Clinical trial NCT04365153
Conditions: COVID-19 SARS-CoV 2
Sponsor: The Cleveland Clinic
Start date: 2020-04-24; Completion date: 2021-04-01
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
TThe purpose of this prospective, Phase 2, single center, blinded, randomized controlled study is to demonstrate as a proof of concept that early treatment with canakinumab prevents progressive heart and respiratory failure in patients with COVID-19 infection. These results will lead to and inform a Phase III randomized placebo-controlled trial.

Detailed description:
This is a prospective, Phase 2, single center, blinded randomized-controlled study designed as a proof of concept to demonstrate that early treatment with canakinumab prevents progressive heart and respiratory failure in patients with COVID 19 infection, myocardial injury and hyperinflammation. These results will lead to a Phase III randomized placebo-controlled trial.

The study will be performed in approximately 7 months total, starting from the first patient enrolled with enrollment expected to complete within 2 months. The follow-up period is 5 months for each patient enrolled. The end of the study, including statistical analysis and drafting of the final report is expected within 1 month from the last patient enrolled.

A total of 45 patients will be randomized using a 1:1:1 allocation ratio: 15 subjects will receive 600 mg intravenous canakinumab (8 mg/kg if \</= 40 kg), 15 subjects will receive 300 mg intravenous canakinumab (4 mg/kg if \</= 40 kg), and 15 patients will receive placebo infusion.

The investigator, clinical team, and subject will be blinded to treatment assignment.

Arms: arm 1: 600 mg of canakinumab (8 mg/kg for patients \</= 40 kg) arm 2: 300 mg of canakinumab (4 mg/kg for patients \</= 40 kg) arm 3: Placebo
Interventions: intervention 1: Canakinumab Injection 600mg intervention 2: Canakinumab Injection 300mg intervention 3: Placebos
Intervention descriptions: intervention 1: Subjects will be given one-time intravenous infusion of 600 mg of canakinumab (8 mg/kg for patients \</= 40 kg) in 250 mL of 5% dextrose infused IV over 2 hours intervention 2: Subjects will be given one-time intravenous infusion of 300 mg of canakinumab (4 mg/kg for patients \</= 40 kg) in 250 mL of 5% dextrose infused IV over 2 hours intervention 3: 250 mL of 5% dextrose infused IV over 2 hours

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Canakinumab to Reduce Deterioration of Cardiac and Respiratory 
Function in SARS-CoV2 Associated Acute Myocardial Injury and 
Hyperinflammation 
Protocol Version 3.0 
NCT04365153 
11 MAY 2020 
 


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Covid 19 Protocol_3.0_ 11MAY2020  
Document type: 
Clinical Trial Protocol 
 
 
Version number: 
3.0 
Clinical Trial Phase: 
II 
Release date: 
11 MAY-2020 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Background .............................................................................................................. 7 
1.2 
Purpose .................................................................................................................... 8 
2 
Objectives and endpoints ..................................................................................................... 8 
3 
Study design ...................................................................................................................... 10 
4 
Rationale ............................................................................................................................ 10 
4.1 
Rationale for study design ..................................................................................... 10 
4.1.1 
Rationale for choice of background therapy ......................................... 10 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 10 
4.3 
Risks and benefits .................................................................................................. 11 
5 
Population .......................................................................................................................... 11 
5.1 
Inclusion criteria .................................................................................................... 11 
5.2 
Exclusion criteria ................................................................................................... 12 
6 
Treatment ........................................................................................................................... 13 
6.1 
Study treatment ...................................................................................................... 13 
6.1.1 
Investigational and control drugs .......................................................... 13 
6.1.2 
Additional study treatments .................................................................. 14 
6.1.3 
Treatment arms/group ........................................................................... 14 
6.1.4 
Concomitant therapy ............................................................................. 14 
6.1.5 
Prohibited medication ........................................................................... 14 
6.1.6 
Subject numbering ................................................................................ 15 


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6.1.7 
Treatment assignment, randomization .................................................. 15 
6.2 
Treatment blinding ................................................................................................. 15 
6.3 
Preparation and dispensation ................................................................................. 15 
6.3.1 
Handling of study treatment and additional treatment .......................... 15 
7 
Informed consent procedures ............................................................................................ 16 
7.1 
Visit schedule and assessments ............................................................................. 16 
7.2 
Subject demographics/other baseline characteristics ............................................. 20 
7.2.1 
Laboratory evaluations .......................................................................... 20 
7.2.2 
Electrocardiogram (ECG) ..................................................................... 20 
7.2.3 
Echocardiogram (Echo) ........................................................................ 20 
7.2.4 
Pregnancy assessments .......................................................................... 20 
8 
Study discontinuation and completion .............................................................................. 21 
8.1 
Discontinuation ...................................................................................................... 21 
8.1.1 
Discontinuation of study treatment ....................................................... 21 
8.1.2 
Withdrawal of informed consent ........................................................... 22 
8.1.3 
Lost to follow-up ................................................................................... 22 
8.1.4 
Early study termination by the sponsor ................................................. 22 
8.2 
Study completion and post-study treatment .......................................................... 23 
9 
Safety monitoring and reporting ........................................................................................ 23 
9.1 
Definition of adverse events and reporting requirements ...................................... 23 
9.1.1 
Adverse events ...................................................................................... 23 
9.1.2 
Serious adverse events .......................................................................... 25 
9.1.3 
SAE reporting........................................................................................ 26 
9.1.4 
Pregnancy reporting .............................................................................. 26 
9.1.5 
Reporting of study treatment errors ...................................................... 26 
9.1.6 
Data Monitoring Committee ................................................................. 27 
10 Data Collection and Database management ...................................................................... 28 
10.1 
Data collection ....................................................................................................... 28 
10.2 
Site monitoring ...................................................................................................... 28 
11 Data analysis and statistical methods ................................................................................ 28 
11.1 
Analysis sets .......................................................................................................... 28 
11.2 
Subject demographics and other baseline characteristics ...................................... 28 
11.3 
Analysis of the primary endpoint and secondary endpoints .................................. 29 
11.3.1 
Adverse events ...................................................................................... 29 
12 Ethical considerations and administrative procedures ...................................................... 29 
12.1 
Regulatory and ethical compliance ........................................................................ 29 
12.2 
Responsibilities of the investigator and IRB ......................................................... 30 


