A Randomized, Double-blind, Placebo-controlled, Event-driven Trial of Quarterly Subcutaneous Canakinumab in the Prevention of Recurrent Cardiovascular Events Among Stable Post-myocardial Infarction Patients With Elevated hsCRP
Phase: PHASE3
Conditions: Atherosclerosis
Sponsor: Novartis Pharmaceuticals

Clinical Development
ACZ885M/Canakinumab
Clinical Trial Protocol CACZ885M2301 / NCT01327846
A randomized, double-blind, placebo-controlled, event-
driven trial of quarterly subcutaneous canakinumab in the 
prevention of recurrent cardiovascular events among 
stable post-myocardial infarction patients with elevated 
hsCRP
Authors:
 
Document type:
Amended Protocol Version
EUDRACT number:
2010-022970-14
Version number:
v09 Clean
Development phase:
III
Release date:
13-SEP-2016
Template Version 26-May-2009
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 9 ...........................................................................................................................11
Amendment 8 ...........................................................................................................................12
Amendment 7 ...........................................................................................................................13
Amendment 6 ...........................................................................................................................14
Amendment 5 ...........................................................................................................................15
Amendment 4 ...........................................................................................................................15
Amendment 3 ...........................................................................................................................15
Amendment 2 ...........................................................................................................................16
Amendment 1 ...........................................................................................................................16
1
Introduction .......................................................................................................................27
1.1
Background............................................................................................................27
1.2
Purpose ..................................................................................................................29
2
Study objectives.................................................................................................................29
2.1
Primary objective...................................................................................................29
2.2
Secondary objectives .............................................................................................29
30
3
Investigational plan ...........................................................................................................31
3.1
Study design...........................................................................................................31
3.2
Rationale of study design.......................................................................................38
3.3
Rationale of dose/regimen, duration of treatment .................................................39
3.4
Rationale for choice of comparator .......................................................................41
3.5
Purpose and timing of interim analyses/design adaptations..................................42
4
Population..........................................................................................................................42
4.1
Inclusion criteria ....................................................................................................43
4.2
Exclusion criteria...................................................................................................44
5
Treatment...........................................................................................................................48
5.1
Investigational and control treatment ....................................................................48
5.2
Treatment arms......................................................................................................49
5.3
Treatment assignment............................................................................................50
5.4
Treatment blinding.................................................................................................53

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5.5
Treating the patient................................................................................................54
5.5.1
Patient numbering .................................................................................54
5.5.2
Dispensing the study treatment.............................................................55
5.5.3
Supply, storage and tracking of study treatment...................................55
5.5.4
Instructions for prescribing and taking study treatment........................56
5.5.5
Permitted interruptions of study treatment............................................56
5.5.6
Concomitant treatment..........................................................................57
5.5.7
Prohibited treatment..............................................................................57
5.5.8
Interruption and Discontinuation of study treatment and premature 
patient withdrawal.................................................................................58
5.5.9
Emergency unblinding of treatment assignment...................................61
5.5.10
Study completion and post-study treatment..........................................61
5.5.11
Early study termination.........................................................................62
6
Visit schedule and assessments .........................................................................................62
6.1
Information to be collected on screening failures..................................................75
6.2
Patient demographics/other baseline characteristics .............................................75
6.3
Treatment exposure and compliance .....................................................................75
6.4
Efficacy..................................................................................................................76
6.4.1
Primary Efficacy assessment (primary objective).................................76
6.4.2
Secondary efficacy assessment (secondary objectives)........................76
6.4.3
Appropriateness of efficacy assessments..............................................77
6.5
Safety.....................................................................................................................77
6.5.1
Physical examination ............................................................................78
6.5.2
Vital signs..............................................................................................78
6.5.3
Height, weight and waist circumference...............................................78
6.5.4
Laboratory evaluations..........................................................................79
6.5.5
Electrocardiogram (ECG) .....................................................................80
6.5.6
Pregnancy and assessments of fertility .................................................80
6.5.7
Appropriateness of safety measurements..............................................80
81
81
81
81
82
84

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85
86
87
88
89
90
7
Safety monitoring..............................................................................................................90
7.1
Adverse events.......................................................................................................90
7.2
Serious adverse event reporting.............................................................................92
7.3
Reporting of study treatment errors including misuse/abuse ................................96
7.4
Pregnancies............................................................................................................97
7.5
Data Monitoring Committee..................................................................................97
7.6
Adjudication Committees......................................................................................97
7.6.1
Cardiovascular clinical events adjudication committee........................97
7.6.2
Infection Adjudication Committee........................................................98
7.6.3
Malignancy Adjudication Committee...................................................99
8
Data review and database management.............................................................................99
8.1
Site monitoring ......................................................................................................99
8.2
Data collection.....................................................................................................100
8.3
Database management and quality control..........................................................100
9
Data analysis....................................................................................................................101
9.1
Analysis sets ........................................................................................................101
9.2
Patient demographics and other baseline characteristics.....................................102
9.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)..........................................................................................................104
9.4
Analysis of the primary variable(s) .....................................................................105
9.4.1
Variable...............................................................................................105
9.4.2
Statistical model, hypothesis, and method of analysis........................106
9.4.3
Handling of missing values/censoring/discontinuations.....................109
9.4.4
Supportive analyses.............................................................................110
9.5
Analysis of key secondary and exploratory variables .........................................111
9.5.1
Secondary variables ............................................................................111
113
9.5.3
Safety variables ...................................................................................114
116
116

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117
117
117
118
9.6
Sample size calculation........................................................................................118
9.7
Power for analysis of key secondary variables....................................................120
9.8
Interim analyses...................................................................................................120
10 Ethical considerations......................................................................................................120
10.1
Regulatory and ethical compliance......................................................................120
10.2
Informed consent procedures...............................................................................121
10.3
Responsibilities of the investigator and IRB/IEC................................................121
10.4
Publication of study protocol and results.............................................................122
10.5
Quality Control and Quality Assurance...............................................................122
11 Protocol adherence ..........................................................................................................122
11.1
Protocol Amendments .........................................................................................122
12 References .......................................................................................................................124
13 Appendix 1: Clinically notable laboratory values and vital signs...................................127
128
15 Appendix 3  Study Endpoint Definitions ........................................................................129
15.1
Definition of Cardiovascular Death.....................................................................129
15.2
Non-cardiovascular death....................................................................................131
15.3
Definition of Non-fatal Myocardial Infarction....................................................131
15.4
Definition of Stroke.............................................................................................134
136
15.6
Definition of Unstable Angina Requiring Unplanned Revascularization ...........137
15.7
Definition of Heart Failure requiring Hospitalization .........................................139
15.8
Definition of New Onset Diabetes.......................................................................139
15.9
Definition of Transient Ischemic Attack .............................................................140
15.10 Definition of Critical Limb Ischemia ..................................................................140
15.11 Definition of Limb Amputation due to Vascular Cause......................................141
141
142
142
15.15 Definition of Coronary Angiography ..................................................................143
15.16 Definition of Coronary Revascularization...........................................................143
143

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16 Appendix 4  Instructions for use of the safety syringe....................................................145
List of tables
Table 5-1
Injection Description.............................................................................48
Table 6-1
Assessment schedule of pivotal phase ..................................................65
Table 6-2
Assessment schedule of extension epoch for patients not
participating in study drug washout ......................................................70
Table 6-3
Assessment schedule of extension epoch for prediabetic patients 
participating in 6-month study drug washout........................................73
Table 9-1
Power at the final analysis for 1,400 patients with a MACE..............119
128
List of figures
Figure 3-1
Study design pivotal phase....................................................................36
Figure 3-2
Study design of extension phase for patients not participating in 
study drug washout ...............................................................................36
Figure 3-3
Study design of extension phase for prediabetic patients .....................37
Figure 5-1
Transition from pivotal phase to extension phase.................................53
Figure 9-1
Closed testing procedure for primary and key secondary endpoints ..108

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List of abbreviations
ADL
Activities of Daily Living
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BMI
Body Mass Index
CABG
Coronary Artery Bypass Graft
CAPS
Cryopyrin-Associated Periodic Syndromes
CHD
Coronary Heart Disease
CHF
Congestive Heart Failure
CRF
Case Report/Record Form
CPO
Country Pharma Organization
CRO
Contract Research Organization
CV
Cardiovascular
CVD
Cardiovascular Disease
DAR
Dose Administration Record
DBP
Diastolic Blood Pressure 
DMC
Data Monitoring Committee
DS&E
Drug Safety and Epidemiology
eCRF
electronic Case Report/Record Form
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
estimated Glomerular Filtration Rate
EOS
End of Study
FAS
Full Analysis Set
FPG
Fasting Plasma Glucose
GCP
Good Clinical Practice
GWA
Genome-wide association
HbA1c
Glycosylated hemoglobin 
HDL
High-Density Lipoprotein
HIV
Human Immunodeficiency Virus

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hsCRP
High Sensitivity C-Reactive Protein
IA
Interim Analysis
IAC
Infection Adjudication Committee
IB
Investigators Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IL-1β
Interleukin 1 Beta
IN
Investigator Notification
INR
International Normalized Ratio
IRB
      Institutional Review Board
i.v.
      intravenous
IVRS/IWRS  Interactive Voice Response System/ Interactive Web Response System
LDL
Low density lipoprotein
LFT
Liver Function Test
MACE
Major Adverse Cardiovascular Event
MedDRA  Medical dictionary for regulatory activities
MI
Myocardial Infarction
MRS
Modified Rankin Scale
NOD
New Onset Diabetes
NYHA
New York Heart Association
OC/RDC   Oracle Clinical/Remote Data Capture
PCI
Percutaneous coronary intervention
PCP
Primary Care Physician
PP
Per Protocol Set
PPD
Purified protein derivative
PRO
Patient Reported Outcomes
PTCA
Percutaneous transluminal coronary angioplasty

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PVD
Peripheral Vascular Disease
QFT-g
QuantiFERON-TB Gold
QoL
Quality of Life
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SBP
Systolic Blood Pressure
s.c.
Subcutaneous
SOC        System Organ Class
SMQ       Standardized MedDRA Queries
SUSAR   Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 Diabetes Mellitus
TB
Tuberculosis
TIA
Transient Ischemic Attack
VLDL
Very-Low-Density Lipoprotein

