An early dropout without requiring invasive mechanical ventilation is considered as a responder if discharged from hospital with 9-point ordinal scale<=1 or with last 9-point ordinal scale on/after Day 15 better than baseline.

Secondary Outcome Measures

1. COVID-19-related Death After Study Treatment [29 days]

   Participants with COVID-19 related (as assessed by investigator) death up to Day 29

2. Geometric Mean Ratio to Baseline in the C-reactive Protein (CRP) [Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.]

   Measurement of C Reactive Protein (mg/L), Serum Or Plasma over time. The level of C-reactive protein (CRP), which can be measured in the blood, increases when there's inflammation in the body. Lower values of ratio to baseline in the CRP indicates less inflammation. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.

3. Geometric Mean Ratio to Baseline in the D-dimer [Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.]

   Clinical chemistry measurement D-Dimer (mg/L FEU), Blood in a blood sample over time D-dimer is one of the protein fragments produced when a blood clot gets dissolved in the body. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.

4. Geometric Mean Ratio to Baseline in Ferritin [Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.]

   Clinical chemistry measurement for amount of ferritin (ug/L) in Serum. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.

5. Number of Participants With Treatment Emergent Adverse Events [Up to day 127]

   Number of participants with treatment emergent adverse events, including changes from baseline in vital signs and laboratory results qualifying and reported as adverse events. Safety was monitored from the canakinumab or placebo dose (Day 1) up to 126 days post-dose (Day 127).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key inclusion Criteria:

• Adults ≥ 18 years old (for US only: patients ≥ 12 years old, although no children ever enrolled. This was an adult trial.)

• Body weight ≥40 kg

• 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.

• Clinically diagnosed with SARS-CoV-2 virus by PCR or by other approved diagnostic methodology

• Hospitalized with COVID-19-induced pneumonia evidenced by chest x-ray or CT scan with pulmonary infiltrates

• SpO2 ≤ 93% on room air or arterial oxygen partial pressure (PaO2)/ fraction of inspired oxygen (FiO2) < 300mmHg

• C-reactive protein ≥20 mg/L or ferritin level ≥600 µg/L

Key exclusion Criteria:

• History of hypersensitivity to canakinumab or to biologic drugs

• Intubated and on mechanical ventilation (invasive) at time of randomization

• 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.

• Suspected or known untreated active bacterial, fungal, viral, or parasitic infection with the exception of COVID-19

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35294
2	Novartis Investigative Site	Glendale	California	United States	91206
3	Novartis Investigative Site	San Francisco	California	United States	94110
4	Novartis Investigative Site	San Francisco	California	United States	94143
5	Novartis Investigative Site	Chicago	Illinois	United States	60611
6	Novartis Investigative Site	Baltimore	Maryland	United States	21201
7	Novartis Investigative Site	Boston	Massachusetts	United States	02115
8	Novartis Investigative Site	Boston	Massachusetts	United States	02118
9	Novartis Investigative Site	Brooklyn	New York	United States	11219
10	Novartis Investigative Site	Chapel Hill	North Carolina	United States	27599
11	Novartis Investigative Site	Cleveland	Ohio	United States	44106-5000
12	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19140
13	Novartis Investigative Site	Houston	Texas	United States	77030
14	Novartis Investigative Site	Richmond	Virginia	United States	23298
15	Novartis Investigative Site	Tacoma	Washington	United States	98405
16	Novartis Investigative Site	Toulouse Cedex 4		France	31054
17	Novartis Investigative Site	Bergamo	BG	Italy	24127
18	Novartis Investigative Site	Cona	FE	Italy	44100
19	Novartis Investigative Site	Barnaul		Russian Federation	656045
20	Novartis Investigative Site	Moscow		Russian Federation	111539
21	Novartis Investigative Site	Moscow		Russian Federation	121309
22	Novartis Investigative Site	Moscow		Russian Federation	123056
23	Novartis Investigative Site	Moscow		Russian Federation	123182
24	Novartis Investigative Site	Ryazan		Russian Federation	390039
25	Novartis Investigative Site	S-Petersburg		Russian Federation	194354
26	Novartis Investigative Site	Saint Petersburg		Russian Federation	197022
27	Novartis Investigative Site	Sestroretsk		Russian Federation	197706
28	Novartis Investigative Site	St Petersburg		Russian Federation	193312
29	Novartis Investigative Site	Hospitalet de Llobregat	Barcelona	Spain	08907
30	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
31	Novartis Investigative Site	San Sebastian de los Reyes	Madrid	Spain	28702
32	Novartis Investigative Site	Madrid		Spain	28034
33	Novartis Investigative Site	Madrid		Spain	28040
34	Novartis Investigative Site	Madrid		Spain	28041
35	Novartis Investigative Site	Barnet		United Kingdom	EN5 3DJ
36	Novartis Investigative Site	Coventry		United Kingdom	CV2 2DX
37	Novartis Investigative Site	Leeds		United Kingdom	LS9 7TF
38	Novartis Investigative Site	London		United Kingdom	NW3 2QG
39	Novartis Investigative Site	London		United Kingdom	SE5 9RS