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13 Protocol adherence ............................................................................................................ 30 
13.1 
Protocol Amendments ........................................................................................... 30 
14 References ......................................................................................................................... 31 
  


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List of abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
Body Mass Index 
BUN 
blood urea nitrogen 
CDS 
Core Data Sheet (for marketed drugs) 
CFR 
Code of Federal Regulation 
CK 
creatinine kinase 
CK-MB 
creatinine kinase MB 
COAR 
Clinical Operations, Analytics & Regions 
COVID-19 
coronavirus disease 2019 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CTC 
Common Toxicity Criteria 
CTRD 
Clinical Trial Results Database 
CV 
coefficient of variation 
DMC 
Data Monitoring Committee 
EC 
Ethics committee 
Echo 
Echocardiogram 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
eSAE 
Electronic Serious Adverse Event 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
h 
hour 
HIV 
human immunodeficiency virus 
Hs-TnT 
High-sensitivity troponin T 
IL-6 
Interleukin-6 
i.v. 
intravenous 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
lactate dehydrogenase 
LFT 
Liver function test 
LLN 
lower limit of normal 


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LLQ 
lower limit of quantification 
MABEL 
minimum anticipated biological effect level 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
MI 
myocardial infarction 
mL 
milliliter(s) 
ml 
milliliter(s) 
MRSD 
maximum recommended starting dose 
NT-
proBNP 
N-terminal pro-brain natriuretic peptide 
o.d. 
once a day 
p.o. 
oral 
PD 
pharmacodynamic(s) 
 
 
RBC 
red blood cell(s) 
RDC 
Remote Data Capture 
REB 
Research Ethics Board 
s.c. 
subcutaneous 
SAE 
serious adverse event 
SARS-
CoV2 
severe acute respiratory syndrome coronavirus 2 
sCR 
serum creatinine 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOM 
Site Operations Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TB 
tuberculosis 
TBL 
total bilirubin 
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
WBC 
white blood cell(s) 
WHO 
World Health Organization 


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1 
Introduction 
1.1 
Background 
In December 2019, a novel coronavirus (SARS-CoV2) resulted in an outbreak of pneumonia 
in Wuhan, China (coronavirus disease 2019, COVID-19) which has subsequently spread 
rapidly and resulted in a worldwide pandemic. The case fatality rate was initially reported 
~2.3% (1), though a more recent study suggested a case fatality rate of 7.2% (2), and given the 
expected burden of disease, effective treatments are urgently required. 
Even though the predominant manifestations are respiratory symptoms, concomitant 
cardiovascular complications result in substantial morbidity and mortality (3). Among an initial 
179 patients with COVID-19 from Wuhan, 15 (8.4%) had acute cardiac injury syndrome, 
defined as abnormal serum cardiac markers or new electrocardiographic or echocardiographic 
abnormalities (4-6). In 49 patients admitted to the intensive care unit, 12 (24.4%) had acute 
cardiac injury. A separate study of 150 patients with COVID-19, including 68 deaths, 
demonstrated that the cause of death was related to myocardial damage in 27 patients (39.7%). 
In addition, cardiac troponin was higher in patients who died (30.3 vs 3.5 pg/mL, p <0.001) (7). 
Another study of 50 patients reported in-hospital death only in the 18 patients with abnormal 
NT-proBNP (8). In a study of 113 patients who died and 161 patients who recovered from 
COVID-19, deceased patients had higher high-sensitivity troponin I (40.8 versus 3.3 pg/mL), 
NT-proBNP (800 versus 72 pg/mL), and CRP (113.0 versus 26.2 mg/L)(9).  
Furthermore, in an initial US experience of 21 ICU patients who were COVID-19 positive, 7 
developed cardiomyopathy, defined as a decrease in left ventricular systolic function without a 
past history of systolic dysfunction and clinical signs of cardiogenic shock(10). Moreover, in 
another study of 416 patients, 82 (19.7%) developed acute cardiac injury. These patients had 
higher levels of C reactive protein, were more likely to require mechanical ventilation and 
ARDS, and had a 51.2% mortality (11).   
In patients who succumb to COVID-19, the troponin may continue to rise throughout the illness, 
a pattern distinct from the typical rise and fall after an ischemic insult (11). In some patients, 
this troponin elevation goes beyond what is typically observed in Type II MIs (12).  Importantly, 
patients with elevated troponins have higher levels of C-reactive proteins (CRPs). The increases 
in troponin and CRP appear to parallel each other, and the overall correlation is similar in 
magnitude to the correlation between troponin and N-terminal pro-brain natriuretic peptides. 
These observations suggest that some patients may develop a hyperinflammatory state that 
perpetuates the non-ischemic myocardial injury. 
Importantly, even though the current management of COVID-19 is supportive, morbidity and 
mortality may be driven by hyperinflammation in patients with severe COVID-19 infection 
(13). Hyperinflammation may progress to secondary hemophagocytic lymphohistiocystosis and 
resultant fatal hypercytokinemia with multiorgan failure. In this inflammatory state, 
immunosuppression may improve outcomes. In fact, in a subgroup analysis of a randomized 
controlled trial, patients with sepsis and organ dysfunction or hyperinflammation had improved 
survival with IL-1 receptor antagonism (14-15). Of note, in sepsis, IL-1 receptor antagonism 
has not been associated with adverse events, even at high doses (16). 
Canakinumab is a fully human monoclonal antibody targeting IL-1β that has anti-
inflammatory effects and is approved to treat auto-inflammatory diseases such as cryopyrin-