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
A study drug or placebo used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs are: 
screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.”
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IVR system
Patient number
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
patient in the study.
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Randomization number
A unique identifier assigned to each randomized patient, corresponding to 
a specific treatment arm assignment
Study drug
Any drug administered to the patient as part of the required study 
procedures; includes investigational drug and any control drugs
Variable
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points

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Amendment 9
Amendment Rationale
CACZ885M2301 Protocol Amendment 9 provides details for the study extension described in 
the current protocol. Following accrual of the target number of primary events, eligible 
patients will have the option to continue study participation in the extension phase at their end 
of study visit. The objective of the extension phase is to obtain further follow-up information 
on long-term safety on continued exposure to canakinumab in trial participants. Additionally, 
as defined in the current protocol, 
 
 
. Persistence of a 
potential effect of canakinumab on quality of life and the impact of a treatment switch to the 
open-label dose on quality of life will also be explored. Patients who choose to participate will 
remain on their pivotal phase blinded assigned treatment arm for the first three extension 
phase visits, except for prediabetic patients who will undergo a 6-month study drug washout 
by skipping two doses of their pivotal phase blinded assigned treatment arm. After the 
database from the pivotal study is locked all participants will be switched to an open-label 
dose of 150 mg canakinumab. The 150 mg dose is predicted to have the highest likelihood of 
having the most favorable benefit: risk ratio based on biomarker and clinical data from phase 
II studies in Type 2 diabetics. The final canakinumab dose will be based on the results from 
the pivotal phase. The transition to an intermediate dose of 150 mg will avoid further placebo 
treatment until the final dose of canakinumab is implemented at the study sites. The extension 
phase will continue in an individual country for a minimum of two years from the date of the 
first patients enrolled in that country. The maximum duration of the extension phase will be 
2.5 years from the date of the first patient enrolled in that country or until marketed product is 
available in that country, whichever comes first. While the extension phase is then deemed 
complete the safety follow-up is anticipated to be continued in registries following study 
results and discussion with Health Authorities. 
Changes to the protocol
The described changes under the amendment rationale are implemented throughout the 
protocol.
In addition, the following updates, clarifications and omissions are included in this protocol 
amendment:

Implementation of global and local registries post approval will be subject to discussion 
and agreement with 
health authorities 
during 
Biologic 
License Application 
(BLA)/Marketing Authorization Application (MAA) review and will be conducted via
separate protocols. Section 5.5.10 updated to reflect this.

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
Section 7.1: described the reporting of adverse events during the extension phase.  During 
the extension phase, endpoints will no longer be collected. 
 
 
 
During the extension phase ALL adverse events will be reported as AEs following the 
procedures described in Section 7.1 and Section 7.2.

Section 7.2: clarification regarding the instructions for Serious Adverse Event (SAE)
reporting, allowing also electronic SAE reporting 

Section 7.3 added to describe reporting of study treatment errors including misuse/abuse
during the extension phase of the study

Section 7.6.2 added that the Infections Adjudication Committee will not adjudicate cases 
during the extension phase 

Section 7.6.3 added that the Malignancy Adjudication Committee will not adjudicate 
cases during the extension phase 

Section 10.5 added to describe the Quality Management system that applies to this trial.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities. The changes described in this amended 
protocol require IRB/IEC approval prior to implementation. In addition, sites are required to 
submit for approval an updated informed consent that covers the extension phase of the study, 
which will be signed by patients before they move into main drug dispensing period (Visit 
201 and beyond) of the extension phase.
Other minor updates and corrections were also included.
Summary of previous amendments
Amendment 8
Amendment Rationale
CACZ885M2301 Protocol Amendment 8 adjusts the number of patients to be randomized 
into the study from 17,200 patients to approximately 10,000 patients. This change is not based 
on safety or efficacy concerns, instead it resulted from a strategic decision that considered the 
higher than anticipated primary event endpoint rate observed thus far.
Importantly, the study objectives and power remain unchanged and the study will still 
complete when 1,400 primary event endpoints are accrued as originally planned. The elapsed 
calendar time to reach the conclusion of the study is now estimated to be approximately 6 
years (instead of 5 years) of treatment and follow-up from the start of enrollment in the trial to 
when 1,400 primary cardiovascular events have been accrued.   

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Protocol Amendment 8 also introduces the option to perform a futility analysis earlier than the 
first planned efficacy interim analysis (IA) (at approximately 50% primary events) but only 
after a sufficient number of primary events are accrued, i.e., >25%.  This may be performed 
by the DMC in consideration of the longer period of time that may be needed to reach the first 
IA from the start of enrollment.
Changes to the protocol
The described changes in the amendment rationale are implemented throughout the protocol.
The following minor updates, clarifications and omissions are included in this protocol 
amendment:

In accordance with the change in sample size, the total planned patients screened changed 
from 29,000 to 17,000.

Spelled out the CANTOS acronym (Section 3.1)

Informed that CACZ885M2301 Sub-study S1 and S2 have been terminated.  Of note, the 
Sponsor decision to terminate these sub-studies was not due to safety or efficacy concerns 
(Section 3.1).  

Clarified that the full committee DMC safety reviews will occur on a six-month basis and 
the DMC chair will review the safety data on a three-month basis (Section 3.5).

In Section 5.5.8, added information specifying that the patient contact information should
be reviewed at each visit and clarified the process for visits/patient contact following 
study drug discontinuation.

Added Years 5 and 6 to Table 6-1

In Section 6.5.7, informed as a correction that Allergies/Immunological are not 
adjudicated events.  

Corrected the following statement noting that all malignancies including basal cell 
carcinoma should be reported as SAEs meeting the criteria of “medically significant” 
(Section 7.1)

In the site monitoring section (Section 8.1), incorporated the various methods utilized to 
ensure protocol and GCP compliance and the quality/integrity of the sites’ data.  
Continuous remote monitoring and a central analytics organization have been added as a 
complement to field monitoring.

A discussion of the currently observed event rates, the impact on trial duration and the 
lack of an impact on study power was added to the statistical section.
Other minor updates and corrections were also included.
Amendment 7
Short summary of the amendment rationale and major changes
 Visit 1 screening 
tests for HBc antibody and HBs antibody are added in Japan only to prevent enrolling 
Japanese patients who have a history of hepatitis B infection and/or are hepatitis B carriers. In 

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 specific language 
regarding post-menopausal status determination in women less than 50 years of age is added 
for Croatia only.  
Additional updates and clarifications were also noted in this protocol amendment such as 
allowing the prescreen hsCRP if performed at the central laboratory less than 60 days prior to 
Visit 2 and ≥ 2mg/L to be used as the qualifying hsCRP, clarifying the tuberculosis status 
determination for study entry, informing that recruitment will target approximately 50% of 
randomized patients with an index MI 30 days to 12 months prior to randomization and 50% 
with an index MI >12 months prior to randomization, and noting that for patients whose 
treatment is stopped as a result of a data monitoring committee recommendation to suspend 
treatment in one dose group, follow-up for cardiovascular and safety events will continue at 6 
month intervals. The amendment also removed mention of a recruitment duration of 21 
months and informed that the elapsed calendar to time to reach the conclusion of the study is 
estimated to be approximately 5 years of treatment from the start of enrollment to the 
occurrence of when 1,400 patients have had confirmed adjudicated primary cardiovascular 
events. In Section 5.5.8, additional clarity was added to the situations under which patients 
may restart study treatment, the liver function test discontinuation criteria was aligned with 
recent company guidance for liver enzyme elevations, and it was noted that patients who 
develop any malignancy other than excised basal cell skin carcinoma must discontinue from 
study treatment. 
 
 
 
Other minor updates and corrections were also included.
Amendment 6
Short summary of the amendment rationale and major changes
 Amendment 6 included a lower 50 mg 
dose arm in order to examine canakinumab’s dose response in preventing recurrent 
cardiovascular events, 
 
 
 
 
 
Amendment 6 also increased the sample size to 17,200 patients in order to have the power of 
having at least one dose significant of ≥ 90% and to also have ≥ 80% power for the 50 and 
150 mg doses individually when assuming that all doses have a 20% relative risk reduction. 
Following this amendment, randomized allocation to the four trial arms will be unbalanced in 
order to optimize power, now that three active arms are compared versus a common control 
arm. Overall across both trial parts an approximately 1.5:1:1:1 (placebo: 50 mg canakinumab: 
150 mg canakinumab: 300 mg canakinumab) allocation is targeted. 

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Amendment 6 also clarified the documentation requirements for spontaneous MI inclusion 
criteria, women of child-bearing potential exclusion criteria and tuberculosis exclusion criteria. 
 
 
 
  The analysis plan was updated to insert the evaluation of the 50 
mg dose into the pre-specified closed testing procedure for primary and key secondary 
endpoints.
Amendment 5
Short summary of the amendment rationale and major changes
In order to comply with the European Competent Authorities request in the context of the 
Voluntary Harmonization Procedure (VHP), additional information regarding potential early 
study termination was added to Section 5.5.1.
Amendment 4
Short summary of the amendment rationale and major changes
 additional 
instruction for reporting of specific pre-defined endpoints in Japan was added. This 
instruction applies to Japan only. Section 7.2 describes the specific pre-defined endpoints in 
Japan that require expedited reporting to Novartis Pharma K.K.  
Amendment 3
Short summary of the amendment rationale and major changes
In amendment 1 an early high dose regimen was selected for both the 150 mg and 300 mg 
arms whereby each of these doses would be administered twice, over two week period, at 
randomization (month 0) and at week 2 (month 0.5). To provide a greater separation between 
the active-dose arms, the early high dose regimen in the 150 mg arm has been removed. This 
is in agreement with health authority feedback.
 