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartiis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jun 1, 2020
• Statistical Analysis Plan - Feb 15, 2021

More Information

Additional Information:

• JAMA 20 July 2021
• A Plain Language Trial Summary is available on novctrd.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04362813
• Other Study ID Numbers: CACZ885D2310; 2020-001370-30
• First Posted: Apr 27, 2020
• Last Update Posted: Jan 24, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: COVID-19; cytokine release syndrome; SARS-CoV-2; canakinumab; COVID; coronavirus; CAN-COVID; pneumonia; CRS
• Additional relevant MeSH terms: COVID-19; Pneumonia; Syndrome; Cytokine Release Syndrome

Study Results

Participant Flow

Recruitment Details	Participants took part at 39 investigative sites in 6 countries. While patient flow shows 454 participants enrolled, only 451 randomized. 3 were "mis-randomized" i.e. assigned a randomization number in error and not treated.
Pre-assignment Detail	Participants were screened within 24 hours prior to enrollment.

Arm/Group Title	Canakinumab	Placebo
Arm/Group Description	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.	250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
Period Title: Overall Study
STARTED	227	227
Safety Set	225	223
Completed Day 29	211	206
COMPLETED	209	202
NOT COMPLETED	18	25

Baseline Characteristics

Arm/Group Title	Canakinumab	Placebo	Total
Arm/Group Description	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.	250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.	Total of all reporting groups
Overall Participants	227	227	454
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.5 (14.55)	57.8 (13.89)	58.2 (14.21)
Age, Customized (Count of Participants)
< 18 years	0 0%	0 0%	0 0%
Between 18 and 64 years	149 65.6%	155 68.3%	304 67%
>=65 years	78 34.4%	72 31.7%	150 33%
Sex: Female, Male (Count of Participants)
Female	92 40.5%	95 41.9%	187 41.2%
Male	135 59.5%	132 58.1%	267 58.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1.3%	8 3.5%	11 2.4%
Asian	10 4.4%	9 4%	19 4.2%
Native Hawaiian or Other Pacific Islander	1 0.4%	5 2.2%	6 1.3%
Black or African American	35 15.4%	37 16.3%	72 15.9%
White	159 70%	156 68.7%	315 69.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	19 8.4%	12 5.3%	31 6.8%

Outcome Measures

1. Primary Outcome

Title	Participants Who Survived Without Requiring Invasive Mechanical Ventilation From Day 3 to Day 29, Primary Analysis
Description	Number of responders who survived without requiring invasive mechanical ventilation from Day 3 to Day 29. An early dropout without requiring invasive mechanical ventilation is considered as a responder if discharged from hospital with 9-point ordinal scale<=1 or with last 9-point ordinal scale on/after Day 15 better than baseline.
Time Frame	Day 3 to Day 29

Outcome Measure Data

Analysis Population Description

Randomized participants with at least one assessment of the 9-point ordinal scale between Day 3 and Day 29 (where value 0 = uninfected, and 8 = death)

Arm/Group Title	Canakinumab	Placebo
Arm/Group Description	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.	250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
Measure Participants	223	223
Count of Participants [Participants]	198 87.2%	191 84.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Canakinumab, Placebo
	Comments	Odds ratio is based on a Logistic regression model adjusted by treatment, region (North America vs Europe), and baseline 9-point ordinal scale (<=4, >=5).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2874
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.39
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	COVID-19-related Death After Study Treatment
Description	Participants with COVID-19 related (as assessed by investigator) death up to Day 29
Time Frame	29 days

Outcome Measure Data

Analysis Population Description

All randomized participants including those who did not receive any dose, as per intent-to-treat principle, and excluding early dropouts if the last available 9-point ordinal scale >1 (including non-COVID-19 related death)