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associated periodic syndromes and Familial Mediterranean Fever (17, 18). Canakinumab has 
been approved at a dose of 300 mg SC, and in clinical trials, doses of 600 mg SC have been 
safely tolerated (19). In the CANTOS trial, a randomized double-blind trial in 
autoinflammatory atherosclerotic disease, over 2000 patients received the 300 mg dose of 
canakinumab. Importantly, IL-1β drives the IL-6 pathway, and preliminary evidence of IL-6 
antagonism in severe or critical COVID-19 disease has shown promise (20). Given the 
importance of myocardial dysfunction in the death of patients with COVID-19, the likely role 
of hyperinflammation, and the proven efficacy of canakinumab in autoinflammatory 
cardiovascular disease, we aim to identify high risk patients with acute myocardial injury 
related to COVID-19 and assess whether immunosuppressive treatment with canakinumab 
prevents further myocardial damage and heart as well as respiratory failure.  
 
1.2 
Purpose 
 
The purpose of this prospective, Phase 2, single center, blinded, randomized controlled study is 
to demonstrate as a proof of concept that early treatment with canakinumab prevents 
progressive heart and respiratory failure in patients with COVID-19 infection. These results 
will lead to and inform a Phase III randomized placebo-controlled trial. 
2 
Objectives and endpoints 
Primary Objective 
To demonstrate that early treatment with canakinumab prevents progressive respiratory and 
heart failure in patients with SARS-CoV2 associated acute myocardial injury and 
hyperinflammation. 
 
Secondary Objectives 
• 
To evaluate in-hospital and overall mortality rates 
• 
To evaluate progression of myocardial damage 
• 
To evaluate progression of cardiogenic shock requiring mechanical circulatory support 
• 
To evaluate the length of hospitalization 
• 
To evaluate safety of canakinumab 
 
Primary Endpoint 
The primary end-point is the time to clinical improvement up to day 14, defined as the time in 
days from randomization to either an improvement of two points on a seven-category ordinal 
scale or discharge from the hospital, whichever occurs first.  
The ordinal scale consists of the following:  


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1. Not hospitalized with resumption of normal activities 
2. Not hospitalized but unable to resume normal activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, requiring nasal high-flow oxygen, non-invasive mechanical ventilation or 
both 
6. Hospitalized, requiring ECMO, invasive mechanical ventilation, or both 
7. Death 
 
Secondary Endpoint 
The secondary end-point is mortality at day 28.  
 
Exploratory Endpoints 
• 
Need for mechanical ventilation in non-intubated patients 
• 
Duration of mechanical ventilation in intubated patients 
• 
Clinical status using the ordinal scale at day 7, day 14, day 21, and day 28: 
1. Not hospitalized with resumption of normal activities 
2. Not hospitalized but unable to resume normal activities 
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, requiring nasal high-flow oxygen, non-invasive mechanical ventilation or 
both 
6. Hospitalized, requiring ECMO, invasive mechanical ventilation, or both 
7. Death 
• 
In-hospital and overall mortality at day 90 and day 150 
• 
Length of intensive care unit (ICU) and total hospitalization stay 
• 
Need for escalation to mechanical circulatory support (IABP, Impella, VA ECMO) 
• 
Worst value for PaO2/FiO2 (or SaO2/FiO2 if PaO2 unavailable) at day 3, day 5, day 7, 
day 14, day 21, day 28, or until discharge  
• 
Change in SOFA score at day 7, day 14, day 21, and day 28, or until discharge 
• 
The time to peak in troponin  
• 
Rate of decline of troponin  after peak 
• 
Time to peak c-reactive protein and subsequent rate of decline 


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• 
Time to peak ferritin levels and subsequent rate of decline 
• 
Time to peak IL-6 levels and subsequent rate of decline 
• 
Change in left ventricular ejection fraction from baseline to day 14 if still hospitalized 
and at day 90 if feasible 
• 
Change in NT-proBNP from baseline to day 14 if still hospitalized and at 90 days if 
feasible 
• 
      Time to negative SARS-CoV2 RNA levels in oropharyngeal or nasopharyngeal samples 
3 
Study design 
This is a prospective, Phase 2, single center, blinded randomized-controlled study designed as 
a proof of concept to demonstrate that early treatment with canakinumab prevents progressive 
heart and respiratory failure in patients with COVID 19 infection, myocardial injury and 
hyperinflammation. These results will lead to a Phase III randomized placebo-controlled trial. 
Enrollment: The study will be performed in approximately 7 months total, starting from the first 
patient enrolled with enrollment expected to complete within 2 months.  
Follow-up period: The follow-up period is 5 months for each patient enrolled.  
Study completion: The end of the study, including statistical analysis and drafting of the final 
report is expected within 1 month from the last patient enrolled. 
A total of 45 patients will be randomized using a 1:1:1 allocation ratio: 15 subjects will receive 
600 mg intravenous canakinumab (8 mg/kg if </= 40 kg), 15 subjects will receive 300 mg 
intravenous canakinumab (4 mg/kg if </= 40 kg), and 15 patients will receive placebo infusion. 
The investigator, clinical team, and subject will be blinded to treatment assignment. 
Randomization will be stratified on whether or not the patient is intubated at the time of 
enrollment.  
4 
Rationale 
4.1 
Rationale for study design 
We aim to identify high risk patients with acute myocardial injury related to COVID-19 and 
assess whether immunosuppressive treatment with canakinumab prevents further respiratory 
and heart failure. 
4.1.1 
Rationale for choice of background therapy 
Given the importance of myocardial dysfunction in the death of patients with COVID-19, the 
likely role of hyperinflammation, and the proven efficacy of canakinumab in autoinflammatory 
cardiovascular disease, it was selected for further study in this patient population. 
4.2 
Rationale for dose/regimen and duration of treatment 
Canakinumab is a fully human monoclonal antibody targeting IL-1β that has anti-inflammatory 
effects and is approved to treat auto-inflammatory diseases such as cryopyrin-associated 