 
 
 
 

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Amendment 2
Short summary of the amendment rationale and major changes
In the original protocol all deaths, cardiovascular and non-cardiovascular, were reported as 
potential endpoints and were adjudicated by cardiovascular clinical adjudication committee. 
Only those deaths, which the adjudication committee determined to be non-cardiovascular 
deaths, were reported as SAEs after adjudication was completed.
In order to comply with the recent 21 CFR Parts 312 and 320 regulation and draft FDA 
guidance on Safety Reporting Requirements for INDs and BE/BA Studies, section on 
reporting clinical endpoints (21 CFR 312.32 (c)(5)), protocol section 7.2 has been revised to 
assure that certain selective study drug related non-cardiovascular deaths will be reported both 
as study endpoints and SAEs as soon as study site has been notified of such events without 
waiting for adjudication committee to complete the adjudication process. This revised SAE 
reporting procedure fulfills requirements in the above mentioned regulation and draft FDA 
guidance.
In addition, the definition of pre-diabetes was revised to include impaired fasting glucose, 
FPG 100-125 mg/dL (5.6-6.9 mmol/L), as a criterion together with the original criterion of 
HbA1c 5.7-6.4% based on FDA feedback on IND filing of this protocol. 
Amendment 1
Short summary of the amendment rationale and major changes 
In the original protocol, the dose of canakinumab that provided near maximal biomarker 
suppression was selected as 150 mg quarterly, and an additional lower dose was selected 
below this level at 50 mg quarterly. However, as more efficacy data has been analyzed and 
safety data has accumulated for canakinumab in rheumatoid arthritis and gout patients, safety 
across a wide range of doses has continued to show a well tolerated and safe profile following 
higher dose administration. Thus the opportunity has arisen for the CACZ885M2301 protocol 
to evaluate a higher canakinumab dose since the dose needed for adequate IL-1β 
neutralization within the plaque or systemically in inflammation-based atherosclerosis is not 
established. Therefore, a higher dose might deliver greater efficacy than originally selected 
doses. Thus, as indicated here prior to randomization of any trial participants, the doses to be 
evaluated in CACZ885M2301 will be placebo s.c. quarterly, 150 mg canakinumab s.c. 
quarterly and 300 mg canakinumab s.c. quarterly. In addition, currently available safety data 
provides the opportunity to introduce an early higher dose administration in order to achieve 
early anti-inflammatory benefit in this high risk cardiovascular population. This induction 
period provides drug administration twice over a 2 week period and seeks to achieve optimal 
IL-1β suppression early to provide optimal clinical benefit. Thus, the CACZ885M2301 trial 
regimens will consist of:
(a) placebo s.c. at randomization (month 0), placebo s.c. at week 2 (month 0.5), placebo s.c. at 
week 12 (month 3), and then placebo s.c. quarterly; 

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(b) canakinumab 150 mg s.c. at randomization (month 0), canakinumab 150 mg s.c. at week 2 
(month 0.5), canakinumab 150 mg s.c. at week 12 (month 3), and then canakinumab 150 mg 
s.c. quarterly; and 
(c) canakinumab 300 mg s.c. at randomization (month 0), canakinumab 300 mg s.c. at week 2 
(month 0.5), canakinumab 300 mg s.c. at week 12 (month 3), and then canakinumab 300 mg 
s.c. quarterly. 
Advantages of a 300 mg quarterly dose rather than the 50 mg quarterly dose and an additional 
early dose of canakinumab (either 150 mg or 300 mg) are supported by data that de-couples 
the biomarker dose effect from gene expression dose effect. The proposed dose regimens are 
aimed to provide optimal suppression of potential auto-induction of IL-1β and greater early 
suppression of IL-1β related gene expression.  IL-1β auto-induction has been shown in human 
mononuclear blood, vascular endothelial and vascular smooth muscle cells in vitro and in 
rabbits in vivo where IL-1 has been shown to induce its own gene expression and circulating 
IL-1β level (Dinarello et al. 1987, Warner et al. 1987a, and Warner et al. 1987b).  These 
studies suggested that IL-1 induced IL-1 gene expression may provide a positive feedback 
mechanism in the pathogenesis of atherosclerosis and promote atherosclerosis. This 
consequently suggests that suppression this feedback mechanism may provide benefits in the 
atherosclerotic lesion. To accommodate this change in administration of canakinumab, a week 
2 visit for drug administration and safety assessments was added to the study visit schedule. 
The change in dosing regimen necessitated an update to the definition of the safety set. The 
safety set definition was based on the new Novartis Cardiovascular Clinical Science Unit 
standards. Similarly, the definition of the censoring date was aligned with these standards.  
This definition reflects that if there was contact with a patient without the patient attending a 
visit, then the visit date – in the absence of other information – should be the date of the last 
contact with the patient.    
In addition, the following errors and omissions in the original protocol were corrected: 


Troponin I and creatinine kinase MB fraction were added for patients with elevated total 
creatinine kinase


SAE reporting instructions were corrected to direct investigators to follow instructions 
provided in the investigator folder



Diabetes related definitions used in stratification section were updated


HOMA calculation was removed

A confirmation of elevated ALT/AST and total bilirubin is no longer required at screening

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Protocol synopsis
Title of study: A randomized, double-blind, placebo-controlled, event-driven trial of quarterly 
subcutaneous canakinumab in the prevention of recurrent cardiovascular events among stable post-
myocardial infarction patients with elevated hsCRP
Purpose and rationale: The purpose of this trial is to test the hypothesis that canakinumab treatment 
of patients with MI at least one month prior to study entry and elevated hsCRP will prevent recurrent 
cardiovascular events. A secondary hypothesis, that canakinumab treatment in patients with MI and 
prediabetes, will prevent new onset diabetes (NOD) will also be tested. 
 
  An optional extension to the study will 
be conducted following the completion of the pivotal phase with the purpose to further characterize 
long-term safety on continued exposure to canakinumab in trial participants.
Objectives: 
Primary Objective
The primary objective of this clinical trial is to demonstrate the superiority of at least one dose of 
canakinumab compared to placebo in reducing the risk of recurrent major cardiovascular disease 
events (cardiovascular death, non-fatal MI and stroke) in a population of clinically stable post-MI 
patients with elevated hsCRP receiving standard of care.
Key and other secondary objectives

To demonstrate superiority of canakinumab compared to placebo on the composite endpoint 
of CV death, non-fatal MI, stroke, and hospitalization for unstable angina requiring unplanned 
revascularizations. 

To demonstrate superiority of canakinumab compared to placebo on the endpoint of new 
onset type 2 diabetes among those with pre-diabetes at randomization

To demonstrate superiority of canakinumab compared to placebo on the composite endpoint 
of all-cause mortality, non-fatal MI and stroke.

To demonstrate superiority of canakinumab as compared to placebo on the endpoint of all-
cause mortality

To evaluate the long-term safety of canakinumab therapy in a placebo (standard of care)-
controlled setting

Extension: to obtain further follow-up information on long-term safety on continued exposure to 
canakinumab in trial participants

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Population: Participants eligible for this trial will include male and non-child-bearing potential female 
patients age 18 years and older who (a) have suffered a documented acute myocardial infarction at 
least 30 days before randomization and (b) have evidence of systemic inflammation on the basis of a 
hsCRP > 2 mg/L despite the use of standard of care post-MI medical therapies. Standard of care post-
MI background therapy includes, but is not limited to, lipid lowering, anti-hypertensive, beta blockers, 
and anti-platelet therapy as appropriate. 
The pivotal phase will be an event-driven global trial conducted in the outpatient setting. It is 
anticipated that approximately 1,400 cardiovascular endpoints will accrue during the course of the trial 
(see Section 9.7 for Power Calculations). To accomplish this goal, it is expected that approximately 
17,000 patients will need to be screened in order to randomize approximately 10,000 patients. All 
participants of the pivotal phase who continue to be eligible to receive study drug will be offered the 
option to enter the extension phase.
Key Inclusion/Exclusion criteria: 
Inclusion
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1.
Written informed consent must be obtained before any assessment is performed. 
2.
Male, or Female of non-child-bearing potential 
3.
Age ≥ 18 years at Visit 1.
4.
Documented spontaneous MI (diagnosed according to the universal MI criteria with or without 
evidence of ST segment elevation) at least 30 days before randomization. (Thygesen et al 
2007)

Diagnosis of the qualifying MI should be based on medical history of clinical symptoms 
consistent with myocardial ischemia associated with elevation of cardiac biomarkers 
above the 99th percentile of the upper reference limit (preferably troponin) OR
development of new pathological Q waves regardless of symptoms. For details, refer to 
the Universal Definition of MI (Thygesen et al 2007).

Please see below for documentation requirements. 
a.
Acute MI (hospitalization records): requires documentation of a rise and/or fall of 
cardiac biomarkers (preferably troponin) with at least one value above the 99th 

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percentile of the upper reference limit (URL) or above criteria diagnostic for MI AND 
evidence of myocardial ischemia as demonstrated by at least one of the following :
i.
Symptoms of ischemia
ii.
ECG changes indicative of new ischemia (new ST-T changes or new LBBB)
iii.
Development of pathologic Q waves (please see appendix 3 for definitions of 
pathological Q waves)
iv.
Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality
b.
Prior MI (no hospital records for acute event available): requires documentation of any 
one of the following :
i.
Development of pathological Q waves with or without symptoms (please see 
appendix 3 for definitions of pathological Q waves)
ii.
Imaging evidence of a region of loss of viable myocardium that is thinned and 
fails to contract, in the absence of a non-ischemic cause
iii.
Pathologic findings of a healed or healing MI

Patients with MI resulting from PCI or CABG will not be eligible
5.
Have an hsCRP ≥ 2 mg/L at screening (Visit 1) (collected less than 60 days prior to Visit 2 and 
performed at the central laboratory, which is a minimum of 28 days after qualifying MI or after 
any PCI performed separately from qualifying MI) on stable (at least 4 weeks) long-term 
(cardiovascular) medications.
Exclusion
Patients fulfilling any of the following criteria are not eligible for inclusion in this trial:
1.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test 
2.
Women of child-bearing potential defined as all women physiologically capable of becoming 
pregnant, UNLESS they are

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) or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone or partial or total hysterectomy, only when the 
reproductive status of the woman has been confirmed by follow up hormonal level 
assessment is she considered not of child bearing potential 
[For Croatia only]
[In Croatia, women who are < 50 years of age must have >2 years of amenorrhea or 
minimum of 1 year of amenorrhea with FSH levels of ≥40 IU determined on 2 or more 
occasions at least one month apart]
3.
Any of the following concomitant diseases

Planned coronary revascularization (PCI or CABG) or any other major surgical procedure

Major non-cardiac surgical or major endoscopic procedure within the past 6 months prior 
to Visit 1

Multi-vessel CABG surgery within the past 3 years 

Symptomatic patients with Class IV heart failure (HF) (New York Heart Association 
[NYHA])

Uncontrolled hypertension (defined as an average SBP >160 mmHg or an average   
diastolic blood pressure (DBP) >100 mmHg at Visit 1. Patients are allowed to be re-
evaluated, at the discretion of investigator for this criterion if anti-hypertensive therapy has 
been started or increased as a result of initial screening blood pressure above these limits. 
(Mancia et al 2009).