Arm/Group Title	Canakinumab	Placebo
Arm/Group Description	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.	250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
Measure Participants	223	222
Count of Participants [Participants]	11 4.8%	16 7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Canakinumab, Placebo
	Comments	Odds ratio is based on a Logistic regression model adjusted by treatment, region (North America vs Europe), and baseline 9-point ordinal scale (<=4, >=5)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3303
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.30 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Geometric Mean Ratio to Baseline in the C-reactive Protein (CRP)
Description	Measurement of C Reactive Protein (mg/L), Serum Or Plasma over time. The level of C-reactive protein (CRP), which can be measured in the blood, increases when there's inflammation in the body. Lower values of ratio to baseline in the CRP indicates less inflammation. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.
Time Frame	Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.

Outcome Measure Data

Analysis Population Description

Randomized participants with a valid assessment for the outcome measure.

Arm/Group Title	Canakinumab	Placebo
Arm/Group Description	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.	250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
Measure Participants	227	227
Day 2	0.726	0.785
Day 3	0.479	0.649
Day 5	0.255	0.384
Day 7	0.160	0.238
Day 9	0.131	0.159
Day 11	0.099	0.133
Day 13	0.108	0.141
Day 15	0.133	0.149
Day 17	0.123	0.289
Day 19	0.123	0.368
Day 21	0.115	0.296
Day 23	0.106	0.400
Day 25	0.126	0.368
Day 27	0.175	0.331
Day 29	0.240	0.258

4. Secondary Outcome

Title	Geometric Mean Ratio to Baseline in the D-dimer
Description	Clinical chemistry measurement D-Dimer (mg/L FEU), Blood in a blood sample over time D-dimer is one of the protein fragments produced when a blood clot gets dissolved in the body. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.
Time Frame	Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Canakinumab	Placebo
Arm/Group Description	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.	250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
Measure Participants	227	227
Day 2	1.032	1.028
Day 3	0.992	1.188
Day 5	1.094	1.188
Day 7	1.038	1.244
Day 9	1.164	1.184
Day 11	1.162	1.115
Day 13	1.135	1.184
Day 15	1.100	1.078
Day 17	1.033	1.384
Day 19	1.520	1.446
Day 21	1.431	1.443
Day 23	1.208	1.521
Day 25	2.670	1.808
Day 27	1.785	2.262
Day 29	1.818	2.441

5. Secondary Outcome

Title	Geometric Mean Ratio to Baseline in Ferritin
Description	Clinical chemistry measurement for amount of ferritin (ug/L) in Serum. The ratio to baseline at each time point (day) for each patient is calculated as the level of a specific biomarker at the time point divided by the baseline level of the biomarker, where baseline is the last non-missing value before study treatment. The geometric mean of ratio to baseline at each time point for each treatment group is calculated by first averaging the logarithms of the ratios to baseline and then take the exponential function of the same base.
Time Frame	Over time and up to day 29: Baseline, Day 2, Day 3, Day 5, Day 7, Day 9, Day 11, Day 13, Day 15, Day 17, Day 19, Day 21, Day 23, Day 25, Day 27 and Day 29.

Outcome Measure Data

Analysis Population Description

Randomized participants with a valid assessment for the outcome measure.

Arm/Group Title	Canakinumab	Placebo
Arm/Group Description	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.	250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
Measure Participants	227	227
Day 2	0.996	1.014
Day 3	0.921	1.014
Day 5	0.825	0.879
Day 7	0.761	0.815
Day 9	0.676	0.764
Day 11	0.618	0.735
Day 13	0.582	0.684
Day 15	0.535	0.618
Day 17	0.534	0.641
Day 19	0.545	0.644
Day 21	0.514	0.644
Day 23	0.469	0.692
Day 25	0.542	0.745
Day 27	0.490	0.809
Day 29	0.543	0.517

6. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events
Description	Number of participants with treatment emergent adverse events, including changes from baseline in vital signs and laboratory results qualifying and reported as adverse events. Safety was monitored from the canakinumab or placebo dose (Day 1) up to 126 days post-dose (Day 127).
Time Frame	Up to day 127

Outcome Measure Data

Analysis Population Description

Safety Set comprises all participants who received at least one dose of study treatment

Arm/Group Title	Canakinumab	Placebo
Arm/Group Description	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.	250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
Measure Participants	225	223
Count of Participants [Participants]	141 62.1%	140 61.7%