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periodic syndromes and Familial Mediterranean Fever (17, 18). Promising immune treatments 
for cardiac disease also target autoinflammation, a process driven by endogenous danger signals 
and perpetuated by inflammasome-induced cytokine production. Canakinumab has previously 
demonstrated efficacy in inflammatory atherosclerotic disease (17).  Canakinumab has been 
approved at a dose of 300 mg SC, and in clinical trials, doses of 600 mg SC have been safely 
tolerated (19).Importantly, IL-1β is the central cytokine in the inflammasome pathway and also 
drives the IL-6 pathway, and preliminary evidence of IL-6 antagonism in severe or critical 
COVID-19 disease has shown promise (20). 
4.3 
Risks and benefits 
Interleukin-1 blockade may interfere with immune response to infections. Treatment with 
medications that work through inhibition of IL-1 has been associated with an increased risk of 
serious infections, particularly if used for a longer duration to treat a chronic disease.  
The impact of treatment with anti-interleukin-1 (IL-1) therapy on the development of 
malignancies is not known. However, treatment with immunosuppressants, may result in an 
increase in the risk of malignancies.  
Hypersensitivity reactions have been reported. During clinical trials, no anaphylactic reactions 
have been reported. It should be recognized that symptoms of the underlying disease being 
treated may be similar to symptoms of hypersensitivity.  
In general, the risk to subjects in this trial may be minimized by compliance with the eligibility 
criteria and study procedures, close clinical monitoring, as well as periodic review of all safety 
data by an independent data monitoring committee (DMC).  
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
not be entered or continue in the study. 
The benefit a patient might have by participating in the study is the close monitoring of their 
condition and optimization of treatment of known risk factors during the full duration of the 
study. 
5 
 Population 
The study will enroll patients suffering from acute myocardial injury from SARS-CoV2 AND 
clinical and biological markers of systemic hyperinflammatory syndrome. The study will 
include patients hospitalized due to COVID-19 infection. The majority of these patients will 
likely have severe pneumonia, defined as tachypnea, severe respiratory distress, or SpO2 </= 
93% on room air. However, because initial acute cardiac injury in the absence of severe 
pneumonia has been reported, severe pneumonia is not required for inclusion.  
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 


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2. Hospitalized due to COVID-19 infection 
3. Documented SARS-CoV2 acute myocardial injury: Defined as upper respiratory tract 
specimen positive for COVID-19 AND troponin greater than 99th percentile upper 
reference range without signs or symptoms of acute myocardial ischemia 
4. NT-proBNP or BNP greater than upper reference limit  
5. Receiving current standard therapy 
6. C-reactive protein (CRP) > 50 mg/L  
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Alternative explanation for acute cardiac injury (Type I or Type II MI according to 4th 
Universal Definition of Myocardial Infarction, which in addition to a rise and fall of 
tropnonin above the 99th percentile upper reference limit, includes symptoms of acute 
myocardial ischemia, new ischemic ECG changes, development of pathologic Q waves, 
and imaging evidence of damage in a pattern consistent with an ischemic etiology)  
2. Chronic Systolic Heart Failure with EF<35% 
3. Age < 18 years-old 
4. Uncontrolled systemic bacterial or fungal infection  
5. Concomitant viral infection (e.g., Influenza or other respiratory virus) 
6. Pregnant. Breast-feeding women are eligible with the decision to continue or discontinue 
breast-feeding during therapy taking into account the risk of infant exposure, the benefits 
of breast-feeding to the infant, and benefits of treatment to the mother.   
7. On mechanical circulatory support 
8. On mechanical ventilation for greater than 48 hours 
9. Resuscitated cardiac arrest 
10. Has a known hypersensitivity to canakinumab or any of its excipients 
11. Neutrophil count <1000/mm3 
12. Has a history of myeloproliferative disorder or active malignancy receiving chemotherapy 
13. Known active tuberculosis or history of incompletely treated tuberculosis 
14. Current treatment with immunosuppressive agents 
15. Chronic prednisone use >10 mg/daily (for more than 3 weeks prior to admission) 
16. Has a history of solid-organ or bone marrow transplant 
17. Severe pre-existing liver disease with clinically significant portal hypertension 
18. End-stage renal disease on chronic renal replacement therapy 
19. Enrollment in another investigational study using immunosuppressive therapy  
20. In the opinion of the investigator and clinical team, should not participate in the study 
21. If male and sexually active, must have documented vasectomy or must practice birth 
control and not donate sperm during the study and for 3 months after study drug 
administration. 