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
Uncontrolled diabetes as defined by the investigator

Nephrotic syndrome or eGFR < 30 mL/min/1.73 m2 per MDRD formula or kidney 
transplant (regardless of renal function), at Visit 1

Known active or recurrent hepatic disorder (including cirrhosis, hepatitis B and hepatitis C 
(positive or indeterminate central laboratory results), or ALT/AST levels > 3 times ULN or 
total bilirubin > 2 times ULN), Visit 1

Prior malignancy other than basal cell skin carcinoma 
4.
A history of alcohol and/or substance abuse that could interfere with the conduct of the trial
5.
History or evidence of tuberculosis (TB) (active or latent) infection or one of the risk factors for 
TB such as but not limited or exclusive to:
a.
History of any of the following: residence in a congregate setting (e.g. jail or prison, 
homeless shelter, or chronic care facility), substance abuse (e.g. injection or non-injection), 
health-care workers with unprotected exposure to patients who are at high risk of TB or 
patients with TB disease before the identification and correct airborne precautions of the 
patient 
b.
Close contact (i.e. share the same air space in a household or other enclosed 
environment for a prolonged period (days or weeks, not minutes or hours)) with a person 
with active pulmonary TB disease within the last 12 months. 
c.
Evidence of TB (active or latent) infection, at Visit 1, determined by purified protein 
derivative (PPD) skin test and/or QuantiFERON®-TB Gold (QFT-g) assay as defined by  
country guidelines. 
i.
If presence of TB (active or latent) is established, then treatment (according to country 
guidelines for TB treatment or TB treatment with immunomodulating drugs) must have 
been initiated or completed prior to randomization per country guidelines. 
ii.
In the absence of country TB (active or latent) guidelines, the following has been 
demonstrated: TB has been treated adequately with antibiotics, cure can be 
demonstrated, and risk factors resulting in TB exposure and contracting TB have been 
removed (e.g. the patient does not live anymore in high TB exposure setting).  
6.
History of ongoing, chronic or recurrent infectious disease 
7.
Patients with suspected or proven immunocompromised state, including (a) those with 
evidence of Human Immunodeficiency Virus (HIV) infection; Patients on anti-retroviral therapy 
are excluded (b) those with any other medical condition which in the opinion of the investigator 
places the patient at unacceptable risk for participation in immunomodulatory therapy; or (c) 
those requiring systemic or local treatment with any immune modulating agent in doses with 
systemic effects e.g. high dose oral or intravenous steroids (> 20 mg prednisone orally daily 
for > 14 days, > 5 mg prednisone orally daily or equivalent dose of intravenous steroid) or high 
dose methotrexate (> 15 mg weekly). Topical, inhaled, local steroid use in doses that are not 
considered to cause systemic effects are permitted.
8.
Live vaccinations within 3 months prior to the randomization visit or live vaccinations planned 
during the trial.
9.
History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
10. Patients who have received an investigational drug or device within 30 days (inclusive) of 
Visit 1, or who are expected to participate in any other investigational drug or device study 
during the conduct of this trial, except for patients who have an investigational drug eluting 
stent (DES), provided that they have completed the DES trial. FDA/country-specific drug 
regulatory authority approved DES devices are permitted.
11. Any biologic drugs targeting the immune system (for example, TNF blockers, anakinra, 
rituximab, abatacept, tocilizumab) 
12. Any life threatening condition with life expectancy < 5 years, other than vascular disease that 
might prevent the patient from completing the study
Investigational and reference therapy: 

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Following protocol amendment 6 (trial part 2) patients will be assigned to one of the following 4 
treatment arms in a ratio of 1.3 : 1.3 : 1.4 : 2

Canakinumab 300 mg s.c. at randomization, 300 mg s.c. at week 2, 300 mg s.c. at week 12, 
and thereafter 300 mg s.c. quarterly 

Canakinumab 150 mg s.c. at randomization, placebo s.c. at week 2, 150 mg s.c. at week 12, 
and thereafter 150 mg s.c. quarterly 

Canakinumab 50 mg s.c. at randomization, placebo s.c. at week 2, 50 mg s.c. at week 12, 
and thereafter 50 mg s.c. quarterly 

Placebo s.c. at randomization, at week 2, at week 12, and thereafter quarterly
Prior to protocol amendment 6 (trial part 1) patients were assigned to one of the following 3 treatment 
arms in a ratio of 1:1:1

Canakinumab 150 mg s.c. at randomization, placebo s.c. at week 2, 150 mg s.c. at week 12, 
and thereafter 150 mg s.c. quarterly 

Canakinumab 300 mg s.c. at randomization, 300 mg s.c. at week 2, 300 mg s.c. at week 12, 
and thereafter 300 mg s.c. quarterly 

Placebo s.c. at randomization, at week 2, at week 12, and thereafter quarterly
Across trial parts 1 and 2 this is expected to approximately result in a 1:1:1:1.5 allocation.
For patients who are unable to tolerate the protocol-specified dosing intervals, dose interruptions are 
permitted in order to keep the patient on study drug. Patients are encouraged to continue study 
medication; however; they are allowed to interrupt and restart medication at any time during the study 
at the discretion of the investigator.
For the extension phase, all participants except for prediabetic patients will remain on their pivotal
phase assigned treatment arm for the first three extension phase visits (Month 0 to Month 6). After the 
database from the pivotal study is locked they will be switched to an open-label dose of 150 mg 
canakinumab at the fourth scheduled extension visit (visit Month 9) (Figure 3-2). The 150 mg dose will 
be administered until the final dose of canakinumab is implemented at the study sites based on the 
results from the pivotal phase. In contrast to all other participants of the pivotal phase, patients with 
both randomization and pivotal phase EOS prediabetes will enter a 6-month study drug washout at the 
beginning of the extension phase by skipping two doses of their pivotal phase blinded assigned 
treatment arm. At their first visit of the subsequent main drug dispensing period of the extension (visit 
Month 0) they will receive one dose of their assigned pivotal phase blinded treatment arm before they 
switch to the open-label dose of 150 mg canakinumab at their next visit (visit Month 3) (Figure 3-3).
Study design: The study is a Phase 3 multi-center, randomized, parallel group, placebo-controlled, 
double-blind event-driven global clinical trial to evaluate the benefit of quarterly subcutaneous 
canakinumab doses compared to placebo among stable post-MI patients receiving standard of care 
therapy who have been selected for an elevated inflammatory burden as determined by hsCRP > 2 
mg/L. The index qualifying MI must have occurred at least 30 days prior to randomization. Standard of 
care post-MI background therapy includes but is not limited to appropriate lipid lowering, anti-
hypertensive, beta blockers, and anti-platelet therapy as defined by local guidelines. The study is 
composed of a pivotal phase and an extension phase. The pivotal phase is composed of the screening 
period and the double blind treatment period. The extension phase is composed of the study drug 
washout period in prediabetic patients and the main drug dispensing period. PreScreening/Screening 
will take place no earlier than 28 days after the index MI and on stable (at least 4 weeks) long term 
medication. Evaluations will include hsCRP and determination of tuberculosis status among other 
measurements and procedures. After screening visit, patients may be randomized, as soon as, results 
from screening laboratory and other studies are available. However, this can be no earlier than 30 
days after the index MI. For patients who underwent PCI at different hospital admission than the 
qualifying MI; screening can be initiated no earlier than 28 days following this procedure. For patients 
who have history of CABG; screening can be initiated no earlier than 3 years after the procedure 
regardless of timing of the qualifying MI.

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Randomization will be stratified by time since most recent index myocardial infarction (30 days to <6 
months and ≥6 months). Recruitment will target approximately 50% of randomized patients with index 
MI 30 days to 12 months prior to randomization and 50% of randomized patients with index MI > 12 
months prior to randomization. The Steering Committee and Sponsor will monitor the patient profiles 
during recruitment phase and may increase or restrict enrollment of certain sub-groups of patients to 
avoid imbalances. There will be no upper limit for post MI for inclusion into the trial. The trial is event 
driven and designed to complete when a total of 1,400 patients have experienced a primary 
cardiovascular endpoint. Double blind treatment will be continued until the target number of primary 
cardiovascular endpoints has been reached. Sites will then be notified to have all patients return to 
complete a pivotal phase EOS visit. The elapsed calendar time to reach conclusion of the study is 
estimated to be approximately 6 years of treatment and follow-up from the start of enrollment in the 
trial to the occurrence of 1,400 confirmed adjudicated cardiovascular events. 
Interim analyses (IA) of efficacy, futility and safety will be carried out during the study in order to avoid 
exposing study patients to ineffective treatment or undue risks or to allow study discontinuation in case 
of overwhelming efficacy. Two interim analyses of efficacy will be performed when approximately 50% 
of the target number of patients with primary endpoints have been accumulated and the second one 
when approximately 75% of the planned number of patients with primary endpoints are available. A 
futility analysis may be performed earlier than the first planned efficacy IA (at approximately 50% 
primary events) but only after a sufficient number of primary events are accrued, i.e., >25%.  
Following the completion of the pivotal phase, every patient who continues to be eligible to receive 
study drug will be offered the option to continue study drug treatment during the extension phase. The 
objective of the extension phase is to further characterize long-term safety on continued exposure to 
canakinumab in trial participants. Consenting patients will be scheduled for visits to dispense study 
drug and to collect safety data at 3-month intervals. All participants except for prediabetic patients will 
remain on their pivotal phase assigned treatment arm for the first three extension phase visits (Month 
0 to Month 6). After the database from the pivotal study is locked they will be switched to an open-label 
dose of 150 mg canakinumab at the fourth scheduled extension visit (visit Month 9) (Figure 3-2). The 
final canakinumab dose will be based on the results from the pivotal phase. The transition to an 
intermediate dose of 150 mg will avoid further placebo treatment until the final dose of canakinumab is 
implemented at the study sites. In contrast to all other participants of the pivotal phase, patients with 
both randomization and pivotal phase EOS prediabetes will enter a 6-month study drug washout at the 
beginning of the extension phase by skipping two doses of their pivotal phase blinded assigned 
treatment arm. At their first visit of the subsequent main drug dispensing period of the extension (visit 
Month 0) they will receive one dose of their assigned pivotal phase blinded treatment arm before they 
switch to the open-label dose of 150 mg canakinumab at their next visit (visit Month 3) (Figure 3-3).
 