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study at day 127
Adverse Event Reporting Description	Adverse Events (AEs) are any untoward sign or symptom that occurs during the study treatment. Adverse events and all-cause mortality are evaluated in the Safety Set that includes all participants who received at least one dose of double-blind treatment.
Arm/Group Title	Canakinumab		Placebo
Arm/Group Description	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.		250 mL of 5% dextrose infused IV over 2 hours. Single dose on Day 1.
All Cause Mortality
	Canakinumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/225 (9.8%)		26/223 (11.7%)
Serious Adverse Events
	Canakinumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/225 (20.9%)		53/223 (23.8%)
Blood and lymphatic system disorders
Anaemia	0/225 (0%)		1/223 (0.4%)
Blood loss anaemia	0/225 (0%)		2/223 (0.9%)
Coagulopathy	1/225 (0.4%)		1/223 (0.4%)
Febrile neutropenia	1/225 (0.4%)		0/223 (0%)
Leukocytosis	1/225 (0.4%)		0/223 (0%)
Cardiac disorders
Acute myocardial infarction	1/225 (0.4%)		1/223 (0.4%)
Angina pectoris	1/225 (0.4%)		0/223 (0%)
Arrhythmia	0/225 (0%)		1/223 (0.4%)
Atrial fibrillation	1/225 (0.4%)		1/223 (0.4%)
Cardiac arrest	1/225 (0.4%)		2/223 (0.9%)
Cardiac failure acute	0/225 (0%)		1/223 (0.4%)
Cardiac failure chronic	1/225 (0.4%)		0/223 (0%)
Cardiac failure congestive	2/225 (0.9%)		1/223 (0.4%)
Cardiopulmonary failure	2/225 (0.9%)		1/223 (0.4%)
Coronary artery disease	1/225 (0.4%)		0/223 (0%)
Myocardial infarction	1/225 (0.4%)		0/223 (0%)
Pulseless electrical activity	0/225 (0%)		2/223 (0.9%)
Tachycardia	0/225 (0%)		1/223 (0.4%)
Gastrointestinal disorders
Colitis	1/225 (0.4%)		0/223 (0%)
Gastrointestinal haemorrhage	2/225 (0.9%)		1/223 (0.4%)
Lower gastrointestinal haemorrhage	1/225 (0.4%)		0/223 (0%)
Oesophageal motility disorder	0/225 (0%)		1/223 (0.4%)
Small intestinal obstruction	1/225 (0.4%)		0/223 (0%)
Upper gastrointestinal haemorrhage	0/225 (0%)		1/223 (0.4%)
Vomiting	1/225 (0.4%)		0/223 (0%)
General disorders
Asthenia	0/225 (0%)		1/223 (0.4%)
Multiple organ dysfunction syndrome	1/225 (0.4%)		0/223 (0%)
Sudden death	1/225 (0.4%)		0/223 (0%)
Immune system disorders
Haemophagocytic lymphohistiocytosis	1/225 (0.4%)		0/223 (0%)
Infections and infestations
Abscess limb	1/225 (0.4%)		0/223 (0%)
Antibiotic associated colitis	2/225 (0.9%)		0/223 (0%)
Bacterial sepsis	1/225 (0.4%)		0/223 (0%)
COVID-19	2/225 (0.9%)		3/223 (1.3%)
COVID-19 pneumonia	1/225 (0.4%)		3/223 (1.3%)
Candida infection	0/225 (0%)		1/223 (0.4%)
Clostridium difficile colitis	0/225 (0%)		1/223 (0.4%)
Diverticulitis	0/225 (0%)		1/223 (0.4%)
Enterococcal bacteraemia	1/225 (0.4%)		0/223 (0%)
Enterocolitis viral	1/225 (0.4%)		0/223 (0%)
Escherichia sepsis	1/225 (0.4%)		0/223 (0%)
Gastroenteritis	0/225 (0%)		1/223 (0.4%)
Klebsiella infection	0/225 (0%)		1/223 (0.4%)
Pneumonia	2/225 (0.9%)		3/223 (1.3%)
Pneumonia bacterial	1/225 (0.4%)		2/223 (0.9%)
Pneumonia escherichia	0/225 (0%)		1/223 (0.4%)
Pneumonia fungal	1/225 (0.4%)		0/223 (0%)
Pneumonia haemophilus	0/225 (0%)		1/223 (0.4%)