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22. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of investigational drug. Such methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 
 Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential. 
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF. 
6 
Treatment 
 A total of 45 patients will be enrolled: 15 subjects will receive 600 mg intravenous 
canakinumab (8 mg/kg if </= 40 kg), 15 subjects will receive 300 mg intravenous canakinmab 
(4 mg/kg if </= 40 kg), and 15 patients will receive placebo infusion. Canakinumab or placebo 
will be dosed in 250 mL of 5% dextrose infused IV over 2 hours. No patient will receive more 
than one dose.  
 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
For investigation: 300 mg or 600 mg liquid canakinumab will be placed in 250 mL D5%W 
(dextrose 5%) and infused over 2 hours. 
For placebo: 250 mL D5%W (dextrose 5%) will be infused over 2 hours. 


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6.1.2 
Additional study treatments 
No additional treatment beyond investigational drug are included in this trial. 
6.1.3 
Treatment arms/group 
Eligible subjects will be randomized at the baseline visit.  
6.1.4 
Concomitant therapy 
Medication classification used by the subject prior to randomization will be recorded in the 
eCRF pages. 
 
Concomitant medications to track include: antipyretics, antibiotics related to secondary 
infections, anti-virals related to Covid-19, corticosteroids and other immunosuppressives. 
Other concomitant medications will be recorded at baseline and daily thereafter until Day 7, at 
Day 14, Day 21 and Day 28. 
 
6.1.5 
Prohibited medication 
No data are available on either the effects of live vaccination or the secondary transmission of 
infection by live vaccines in patients receiving canakinumab. Therefore, live vaccines should 
not be given concurrently.  
Prohibited medications include any cell-depleting biological therapies (e.g., anti-CD20) within 
12 months prior to Day 0; or previous treatment with noncell-depleting biological therapies 
(such as anti-tumor necrosis factor [TNF], anakinra, anti-Interleukin [IL]-6 receptor [e.g. 
tocilizumab], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer) prior to 
screening, treatment with alkylating agents within 12 weeks prior to screening, intramuscular, 
receipt of live (attenuated) vaccine within the 4 weeks before Day 0, treatment with 
cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 
weeks of screening. 
 
Permitted concomitant therapy requiring caution and/or action: 
TNF-Blocker and IL-1 Blocking Agent 
An increased incidence of serious infections and an increased risk of neutropenia have been 
associated with administration of another IL-1 blocker in combination with TNF inhibitors in 
another patient population. Treatment with TNF-blocker within 8 weeks (or 5 half-lives, 
whichever is longer) is prohibited. More remote treatment with TNF-blockers is allow but 
requires caution, especially for neutropenia and infections, as noted.  
Cytochrome P450 Substrates 
The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) 
during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as 
canakinumab, the formation of CYP450 enzymes could be normalized. This is clinically 
relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually 
adjusted (e.g., warfarin). Upon initiation of canakinumab, in patients being treated with these 


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types of medicinal products, therapeutic monitoring of the effect or drug concentration should 
be performed and the individual dose of the medicinal product may need to be adjusted as 
needed. 
 
6.1.6 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. Upon signing the informed consent form, the 
patient is assigned to the next sequential Subject No. available. 
6.1.7 
Treatment assignment, randomization 
After meeting all inclusion/exclusion criteria and obtaining informed consent, patients will be 
randomized using a 1:1:1 allocation ratio to one of the three treatment groups. Randomization 
will be centralized through REDcap Cloud. Randomization will be stratified on whether or not 
the patient is intubated at the time of enrollment. 
6.2 
Treatment blinding 
Subjects, investigator staff, persons performing the assessments, and the clinical trial team will 
be blinded to treatment. Only the Research Pharmacist and members of the Data Safety 
Monitoring Board will have access to the treatment assignments. If the clinical team decides 
that unblinding the patient is essential for subsequent significant clinical management, then the 
patient may be unblinded after discussion between the clinical team and the Principal 
Investigator, Paul Cremer. 
6.3 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described in the pharmacy 
manual. 
A unique medication number is printed on the study medication label. 
6.3.1 
Handling of study treatment and additional treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the pharmacy manual. Clinical supplies are to be 
dispensed only in accordance with the protocol. Technical complaints are to be reported to the 
respective Novartis CPO Quality Assurance. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log.  


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At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis address provided in the investigator folder at each site. 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB -approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
A copy of the approved version of all consent forms will be kept by the Sponsor/Investigator. 
Visit schedule and assessments 
The assessment schedule lists all of the assessments and indicates with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed.  
 
7.1 
Visit schedule and assessments 
The assessment schedule lists all of the assessments and indicates with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed.  


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Table 7-1 
Assessment Schedule* 
 
  
Study Day a 
 
 
  
Activity 
-3 to 
0 b 
0 
1 
2 
3 
4 
5 
6 
7 
14* 
c   
21* 
c 
28*c 
90 
150 
Unscheduled d 
Informed consent 
 X 
 
  
 
  
 
  
 
  
  
  
  
 
 
  
Demographics 
 X 
 
  
 
  
 
  
 
  
  
  
  
 
 
  
Medical historyα 
 X 
 
  
 
  
 
  
 
  
  
  
  
 
 
  
Eligibility 
X 
 
  
 
  
 
  
 
  
  
  
  
 
 
  
Physical exam 
 X 
 
  
 
  
 
  
 
  
  
  
 
 
 
X 
Vital signs 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body Temperature (Celsius) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Body weight 
X 
 
  
 
  
 
  
 
  
  
 
 
Height 
 X 
 
  
 
  
 
  
 
  
  
  
  
 
 
  
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Electrocardiogram 
 X 
 
  
 
  
 
  
 
  
X  
  
  
X 
 
X 
Chest imaging findings(chest X-Ray or CT) β 
 X 
 
  
 
  
 
  
 
  
  
  
 
 
X 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Clinical assessment (7category scale)a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
2019-nCoV testγ  
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Respiratory Virus Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponin   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
NT-proBNP/BNP 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Creatinine kinase (CK) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Creatinine kinase MB (CK-MB) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
LDH e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
D-Dimer e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Ferritin e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Interleukin 6 (IL-6) e 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
Mechanical ventilation assessment 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 