 
The extension 
phase will collect all safety events (serious and non-serious AEs) including malignancies, infections 
and major cardiovascular adverse events that were defined as the primary endpoint of the pivotal 
phase. No adjudication of events will be performed, neither for CV events nor serious infections or 
malignancies during the extension phase. The extension phase will continue in an individual country 
for a minimum of two years from the date of the first patients enrolled in that country. The maximum 
duration of the extension phase will be 2.5 years from the date of the first patient enrolled in that 
country or until marketed product is available in that country, whichever comes first. While the 
extension phase is then deemed complete the safety follow-up is anticipated to be continued in 
registries following study results and discussion with Health Authorities.
Efficacy assessments: 
Primary efficacy assessment:
The primary endpoint is defined as the time to the first event of a major cardiovascular event (MACE) 
occurring during the double-blind treatment period, which is a composite of CV death, non-fatal MI, 

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and stroke. An independent adjudication committee that is blinded to treatment assignments will 
review and adjudicate all clinical events that constitute the composite endpoint.
Key secondary efficacy assessments: 
Key secondary efficacy assessments will comprise:

Time to first event of a composite cardiovascular endpoint consisting of the primary endpoint, 
and hospitalization for unstable angina requiring unplanned revascularization

Time to new onset type 2 diabetes among those with pre-diabetes at randomization (time to 
NOD) 
Other secondary efficacy assessments:
Other secondary efficacy assessments will comprise 

Time to first event of, non-fatal MI, stroke and all-cause mortality composite

Time to all-cause mortality
Safety Assessments:

Laboratory evaluations 

Height, weight and waist circumference

Adverse events and serious adverse events, including cardiovascular events, malignancies, 
and infections

Discontinuation due to AEs

Hypoglycemia events

Injection site reactions

Physical Examination

 

Vital Signs

ECG
Serious allergies/immunological events, serious infections, and malignancies adverse events will be 
monitored carefully during this trial because these adverse events represent hypothetical mechanism 
of action related risks of canakinumab therapy. 
The extension phase will collect all safety events (serious and non-serious AEs) including 
malignancies, infections and major cardiovascular adverse events that were defined as the primary 
endpoint of the pivotal phase. No adjudication of events will be performed, neither for CV events nor 
serious infections or malignancies.
Data analysis: 

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The primary statistical hypotheses are:

H11: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 300 
mg dose group is greater than or equal to that in the placebo group

H21: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 150 
mg dose group is greater than or equal to that in the placebo group

H31: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 50 
mg dose group is greater than or equal to that in the placebo group
Each tested versus the one-sided alternative that the hazard rate is smaller for the respective active 
dose group than in the placebo group.
These hypotheses will be tested by comparing each dose to placebo with a log-rank test stratified by 
time since index MI and by trial part using exact method for handling ties on the FAS according to the 
intent-to-treat principle. The family-wise error rate will be controlled at the two interim analyses and the 
final analysis using a closed testing procedure that initially assigns all the available significance level to 
the primary null hypotheses relating to the three doses. Key secondary endpoints for a dose are only 
tested after the rejection of the primary null hypothesis for that dose.
A fixed Bonferroni split of the one sided alpha will be used to account for the two efficacy interim 
analyses and the final analysis, with a significance level of 0.01% for the first efficacy interim analysis, 
0.04% for the second efficacy interim analysis and 2.45% for the final analysis. In this fashion the 
family-wise type I error rate will be controlled at the one-sided 2.5% level. This constitutes an 
equivalent level of evidence as the two-sided 5% level and two-sided p-values will also be reported. 
The hazard ratios and their associated confidence intervals will be estimated by means of a Cox 
proportional-hazards model stratified by time since index MI (< 6 months, ≥ 6 months) and by trial part 
using treatment (canakinumab doses and placebo) as a factor in the model using exact method for 
handling ties. Kaplan-Meier type plots will be presented overall and separately by trial part to 
summarize the time to first event in the composite endpoint, by presenting the time-dependent 
cumulative frequency and percentage of patients who reach the primary composite endpoint by 
treatment group.
The components of the composite primary efficacy endpoint (CV death, fatal or non-fatal MI, fatal or 
stroke) will also be analyzed individually in order to evaluate their contributions to the overall treatment 
effect. 
Based on the FAS, all key secondary efficacy variables will be analyzed with a log-rank test stratified 
by time since index MI and by trial part, and displayed by means of Kaplan-Meier type plots according 
to treatment overall and by trial part.
The secondary efficacy variable corresponding to new onset type 2 diabetes in patients with pre-
diabetes at randomization will be the time from randomization to the first occurrence of repeated FPG 
≥ 126 mg/dL (≥ 7.0 mmol/L) or of a repeated HbA1c > 6.5% or of the start of new anti-diabetic 
medication. Due to the discrete nature of the time points when new onset of type 2 diabetes can be 
determined, events identified at the same visit time point for different patients will be considered as 
tied events and exact method for handling ties will be used.
 
 
 
 
Safety
The incidence of adverse events (new or worsened) will be summarized by primary system organ 
class (SOC), preferred term, severity and relationship to study drug. The incidence of death, SAEs, 
and AEs leading to discontinuation will be summarized separately by primary system organ class and 
preferred term. Selected SAEs will be narrated. 

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The incidence of adverse events related to cardiovascular events in constellations relevant for a 
description of safety and death, as well as serious infections and malignancy will be specifically 
investigated. Appropriate time to event assessments will be used if warranted.
Laboratory data will be summarized by shift tables and categorical analyses using extended normal 
ranges if thresholds of interest are identified based on baseline to most extreme post-baseline value, 
with summary statistics of raw and change from baseline by visits. Furthermore, notable values will be 
flagged in data listings.
From the extension phase, the incidence of adverse events (new or worsening) will be summarized by 
primary system organ class (SOC), preferred term, severity and relationship to study drug. SAEs and 
AEs leading to discontinuation will be summarized separately by primary system organ class and 
preferred term. The incidence of death will be summarized by the primary cause. 
Sample Size Calculation 
With a sample size of approximately 10,000 randomized patients and assigned in a 1:1:1 allocation 
ratio to canakinumab 150 mg, canakinumab 300 mg, and placebo in trial part 1 and in a 2 : 1.4 : 1.3 : 
1.3 allocation ratio to placebo, canakinumab 50 mg, canakinumab 150 mg, and canakinumab 300 mg 
in trial part 2, it is expected that 1,400 patients will experience a primary endpoint approximately 6 
years after study initiation. 1,400 endpoints are necessary to achieve a power ≥ 90% to demonstrate 
the superiority of at least one dose of canakinumab compared to placebo on the primary endpoint 
assuming a relative hazard reduction of 20% for all active doses and to also have ≥ 80% power for the 
50 and 150 mg doses individually.
No sample size calculation was performed for the extension phase, because the key objective of the 
extension phase is long-term safety assessment in participants of the pivotal phase.

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1
Introduction
1.1
Background
Atherosclerosis is a disease characterized by chronically high inflammatory state. Arterial 
inflammation and endothelial dysfunction play key roles at all stages of the atherothrombotic 
process. Inflammatory mediators are intimately implicated with the cascade of events leading 
to atherosclerotic plaque initiation, progression and rupture. Vascular endothelial cells express 
a variety of adhesion molecules that recruit monocytes when chronically exposed to noxious 
stimuli or pathological conditions. Adverse conditions such as hyperlipidemia are associated 
with enrichment of a pro-inflammatory subset of monocytes. These monocytes apparently 
enter the intima under the influence of chemotactic stimuli and engulf modified low density 
lipoprotein (LDL) and cholesterol crystals (Duewell et al 2010). The material internalized by 
phagocytes induces phagolysosomal damage and subsequent leakage of contents into cytosol 
to activate inflammasomes and caspase 1, and consequently the generation of interleukin-1b 
(IL-1) from pro-interleukin-1.
Interleukins are key mediators in the chronic vascular inflammatory response in 
cardiovascular (CV) disease and have been demonstrated in animal models and in humans to 
be potent modulators of pro-inflammatory processes. The fact that these cytokines and their 
receptors are highly expressed and are functional in almost all cell types implicated in the 
pathogenesis of atherosclerosis including smooth muscle cells, certain subset of macrophages 
and T cells as well as endothelium support the role of interleukins in vascular disease. For 
example, IL-1β is a potent smooth muscle cell mitogen, an activator of endothelial cells and 
increases extra cellular matrix and collagen deposition, which plays a role in plaque burden 
and arterial thickening. Furthermore, lack of IL-1β or ablation of IL-1 receptor has been 
shown to decrease severity of atherosclerosis in apoE deficient mice. Thus, antagonism of the 
IL-1β mediated inflammation is a primary and attractive target for ameliorating the vessel 
wall inflammation associated with atherosclerosis. 
Canakinumab (ACZ885) is a fully human monoclonal anti-human IL-1β antibody of the 
IgG1/k isotype, being developed for the treatment of IL-1β driven inflammatory diseases. It is 
designed to bind to human IL-1β and thus blocks the interaction of this cytokine with its 
receptors. The antagonism of the IL-1β mediated inflammation using canakinumab in 
lowering high sensitivity C-reactive protein (hs-CRP) and other inflammatory marker levels 
has shown an acute phase response in patients with Cryopyrin-Associated Periodic Syndrome 
(CAPS) and rheumatoid arthritis (data on file). 
 