Pneumonia pseudomonal	0/225 (0%)		2/223 (0.9%)
Pneumonia staphylococcal	0/225 (0%)		1/223 (0.4%)
Sepsis	3/225 (1.3%)		2/223 (0.9%)
Septic shock	3/225 (1.3%)		5/223 (2.2%)
Staphylococcal bacteraemia	0/225 (0%)		2/223 (0.9%)
Urinary tract infection	0/225 (0%)		1/223 (0.4%)
Injury, poisoning and procedural complications
Wound necrosis	1/225 (0.4%)		0/223 (0%)
Musculoskeletal and connective tissue disorders
Arthritis reactive	1/225 (0.4%)		0/223 (0%)
Flank pain	0/225 (0%)		1/223 (0.4%)
Osteonecrosis	1/225 (0.4%)		0/223 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/225 (0.4%)		0/223 (0%)
Lung neoplasm malignant	0/225 (0%)		1/223 (0.4%)
Metastases to liver	1/225 (0.4%)		0/223 (0%)
Nervous system disorders
Cerebral infarction	0/225 (0%)		1/223 (0.4%)
Cerebral ischaemia	0/225 (0%)		1/223 (0.4%)
Cerebrovascular accident	1/225 (0.4%)		1/223 (0.4%)
Encephalopathy	1/225 (0.4%)		0/223 (0%)
Seizure	1/225 (0.4%)		0/223 (0%)
Syncope	0/225 (0%)		1/223 (0.4%)
Psychiatric disorders
Bipolar disorder	1/225 (0.4%)		0/223 (0%)
Mental status changes	0/225 (0%)		1/223 (0.4%)
Renal and urinary disorders
Acute kidney injury	3/225 (1.3%)		7/223 (3.1%)
Chronic kidney disease	1/225 (0.4%)		0/223 (0%)
Renal failure	0/225 (0%)		1/223 (0.4%)
Renal impairment	0/225 (0%)		1/223 (0.4%)
Renal injury	0/225 (0%)		1/223 (0.4%)
Reproductive system and breast disorders
Prostatitis	0/225 (0%)		1/223 (0.4%)
Respiratory, thoracic and mediastinal disorders
Acute lung injury	0/225 (0%)		1/223 (0.4%)
Acute pulmonary oedema	1/225 (0.4%)		0/223 (0%)
Acute respiratory distress syndrome	6/225 (2.7%)		3/223 (1.3%)
Acute respiratory failure	12/225 (5.3%)		13/223 (5.8%)
Atelectasis	0/225 (0%)		1/223 (0.4%)
Chronic obstructive pulmonary disease	1/225 (0.4%)		0/223 (0%)
Dyspnoea	1/225 (0.4%)		3/223 (1.3%)
Haemoptysis	1/225 (0.4%)		0/223 (0%)
Haemothorax	1/225 (0.4%)		0/223 (0%)
Hypoxia	2/225 (0.9%)		4/223 (1.8%)
Pleural effusion	0/225 (0%)		1/223 (0.4%)
Pneumomediastinum	1/225 (0.4%)		0/223 (0%)
Pneumonia aspiration	1/225 (0.4%)		0/223 (0%)
Pneumothorax	2/225 (0.9%)		3/223 (1.3%)
Pulmonary embolism	0/225 (0%)		2/223 (0.9%)
Pulmonary oedema	0/225 (0%)		2/223 (0.9%)
Respiratory failure	8/225 (3.6%)		8/223 (3.6%)
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms	0/225 (0%)		1/223 (0.4%)
Vascular disorders
Haemodynamic instability	0/225 (0%)		1/223 (0.4%)
Hypotension	2/225 (0.9%)		3/223 (1.3%)
Jugular vein thrombosis	0/225 (0%)		1/223 (0.4%)
Peripheral artery occlusion	0/225 (0%)		1/223 (0.4%)
Peripheral ischaemia	1/225 (0.4%)		0/223 (0%)
Peripheral vascular disorder	1/225 (0.4%)		0/223 (0%)
Shock	1/225 (0.4%)		0/223 (0%)
Other (Not Including Serious) Adverse Events
	Canakinumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/225 (6.7%)		19/223 (8.5%)
Blood and lymphatic system disorders
Anaemia	6/225 (2.7%)		12/223 (5.4%)
Vascular disorders
Hypotension	12/225 (5.3%)		10/223 (4.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Publications from a single-site are postponed until publication of the pooled clinical trial data (i.e., data from all sites) or disclosure of trial results in their entirety