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*Given resource limitation related to COVID-19, all laboratory testing is considered standard of care, though as possible, certain tests that 
are not considered standard of care may be obtained for research. If the laboratory tests in the schedule of activities are obtained, they will 
be documented accordingly. If laboratory tests cannot be obtained for other reasons, such as requiring extra use of personal protective 
equipment, unnecessary exposure to healthcare personnel, or safety issues related to obtaining and processing samples, these will not be 
considered a protocol deviation. Visits at 14, 21, 28, 90 and 150 days may happen in-person or telehealth (labs not obtained if telehealth). 
α The medical history must document the onset of symptoms as the time from onset of symptoms to enrollments will be documented. The 
reason for admission will also be documented.    
β Chest imaging findings must document unilateral or bilateral infiltrates. 
γ Nasopharyngeal or oropharyngeal swabs for SARS-CoV2 RNA levels will be performed until negative or discharge. Sampling will include 
both nostrils, or repeat sampling will include the same nostril if only one nostril is used. 
a Study visits are planned for hospitalized patients only; planned activities that fall on study days that occur after the patient is discharged 
will not be done. Assessments with the ordinal scale used for the primary outcome will be completed daily through Day 14 until 
clinical improvement, hospital discharge, or death. 
b Screening activities can occur from -3 and 0 days before enrollment except for Covid-19 testing, which can occur between -5 and 0 days 
before enrollment. 
Respiratory parameters g 
 X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
X 
Viral Serology (inc. anti-2019-nCoV)  
 X 
 
  
 
  
 
  
 
 
 X 
  
  X 
 
 
 X 
TB screening h 
 X 
 
  
 
  
 
  
 
  
  
  
  
 
 
  
HIV antibody h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis profile (Hepatitis B sAg, sAb, cAb; 
Hepatitis C Ab) h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology (CBC + diff) 
X 
 
  
 
X  
 
 
X 
  
X 
 
 
X 
Coagulation (PT, PTT, INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry (lytes, BUN, glucose, CR) 
X 
 
  
 
X  
 
  
 
X 
X 
 
 
X 
Liver profile (AST, ALT, Alb, AlkP, Tbili, Dbili) 
X 
 
  
 
X  
 
  
 
X 
  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Assessment of survival (day of death if occurs) 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
  
Canakinumab/placebo administration 
X 
 
 
 
 
 


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c For hospitalized patients, this visit will include the activities listed. For patients who have been discharged, visits will be conducted by 
phone but will not include any laboratory tests. 
d An unscheduled visit is planned to occur on the day of discharge if the patient is discharged before Day 28; in which case this will serve as 
an early termination visit. If patient is discharged the visit on Study Day 28 will be done by telephone call follow-up and lab tests will not be 
performed. May also be used for adverse event assessments. 
e Collect at least baseline and at least weekly thereafter. 
g Includes FiO2 (degree of supplemental oxygen), SpO2, Respiratory rate and presence of respiratory distress, note if ventilated or not, if 
yes collect PEEP. For FiO2, SpO2, and PEEP, best and worst of daily value. Calculate P to F ratio best and worst for each day; proning; 
neuromuscular blockade; veno-venous or veno-arterial ECMO. 
h Done at Investigator’s discretion; not expected to be used for decision to treat; not a mandatory test. 
i Females of child-bearing potential only, urine or serum at investigator’s discretion.  
J Includes complete blood count (CBC) and differential at screening and CBC on subsequent indicated days. 
  
l Prohibited medications include any cell-depleting biological therapies (e.g., anti-CD20) within 12 months prior to Day 0; or previous 
treatment with noncell-depleting biological therapies (such as anti-tumor necrosis factor [TNF], anakinra, anti-Interleukin [IL]-6 receptor 
[e.g. tocilizumab], or abatacept) within 8 weeks (or 5 half-lives, whichever is longer) prior to screening, treatment with alkylating agents 
within 12 weeks prior to screening, intramuscular, receipt of live (attenuated) vaccine within the 4 weeks before Day 0, treatment with 
cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks of screening 
 
Concomitant medications to track include: antipyretics, anti-infectives related to COVID-19, other antibiotics, corticosteroids and other 
immunosuppressives. The timing of administration of these medications must be recorded. Other concomitant medications recorded at 
baseline day 0 and maximum dose. 


 
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Covid 19 Protocol_3.0_ 11MAY2020  
 
7.2 
Subject demographics/other baseline characteristics 
Patient demographic and baseline characteristic data will be collected on all subjects. The 
number of days between onset of COVID-19 symptoms and initiation of treatment will be 
recorded in all patients.  
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. 
7.2.1 
Laboratory evaluations 
Pre-treatment screening:  
• 
Complete blood count (CBC), serum biochemical tests (including renal and liver 
function), albumin, total protein, coagulation profile, D-dimer, fibrinogen, troponin, CK, CK-
MB, NT-proBNP or BNP, LDH, CRP, serum ferritin, IL-6, quantiferon, HBV, HCV, HIV 
serology, urine or serum pregnancy test. 
On-treatment measurements (as noted in the schedule of activities):  
• 
Complete blood count (CBC), serum biochemical tests (including renal and liver 
function), albumin, total protein, coagulation profile, D-dimer,  5th generation Roche high-
sensitivity troponin T, CK, CK-MB, LDH, CRP, serum ferritin, IL-6 
7.2.2 
Electrocardiogram (ECG) 
A baseline electrocardiogram with assessment for acute or prior myocardial ischemia or 
infarction will be obtained.  
Follow-up ECG will similarly be obtained at day 14 if the patient is still hospitalized or at day 
90 if feasible.  
7.2.3 
Echocardiogram (Echo) 
A baseline echocardiogram with assessment of left ventricular ejection fraction will be 
completed after  onset of COVID-19 symptoms, and as close as possible prior to canakinumab 
or placebo infusion. 
Follow-up echocardiogram with assessment of left ventricular ejection fraction will be collected 
at day 14 if the patient is still hospitalized and at day 90 if feasible. 
7.2.4 
Pregnancy assessments  
All pre-menopausal women who are not surgically sterile will have a urine or serum pregnancy 
test performed at the screening visit. Pregnancy testing is not required for post-menopausal 
women.  
 