 
Therefore, canakinumab is expected to reduce the risk of future occurrence of major 
cardiovascular events in patients with recent past myocardial infarction (MI) by preventing 
IL-1β mediated vascular wall inflammation and endothelial dysfunction. 
Atherosclerotic vascular disease is the primary cause of morbidity and mortality in individuals 
with and without T2DM. The progression of atherosclerosis from endothelial dysfunction to 
vascular occlusion or to plaque rupture is the underlying mechanism responsible for many 

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debilitating and life-threatening diseases such as MI, stroke and peripheral vascular disease 
(PVD). These diseases occur at higher frequency in T2DM patients and continue to increase 
despite use of current optimal therapies. There is also higher mortality rate after first MI in 
patients with T2DM compared to those without T2DM. Mortality associated with impaired 
glucose tolerance is 1.96 times higher compared to normal glucose tolerance. Thus, novel 
therapies that may improve vascular function, decrease atherosclerotic burden, and translate to 
a decrease in cardiovascular events would fill a significant unmet medical need.
T2DM is also a disease that is characterized by a high inflammatory state. Pre-clinical data 
suggests IL-1β is of key importance in the progressive functional impairment and destruction 
of β-cells in type 2 diabetes. Pancreatic cells secrete IL-1in response to elevated glucose 
exposure promoting further impairment of cellular viability via an autocrine action. IL-1
antagonism inhibits cell death, promotes cell proliferation, potentiates cell glucose-
induced insulin secretion and improves insulin sensitivity. Blocking IL-1β activity with an IL-
1 receptor antagonist as well as a neutralizing IL-1β antibody in clinical trials reduced 
glycosylated hemoglobin (HbA1c). Neutralization of IL-1β activity in the pancreatic islets is 
thus emerging as an attractive target for the treatment and prevention of type 2 diabetes. For 
T2DM prevention canakinumab’s primary direct action is expected to prevent the IL-1β 
mediated destruction of pancreatic β-cells and thus prevent or delay progression of disease, 
which to date is a completely unmet need.
Therefore, canakinumab is expected to prevent new onset T2DM in patients with a recent past 
MI and that are pre-diabetic, and who are at risk of developing T2DM.
As demonstrated in a comprehensive 2010 meta-analysis of 54 prospective cohort studies, the 
inflammatory biomarker hsCRP is an independent risk factor for future cardiovascular events 
that (a) has a magnitude of effect similar to or larger than that of blood pressure or cholesterol 
and (b) has long-term stability and reproducibility at least as good as these widely-accepted 
risk factors (Kaptoge et al 2010). Abundant clinical trial data further demonstrate that 
persistent elevations of hsCRP are a major risk factor of recurrent vascular risk following 
myocardial infarction; for example, as demonstrated in the PROVE IT-TIMI 22 (Ridker et al 
2005) and A-to-Z (Morrow et al 2006) trials. In both trials patients with known vascular 
disease and persistent elevation of hsCRP were at roughly double the risk for recurrent events 
compared to those with normal hsCRP levels. Further, stratification by hsCRP has proven 
highly effective in determining populations in who added cardiovascular benefits are observed 
with the use of efficacious lipid lowering agents, which also possess, anti-inflammatory 
properties. This has been proven in primary prevention studies as including the 
AFCAPS/TexCAPS (Ridker et al 2001) and JUPITER trials (Ridker et al 2008, Ridker et al 
2009) as well as in the setting of congestive heart failure (CHF) in the CORONA trial where 
efficacy of intervention was seen only among those with hsCRP ≥ 2 mg/L. Indeed, in this 
latter example, had stratification been done by hsCRP on an a priori basis, the trial would 
have been reported out as an overwhelming positive rather than as a null finding (McMurray 
et al 2009)
A direct anti-inflammatory agent could, in theory, be tested at any stage of the 
atherothrombotic process. However, the most appropriate population to test this hypothesis is 
one in which (a) patients are known to be at increased risk despite current therapy, and (b) 
there is biochemical evidence of a persistent heightened inflammatory response despite usual 

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care. Recognizing these constraints, a primary prevention population would be infeasible due 
to the exceptionally large sample size required and because an extremely low side effect 
profile is typically required in that setting. In contrast, patients who have survived a MI are 
clinically stable, and who have persistently elevated hsCRP levels despite aggressive 
treatment are an optimal population in which to undertake a test of the inflammatory 
hypothesis of atherothrombosis. This population is no longer at risk for plaque rupture due to 
altered wound healing, yet remains at high risk for recurrent vascular events despite use of all 
accepted therapies. If alternatively designed to enroll post-MI patients without regard to 
hsCRP, the proposed trial would substantially lose power and would expose large numbers of 
individuals with already controlled inflammation to IL-1β inhibition. All of these effects 
would result in an adverse shift in the benefit to risk ratio as well as greatly increase study 
costs. 
1.2
Purpose 
The purpose of this trial is to test the hypothesis that canakinumab treatment of patients with 
MI at least one month prior to study entry and elevated hsCRP will prevent recurrent 
cardiovascular events. A secondary hypothesis, that canakinumab treatment in patients with 
MI and prediabetes, will prevent new onset diabetes (NOD) will also be tested. 
 
The purpose of the extension phase is to collect additional long-term safety data on continued 
exposure to canakinumab in patients who participated in the pivotal phase.
2
Study objectives
2.1
Primary objective
The primary objective of this clinical trial is to demonstrate the superiority of at least one dose 
of canakinumab compared to placebo in reducing the risk of recurrent major cardiovascular 
disease events (cardiovascular death, non-fatal MI and stroke) in a population of clinically 
stable post-MI patients with elevated hsCRP receiving standard of care.
2.2
Secondary objectives
Key secondary efficacy objectives

To demonstrate superiority of canakinumab compared to placebo on the composite 
endpoint of CV death, non-fatal MI, stroke, and hospitalization for unstable angina 
requiring unplanned revascularizations. 

To demonstrate superiority of canakinumab compared to placebo on the endpoint of new 
onset type 2 diabetes among those with pre-diabetes at randomization
Other secondary efficacy objectives

To demonstrate superiority of canakinumab compared to placebo on the composite 
endpoint of all-cause mortality, non-fatal MI and stroke.

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
To demonstrate superiority of canakinumab as compared to placebo on the endpoint of all-
cause mortality
Safety objectives

To evaluate the long-term safety of canakinumab therapy in a placebo(standard of care) -
controlled setting 

Extension phase: to obtain further follow-up information on long-term safety on continued 
exposure to canakinumab in trial participants

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3
Investigational plan
3.1
Study design
This study is a Phase 3, multi-center, randomized, parallel group, placebo-controlled, double-
blind event-driven global clinical trial. The CANTOS (Canakinumab Anti-inflammatory 
Thrombosis Outcomes Study) study is designed to evaluate the benefit of quarterly doses of 
50 mg and 150 mg canakinumab and an induction followed by quarterly dose of 300 mg 
canakinumab subcutaneously compared to placebo in stable post-MI patients receiving 
standard of care therapy who have been selected by an elevated inflammatory burden as 
determined by hsCRP ≥ 2 mg/L. The index qualifying MI must have occurred at least 30 days 
prior to randomization. There is no upper limit for post- MI for inclusion into the study. 
Standard of care post-MI background therapy includes but is not limited to appropriate lipid 
lowering, anti-hypertensive, beta blockers, and anti-platelet therapy as defined by local 
guidelines. Patients should also be instructed to follow heart healthy (low fat) diet and regular 
exercise program. 
Pre-Screening: Pre-screening is a key element to successfully identifying the correct 
patients to be screened for this clinical study. All patients should have an available hsCRP 
value prior to the time of screening. The available hsCRP value should be at least 28 days 
after a cardiovascular event or procedure or major surgical procedure, and must be less than 
60 calendar days prior to screening (Note: centrally-performed prescreen hsCRP results must 
be obtained less than 60 calendar days prior to Visit 2 to be used to evaluate Inclusion 
criterion 5, Section 4.1). 
The Pre-screening visit should be used after review of the patient’s charts to determine 
patient’s eligibility and to obtain an hsCRP value.
The Pre-screening visit will take place no earlier than:

28 days after the index MI and on stable long term medication. 

28 days after a PCI if it was during a different hospital admission than the qualifying MI.  
Pre-screening can only be initiated following this procedure. 

3 years post a Multi-vessel CABG procedure regardless of timing of the qualifying MI 
Patients with a prescreen hsCRP ≥ 2 mg/L from the central laboratory do not require an 
hsCRP measurement at Visit 1, provided the prescreen hsCRP blood sample was drawn less 
than 60 days prior to Visit 2 and the patient is on stable (at least 4 weeks) long term 
medications. All pre-screened patients must be called into the Interactive Voice Response 
System/Interactive Web Response System (IVRS/IWRS).  Note: The Pre-screening visit 
should not occur and instead be rescheduled if the patient presents with an acute viral or 
bacterial infection at the Pre-screen visit.
Screening: Screening will take place no earlier than:

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
28 days after the index MI and on stable long term medication. 

28 days after a PCI if it was during a different hospital admission than the qualifying MI.  
Screening can only be initiated following this procedure. 

3 years post a Multi-vessel CABG procedure regardless of timing of the qualifying MI.
All screened patients must be called into the IVRS/IWRS. Screening evaluations will include 
determination of tuberculosis status, other measurements and procedures, and hsCRP 
measurement in patients who proceeded directly to Visit 1 due to a prior (non-centrally 
performed) hsCRP, ≥ 2mg/L performed 60 days to prior Visit 1. After the screening visit, 
patients may be randomized as soon as results from the screening laboratory and other studies 
are available. However, this can be no earlier than 30 days after the index MI. Note: For 
patients who require an hsCRP measurement at Visit 1 only, the Screening Visit/Visit 1 
should not occur and instead be rescheduled if the patient presents with an acute viral or 
bacterial infection at Visit 1.
The time between screening and randomization should be approximately 4 weeks with the 
qualifying centrally-performed hsCRP obtained no less than 60 days prior to Visit 2 (Note: the 
maximum amount of time between Visit 1 and Visit 2 should not exceed 60 days with the 
exception of those who initiate treatment for tuberculosis (TB) as described below). Patients 
may be randomized as soon as eligibility assessments have been completed. Generally 
rescreening is not allowed. However, patients may be re-evaluated as noted in the inclusion 
and exclusion sections (applicable for out of range systolic and diastolic blood pressure and 
patients requiring TB treatment. Note: Patients who initiate treatment for TB and who per 
country guidelines can be randomized into the trial < 60 days after starting TB treatment, must 
have a repeat hsCRP performed just prior to randomization which is ≥ 2 mg/L; those who can 
be randomized into the trial > 60 days after starting TB treatment, must be re-evaluated just 
prior to randomization for all Inclusion/Exclusion criteria including central laboratory 
evaluations).  Patients re-evaluated will retain their screening number and be randomized or 
screen failed based upon the result of the re-evaluation. 
Randomization: Randomization will be stratified by time since most recent index 
myocardial infarction (30 days to <6 months and ≥6 months). Recruitment will target 
approximately 50% of randomized patients with index MI 30 days to 12 months prior to 
randomization and 50% of randomized patients with index MI > 12 months prior to 
randomization.  Patients should be hemodynamically stable at the time of randomization. The 
Steering Committee and Sponsor will monitor the patient profiles during recruitment phase 
and may increase or restrict enrollment of certain sub-groups of patients to avoid imbalances. 
There will be no upper limit for post MI for inclusion into the trial. Once randomized, patients 
will return to the clinic for scheduled visits as shown in the study assessment schedule. Some 
assessments at these visits will include physical examinations, vital sign measurements, 
electrocardiogram (ECG), instruction on how to follow a heart healthy (low fat) diet and 
regular exercise program and clinical laboratory measurements including glucose control, 
lipids, 
 and routine safety assessments. 
Patients will have scheduled assessments at months 0.5, 1.5, and 3 after randomization and 
quarterly visits thereafter to evaluate safety and the occurrence of any trial endpoints, as well 
as, to receive scheduled (excluding month 1.5) subcutaneous injections of active therapy and/ 

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or placebo. 
 
 
 
 
The pivotal phase is event driven and designed to complete when a total of 1,400 patients 
have experienced a primary cardiovascular endpoint. Double blind treatment will be 
continued until the target number of primary cardiovascular endpoints has been reached. Sites 
will then be notified to have all patients return to complete an pivotal phase EOS visit. The 
elapsed calendar time to reach conclusion of the study is estimated to be approximately 6 
years of treatment and follow-up from the start of enrollment in the trial to when 1,400 
patients have had a confirmed adjudicated cardiovascular event. 
Extension phase: At the first visit of the extension phase (visit Month 0), every trial 
participant who continues to be eligible to receive study drug will be offered the option to 
continue study drug treatment during the extension phase. Consenting patients will remain at 
the 3-month intervals between study visits as shown in the study assessment schedule for the 
extension phase (Table 6-2 and Table 6-3). All patients must be called into the IVRS/IWRS at 
every visit throughout the extension phase. For all participants except for prediabetic patients 
the first visit of the extension phase at Month 0 should occur on the same day as the pivotal 
phase EOS visit. In case the last drug administration of the pivotal phase occurred within 4 
weeks before the pivotal phase EOS visit, the study drug administration at the extension phase
Month 0 visit will be skipped and the first injection as part of the extension phase will be 
performed at the Month 3 visit. All participants except for those with prediabetes will remain 
on their pivotal phase assigned treatment arm for the first three extension phase visits (Month 
0 to Month 6). After the database from the pivotal study is locked they will be switched to an 
open-label dose of 150 mg canakinumab at the fourth extension phase visit (Month 9) (Figure 
3-2). The 150 mg dose is predicted to have the highest likelihood of having the most favorable 
benefit: risk ratio based on biomarker and clinical data from phase II studies in Type 2 
diabetics. The final canakinumab dose will be based on the results from the pivotal phase. The 
transition to an intermediate dose of 150 mg will avoid further placebo treatment until the 
final dose of canakinumab is implemented at the study sites. In contrast to all other 
participants of the pivotal phase, patients with both randomization and EOS prediabetes will 
enter a 6-month study drug washout at the beginning of the extension phase by skipping two
doses of their pivotal phase blinded assigned treatment arm. At their first visit of the 
subsequent main drug dispensing period of the extension (visit Month 0) they will receive one 
dose of their assigned pivotal phase blinded treatment arm before they switch to the open-
label dose of 150 mg canakinumab at their next visit (visit Month 3 (Figure 3-3). The pivotal 
phase EOS glycemic status will be assessed based on the last HbA1c and fasting plasma 
glucose (FPG) data available at the EOS visit. For participants of the prediabetes washout, the 
first visit of the extension at Month 0 should occur on the same day as the End of Prediabetes 
Washout visit. The extension phase will collect all safety events (serious and non-serious AEs) 
reported and will no longer adjudicate any pre-specified efficacy or safety events. In addition 
to safety assessments at every visit, annual vital sign measurements will be performed 
according to the extension phase assessment schedule. The extension phase will continue in 
an individual country for a minimum of two years from the date of the first patients enrolled 

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in that country. The maximum duration of the extension phase will be 2.5 years from the date 
of the first patient enrolled in that country or until marketed product is available in that 
country, whichever comes first. Once study closeout date is determined, the site staff is 
contacted to have the patients return for their extension phase EOS visit. While the extension 
phase is then deemed complete the safety follow-up is anticipated to be continued in registries 
following study results and discussion with Health Authorities.
Patients who discontinue study treatment
Every attempt to determine follow-up status of patients who discontinue study treatment, for 
any reason prior to the completion of the trial, must be made unless prohibited by local 
regulations. It is required that these patients are contacted per study schedule (i.e., every 3 
months) to ensure all endpoints (safety and efficacy) are collected and reported. It will be at 
the discretion of the site staff to determine if these patients will be contacted by phone or 
attend the regularly scheduled visits. 
For patients whose treatment is stopped as a result of a Data Monitoring Committee (DMC)
recommendation to suspend treatment in one dose group, follow-up for cardiovascular (CV) 
and safety events will continue. Since these patients will not receive further study medication, 
less frequent follow-up will be conducted every 6 months. Continued follow-up will likely 
enhance understanding of the safety of the other dose groups. 
Any patient who stops study treatment, withdraws consent (if re-consented) or becomes no 
longer lost to follow up, is allowed to restart the study treatment at the discretion of the 
investigator regardless of length of time off study treatment.
Extension phase: for patients whose status is unclear because they fail to appear for study 
visits without stating an intention to withdraw, the investigator should show "due diligence" 
by contacting the patient, family or family physician as agreed in the informed consent and by 
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. A patient should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.
End of Study Follow-up for all prediabetic patients
Once all study endpoints of the pivotal phase have been reached and the site staff is contacted 
to have all patients return for their pivotal phase EOS visit, any patient with a prediabetic 
status at both randomization and at pivotal phase EOS visit (based on last lab results available 
at the EOS visit), will enter into an additional 6-month washout without study drug treatment
by skipping two doses of their pivotal phase blinded assigned treatment arm. At the end of the 
study drug washout, HbA1c and FPG will be performed along with the other study procedures 
shown in Table 6-3. If no HbA1c value is available from the End of Prediabetes Washout visit 
or if a diabetes diagnosis is only based on one FPG value of ≥ 126 mg/dL (≥7 mmol/L) from
the End of Prediabetes Washout visit, an unscheduled visit should be conducted within 6 
weeks. The purpose of this washout period is to assess to what extent a potential lower 
incidence of diabetes diagnoses observed on  canakinumab relative to placebo during pivotal 
phase double-blind treatment is explained by a true delay in progression to diabetes as 
opposed to a lowering of FPG and HbA1c that masks diabetes but does not persist after the 

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washout. At their first visit of the subsequent main drug dispensing period of the extension
(visit Month 0) study drug washout participants will receive one dose of their assigned pivotal 
phase blinded treatment arm before they switch to the open-label dose of 150 mg 
canakinumab at their next visit (visit Month 3) (Figure 3-3).
No adjudication of NOD will be performed during the extension phase.
Sub-Studies
All patients who suffer a stroke during the double-blind period of the pivotal phase will 
participate in the, Post-Stroke Functional Assessment Sub-Study; see Section 6.6.5 for further 
details.
The CACZ885M2301S1 imaging sub-study (to evaluate the effect of quarterly subcutaneous 
canakinumab treatment for 24 months versus placebo, on top of standard of care, on the 
carotid plaque burden measured by vascular MRI in approximately 330 patients) and the 
CACZ885M2301S2 oral glucose tolerance test sub-study (to determine whether canakinumab 
compared to placebo, on top of standard of care, increases insulin secretion and insulin 
sensitivity in approximately 300 patients with type 2 diabetes) were prematurely terminated.  
The termination was not due to safety or efficacy concerns.  
Interim Analysis
Interim analyses will be conducted for this trial; please see Section 3.5 and Section 9.8 for 
details. 

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Figure 3-1
Study design pivotal phase
The pivotal phase is composed of the screening period and the double blind treatment period.
†- canakinumab 300 mg s.c. induction at randomization (month 0) and week 2 (month 0.5), and then 
300 mg s.c. quarterly beginning at week 12.
Figure 3-2
Study design of extension phase for patients not participating in 
study drug washout
For patients not participating in the 6-month study drug washout period, the extension phase 
is only composed of the main drug dispensing period.

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§plus Standard of Care therapy
***The extension phase will continue in an individual country for a minimum of two years from the date 
of the first patients enrolled in that country. The maximum duration of the extension phase will be 2.5 
years from the date of the first patient enrolled in that country or until marketed product is available in 
that country, whichever comes first. 
Patients who choose to participate in the extension phase will remain on their pivotal phase 
blinded assigned treatment arm for the first three extension phase visits (Month 0 to Month 6). 
After the database from the pivotal study is locked they will be switched to an open-label dose 
of 150 mg canakinumab at the fourth extension visit (Month 9). The final canakinumab dose 
will be based on the results from the pivotal phase. The transition to an intermediate dose of 
150 mg will avoid further placebo treatment until the final dose of canakinumab is 
implemented at the study sites.
Figure 3-3
Study design of extension phase for prediabetic patients
For patients with prediabetic status at both randomization and pivotal phase EOS visit the 
extension phase is composed of the study drug washout period and the main drug dispensing 
period.

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§plus Standard of Care therapy
*Only patients with prediabetic status from both randomization and pivotal phase EOS visit will enter 
the study drug washout.
**After the End of Prediabetes Washout visit, the patients will enter the subsequent main drug 
dispensing period of the extension. The first visit of the main drug dispensing period should occur on 
the same day as the End of Prediabetes Washout visit.
***The extension phase will continue in an individual country for a minimum of two years from the date 
of the first patients enrolled in that country. The maximum duration of the extension phase will be 2.5 
years from the date of the first patient enrolled in that country or until marketed product is available in 
that country, whichever comes first. 
Prediabetic patients will participate in a 6-month study drug washout at the beginning of the 
extension phase by skipping two doses of their pivotal phase blinded assigned treatment arm.
At their first visit of the subsequent main drug dispensing period of the extension (visit Month 
0) study drug washout participants will receive one dose of their assigned pivotal phase 
blinded treatment arm before they switch to the open-label dose of 150 mg canakinumab at 
their next visit (visit Month 3, as shown in Figure 3-3).
3.2
Rationale of study design
This study has been designed as a multi-center, randomized, parallel group, placebo-
controlled, double-blind, event-driven trial to provide definitive evidence on the effects of 
canakinumab on cardiovascular adverse events in patients with recent MI and elevated 
inflammatory burden as evidenced by elevated hsCRP. This study will also measure the 
effects of canakinumab on the conversion to NOD as a secondary endpoint. This study design 
is the most robust clinical trial design to test the hypothesis that anti-inflammatory treatment 
with canakinumab will reduce major adverse cardiovascular events. 