 
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Clinically significant abnormalities must be recorded on the relevant section of the CRFs 
capturing medical history/Current medical conditions/AE as appropriate. 
 
8 
Study discontinuation and completion 
8.1 
Discontinuation 
8.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. After study treatment 
discontinuation, patient should remain in the study, unless he/she withdraws consent (Section 
9.1.2), preferably in writing. 
Study treatment must be discontinued under the following circumstances  
 Subject/guardian decision 
 Pregnancy 
 Use of prohibited treatment 
 Any situation in which study participation might result in a safety risk to the subject 
 Any laboratory abnormalities that in the judgment of the investigator prevents the subject 
from continuing study drug administration 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.  
Subjects 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. Where possible, they should return for the assessments indicated in the 
assessment schedule, understanding that this is often not be possible with an ongoing 
COVID-19 pandemic. If they fail to return for these assessments for unknown reasons, every 
effort (e.g. telephone, e-mail, and letter) should be made to contact the subject/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 subject cannot or is unwilling to attend any visit(s), including the planned telehealth visits, 
the site staff should maintain regular telephone contact with the subject, or with a person pre-
designated by the subject. This telephone contact should preferably be done according to the 
study visit schedule. Patient’s vital status can also be verified by the study site upon contact 
with patient’s primary care physician or other sources according to local rules and regulations. 
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 


 
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 adverse events/Serious Adverse Events 
8.1.1.1 
Replacement policy 
Subjects who are enrolled but not randomized will be replaced. Subjects who withdrawal 
consent before receiving study infusion will also be replaced. 
8.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
 Does not want to participate in the study anymore 
And 
 Does not allow  further collection of personal data 
It is encouraged that patient provides withdrawal of consent in writing. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. Patient’s vital status can be verified upon contact with patient’s primary 
care physician or other sources according to local rules and regulations. 
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 subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Cleveland Clinic will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until the time of withdrawal) according to 
applicable law: 
8.1.3 
Lost to follow-up 
For subjects 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 subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until the end 
of the study while due diligence has been completed. 
8.1.4 
Early study termination by the sponsor 
The study can be terminated by the Sponsor/Investigator at any time. Reasons for early 
termination: 
 Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study 
 Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 


 
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In taking the decision to terminate, the Sponsor/Investigator will always consider the subject 
welfare and safety. Should early termination be necessary, subjects must be seen as soon as 
possible and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
8.2 
Study completion and post-study treatment 
Study completion is defined as when the last subject 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.  
9 
Safety monitoring and reporting 
9.1 
Definition of adverse events and reporting requirements 
9.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject 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 subject and 
identifying adverse events. 
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 subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded in the Adverse Events CRF 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. The 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 


 
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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 subject 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
 Dose not changed 
 Dose Reduced/increased 
 Drug interrupted/withdrawn 
 its outcome  
a. not recovered/not resolved; 
b. recovered/resolved; 
c. recovering/resolving, 
d. recovered/resolved with sequelae; 
e. fatal; or unknown. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
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 for at least 16 weeks following the last dose of 
study treatment. 
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 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 


 
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baseline or the previous visit, or values, which are considered to be non-typical in subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Appendix 1. 
9.1.2 
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 subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (coronary heart disease, cerebrovascular disease or 
peripheral vascular disease).  
 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 subject’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 subject 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 subject 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.  
All 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 (Table 10-1). 


 
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9.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until the last study visit must be reported to the Investigator 
within 24 hours of learning of its occurrence.  
Sponsor/investigator is responsible for evaluating all safety information available, and notify 
FDA and all investigators in an IND safety report of potentially serious risks from this clinical 
trial or any other source as soon as possible but not later than 15 calendar days after the 
sponsor/investigator receives the safety information and determines that the information 
qualifies for reporting.  
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected and Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported 
to FDA. 
Any SAEs experienced after the Completion Study should only be reported to 
sponsor/investigator 
 
9.1.4 
Pregnancy reporting 
Pregnancies 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Sponsor/Investigator 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. Newborn will be followed up just until birth 
according to guidelines as there was nothing observed in any studies that would suggest a fetal 
development risk. 
Any SAE experienced during pregnancy must be reported. 
9.1.5 
Reporting of study treatment errors  
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the eCRF irrespective of whether or not associated with an AE/SAE and reported to Safety only 
if associated with an SAE.  


 
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9.1.6 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the 
sponsor/investigator whether to continue, modify or terminate a trial. 
The Data Monitoring Committee will make an assessment after every administration of study 
drug for the first 6 patients using all available data in the patient’s medical record. Summary 
reports will be provided to the DMC after the first six subjects have been reviewed, after 12 
subjects have been reviewed, and after every 6 subsequent patients.  The DMC will include 
representatives from Pulmonary/Critical Care, Rheumatology, Infectious Disease, and 
Cardiology. 
Specific details regarding composition, responsibilities, data monitoring and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor/investigator and the 
DMC. 
Schedule of Safety Assessments:  
 
  
Study Day  
 
 
  
Activity 
-3 
to 
0  
0 
1 
2 
3 
4 
5 
6 
7 
14  21 
28 
90 
150 
Unscheduled  
Vital signs 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
Medications 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
Respiratory 
parameters  
 X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Hypersensitivity 
reaction 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Secondary 
infections 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Hematology (CBC + 
diff: assessment 
for leukopenia, 
neutropenia, and 
thrombocytopenia) 
X 
 
  
 
X  
 
 
X 
  
X 
 
 
X 
Coagulation (PT, 
PTT, INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry (lytes, 
BUN, glucose, CR) 
X 
 
  
 
X  
 
  
 
X 
X 
 
 
X 
Liver profile (AST, 
ALT, Alb, AlkP, 
Tbili, Dbili: 
assessment for 
drug-induced liver 
injury according to 
Hy’s law) 
X 
 
  
 
X  
 
  
 
X 
  
 
X 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
X 


 
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10 
Data Collection and Database management 
10.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
10.2 
Site monitoring 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. 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 subjects will be disclosed. 
11 
Data analysis and statistical methods 
11.1 
Analysis sets 
All patients who provide informed consent, are randomized and receive study medication will 
be included in the analysis. 
 
11.2 
Subject demographics and other baseline characteristics 
The number and percentage of patients who completed the study, who discontinued the study 
and the reason for discontinuation will be presented for all patients. The frequency (%) of 
patients with major protocol deviations as well as the criteria leading to data exclusion from 
analysis will be presented in separate tables, if applicable. Finally, the number of enrolled 
patients by site will be presented descriptively. 


 
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Baseline value is defined as the last non-missing assessment prior to the first dose of study drug 
unless specified otherwise. 
Demographic and background characteristic variables will be summarized using descriptive 
summary statistics. Continuous variables will be summarized using n, mean, standard deviation, 
median, Q1 (25th percentile), Q3 (75th percentile), minimum, and maximum. Categorical 
variables will be summarized using frequency and percentage. 
 
11.3 
Analysis of the primary endpoint and secondary endpoints 
Based on prior reports of poor prognosis in patients who have SARS-CoV2 and an elevated 
troponin in terms of high likelihood of requiring mechanical ventilation, developing acute 
respiratory distress syndrome, and death, as well as low likelihood of demonstrating clinical 
improvement we estimate an event rate of 0.8 in the control group. However, estimates of 
efficacy of canakinumab in this patient population are not established. Therefore, no inferential 
statistics are planned a priori. The results from this pilot study will provide important data 
regarding effect size to inform feasibility of larger studies.  The primary efficacy analysis will 
be on an intention-to-treat basis and include all patients who are randomized. The primary 
efficacy comparison will be between patients receiving canakinumab 600 mg IV versus 
placebo. The time to clinical improvement will be assessed daily until day 14, and for the 
purposes of the primary endpoint, failure to reach clinical improvement or death before day 14 
considered as right-censored at day 14. Of note, we plan to analyze the primary end-point after 
all patients have reached day 14 to expeditiously inform whether a larger study should be 
undertaken. In addition to analysis of the entire cohort, we also planned to perform separate 
analyses of patients who are and who are not intubated at the time of randomization since these 
may represent distinction populations. As noted, as we do not plan inferential statistics, data for 
endpoints will be displayed as point estimates with 95% confidence intervals. None of these 
estimates or intervals should be regarded as definitive for treatment effect.   
11.3.1 
Adverse events 
 
All information obtained on adverse events will be summarized in tabular format. 
A subject with multiple adverse events of the same type is only counted once towards the total 
of that event. 
All deaths and serious adverse events will be tabulated.  
All AEs, deaths and serious adverse events will be provided in patient listings. 
12 
Ethical considerations and administrative procedures 
12.1 
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 


 
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Covid 19 Protocol_3.0_ 11MAY2020  
local regulations US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
12.2 
Responsibilities of the investigator and IRB 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures and any 
other written information to be provided to subjects. Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov. In 
addition, after study completion and finalization of the study report the results of this trial will 
be submitted for publication and posted on Clinicaltrials.gov 
13 
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 subjects should be 
administered as deemed necessary on a case by case basis. 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. 
13.1 
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 subject 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 subject 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 at the study site should be informed according to local 
regulations. 


 
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14 
References 
 
 
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2. 
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Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nature 
Reviews Cardiology 2020. Published March 5, 2020.  
4. 
Wang D, Hu B, Chang H, et al. Clinical characteristics of 138 hospitalized patients with 
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Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
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Gao C, Wang Y, Gu X, et al. Association between cardiac injury and mortality in 
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Ruan W, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 
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Lei G, Wen XS, Cheng XC, et al. Prognostic value of NT-proBNP in patients with 
severe COVID-19. medRXiv; doi:10.1101/2020.03.07.20031575. 
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Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with 
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Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized 
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Reanalysis of a prior phase III trial. Crit Care Med 2016; 44:275-281. 


 
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16. Granowitz EV, Porat R, Mier JW, et al. Pharmacokinetics, safety and immunomodulatory 
effects of recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine 1992; 
4:353-360. 
17. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the 
cryopyrin-associated periodic syndrome. N Engl J Med 2009; 360:2416-25. 
18. Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with canakinumab for 
atherosclerotic disease. N Engl J Med 2017; 377:1119-31. 
19. Kuemmerle-Dsechner JB, Hachulla E, Cartwright R, et al. Two-year results from an open-
label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients 
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tocilizumab. ChinaXiv: 2020003.0026v1. 
 
 
 
Key Words: SARS-CoV2, acute myocardial injury, canakinumab