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The design of the extension phase is appropriate to enable the collection of additional long-
term safety data for the investigational drug and to provide patients the opportunity to receive 
treatment with canakinumab until marketed product is available. The study design also allows 
to evaluate changes in glycemic status following study drug washout in patients with 
prediabetes in order to assess the durability of any potential antidiabetic effect after study drug 
discontinuation. Enrollment will be available to all patients who participated in the pivotal 
phase and who continue to be eligible to receive study drug.
3.3
Rationale of dose/regimen, duration of treatment
Canakinumab 50 mg and 150 mg quarterly
The 50 mg and 150 mg canakinumab dosing schedule has been selected on the basis of 
anticipated efficacy, safety, and biomarker modeling data. In phase II development, all 
canakinumab doses up to 300 mg s.c. every other week have been found safe, well tolerated, 
and free of adverse lipid effects. Canakinumab efficacy in lowering hsCRP, IL-6 and 
fibrinogen was assessed based on studies CACZ885A2213 and CACZ885I2202. The 
maximum efficacy of hsCRP lowering in study CACZ885I2202 was at approximately 50 - 75 
mg of canakinumab monthly, with persistent lowering across a wide range of higher doses. 
Therefore, 50 mg monthly as fully efficacious dose and 15 mg monthly as submaximal dose 
were selected for further development. The optimal dosing interval was examined using data 
from CACZ885A2213 (diabetes) and from gout studies with canakinumab (data on file). 
These studies indicated that canakinumab effect on lowering hsCRP was durable for up to 
approximately 3 months. Further, modeling and simulation methods showed that 150 mg 
quarterly dosing had similar free IL-1β suppression compared to 50 mg monthly dosing and 
50 mg quarterly dosing had similar free IL-1β suppression compared to 15 mg monthly dosing. 
This conclusion was reached by comparing the doses and regimens based on both the time for 
maintenance of suppression and the fraction of patients below a specified suppression 
threshold of ’tissue free’ IL-1β. Therefore, canakinumab 50 mg and 150 mg quarterly 
administration were selected for the doses in this study, CACZ885M2301. The selected doses 
allow examination canakinumab dose response in preventing recurrent cardiovascular events 
and to determine if a lower dose than 150 mg would have a favorable risk benefit ratio.
Canakinumab 300 mg quarterly
Given evidence of safety across a wide dosing range, a 300 mg quarterly dosing schedule for 
canakinumab has also been developed for CACZ885M2301. This allows evaluation of a 
higher canakinumab dose since the dose needed for adequate IL-1β neutralization within the 
plaque or systemically in inflammation-based atherosclerosis is not established. Therefore, a 
higher dose may deliver greater efficacy than the other selected dose, 150 mg quarterly. This 
300 mg quarterly dosing regimen also includes an induction period over 2 weeks, dosing at 
randomization (month 0) and at week 2 (month 0.5), in order to assure that auto-induction of 
IL-1β pathway is adequately inhibited at study initiation. The complete suppression of IL-1β 
related gene expression achieved with this early high dose administration, coupled with the 
continuous canakinumab treatment effect which has been proven to last the entire quarterly 
dosing period, is expected to minimize the potential for IL-1β rebound. This may be relevant 
for pathogenesis of atherosclerosis because it is theorized that IL-1 auto-induction  provides a 

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positive feedback mechanism for vascular disease including atherosclerosis. The lower 50 mg 
and 150 mg quarterly doses does not include an early high, induction dose regimen to ensure 
separation of the three canakinumab dose levels included in this protocol and to allow 
assessment of the impact of the early high dose regimen included in the 300 mg arm on 
clinical cardiovascular events.
Induction dose in the 300 mg quarterly dose arm
In phase II studies in patients with gout, diabetes, and acute inflammatory conditions, safety 
of canakinumab across a wide range of doses has not emerged as a major clinical issue. Due 
to long term suppression of inflammatory biomarkers, quarterly dosing of canakinumab is 
feasible and likely to be clinically effective. In addition, data in the setting of acute 
inflammation suggests that higher initial doses of canakinumab that can be achieved through 
induction are safe and provide an opportunity to ameliorate concern regarding potential auto-
induction of IL-1β and to achieve greater early suppression of IL-1β related gene expression. 
IL-1β auto-induction has been shown in human mononuclear blood, human vascular 
endothelial, and vascular smooth muscle cells in vitro and in rabbits in vivo where IL-1 has 
been shown to induce its own gene expression and circulating IL-1β level (Dinarello et al. 
1987, Warner et al. 1987a, and Warner et al. 1987b). These studies suggested that IL-1 
induced IL-1 gene expression may provide a positive feedback mechanism in the pathogenesis 
of atherosclerosis and promote atherosclerosis. This consequently suggests that suppression of 
this feedback mechanism may provide benefits in the atherosclerotic lesion. Specifically, data 
supporting an induction dose of canakinumab includes the following: In CACZ885A2102, a 
CAPS mechanism of action study of patients with Muckle Wells Syndrome (N=4), 
canakinumab treatment with 10 mg/kg i.v. (equivalent to 600 mg i.v.) single dose induced 
clinical (improved skin lesions and conjuctival injection) and biomarker (hsCRP and SAA) 
responses in 24 hrs which was durable up to 180 days. In contrast, canakinumab doses of 1 
mg/kg i.v. without induction were only durable up to 90 days. Support for more sustained and 
higher dose canakinumab therapy was also seen in the rheumatoid arthritis proof of concept 
study CACZ885A2101, where higher doses of canakinumab were required ( > 3.0 mg/kg i.v.) 
to achieve a significant clinical response as scored by the ACR system. Furthermore, in the 
CACZ885A2102 study, analysis of gene expression known to be related to IL-1 β expression, 
inflammasome activity, and autoinduction of IL-1 β, showed more complete response to 
higher dose (10 mg/kg i.v.) than lower dose (1 mg/kg i.v.) canakinumab. In addition, IL-1β 
and inflammasome related gene expression modification began to decrease with the lower 
dose (1 mg/kg i.v.) compared to the higher dose (10 mg/kg i.v.) between 10 and 12 weeks. 
Similar results were obtained in the rheumatoid arthritis study CACZ885A2201 where IL-1β 
related genes were suppressed more with 300 mg s.c. q2weeks dosing than 150 mg q4weeks 
dosing.  
The documented safety record of canakinumab up to doses of 300 mg s.c. every 2 weeks with 
and without induction dose of 600 mg i.v., study CACZ885A2201 in rheumatoid arthritis 
patients up to 6 months, 300 mg q1month, study CACZ885H2257 in gout patients up to 6 
months, and 150 mg q1month, study CACZ885I2202 in T2DM patients up to 4 months 
supports the use of this higher dose regimen.

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Thus, the CACZ885M2301 trial regimens will consist of (a) placebo s.c. at randomization 
(month 0), placebo s.c. at week 2 (month 0.5), placebo s.c. at week 12 (month 3), and then 
placebo s.c. quarterly; (b) canakinumab 50 mg s.c. at randomization (month 0), placebo s.c. at 
week 2 (month 0.5), canakinumab 50 mg s.c. at week 12 (month 3), and then canakinumab 50 
mg s.c. quarterly; (c) canakinumab 150 mg s.c. at randomization (month 0), placebo s.c. at 
week 2 (month 0.5), canakinumab 150 mg s.c. at week 12 (month 3), and then canakinumab 
150 mg s.c. quarterly; and (d) canakinumab 300 mg s.c. at randomization (month 0), 
canakinumab 300 mg s.c. at week 2 (month 0.5), canakinumab 300 mg s.c. at week 12 (month 
3), and then canakinumab 300 mg s.c. quarterly. 
Dosing regimen in extension phase
Every trial participant who continues to be eligible to receive study drug will be offered the 
option to continue study drug treatment during the extension phase. Consenting patients 
except those with prediabetes will remain on their pivotal phase assigned treatment arm for 
the first three extension phase visits (Month 0 to Month 6). After the database from the pivotal 
phase is locked, participants will be switched to an open-label dose of 150 mg canakinumab at 
the fourth scheduled extension visit (visit Month 9) (Figure 3-2). The 150 mg dose is 
predicted to have the highest likelihood of having the most favorable benefit: risk ratio based 
on biomarker and clinical data from phase II studies in Type 2 diabetics. The final 
canakinumab dose will be based on the results from the pivotal phase. The transition to an 
intermediate dose of 150 mg will avoid further placebo treatment until the final dose of 
canakinumab is implemented at the study sites. The first drug administration as part of the 
extension will be performed at the first visit of the main drug dispensing period of the 
extension phase. The first visit of the main drug dispensing period at Month 0 should occur on 
the same day as the pivotal phase EOS visit. In case the last drug administration of the pivotal 
phase occurred within 4 weeks before the pivotal phase EOS visit, the study drug 
administration at the extension phase Month 0 visit will be skipped and the first injection as 
part of the extension phase will be performed at the Month 3 visit. In contrast to all other 
participants of the pivotal phase, prediabetic patients will enter a 6-month study drug washout
at the beginning of the extension phase after which they will restart study drug administration 
as part of the extension phase. For participants of the prediabetes washout, the first visit of the 
subsequent main drug dispensing period of the extension at Month 0 should occur on the same 
day as the End of Prediabetes Washout visit. At this Month 0 visit study drug washout 
participants will receive one dose of their assigned pivotal phase blinded treatment arm before 
they switch to the open-label dose of 150 mg canakinumab at their next visit (visit Month 3)
(Figure 3-3).
3.4
Rationale for choice of comparator
This trial is placebo controlled to provide robust evidence on the effects of canakinumab on 
clinical events and safety as well tolerability. No comparative anti-inflammatory treatment has 
been shown to date to benefit patients with cardiovascular disease and thus an active 
comparator arm is not available. All patients in all treatment arms will receive standard of 
care post-MI background therapy including, but not limited to, lipid lowering, anti-
hypertensive, beta blockers, and anti-platelet therapy as appropriate. High dose statin 
comparator therapy was initially considered as an appropriate active comparator; however, it 

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was felt that it would be unethical to restrict use of proven benefit high dose statin therapy to 
the comparator arm only. No active comparator will be used in the extension phase. 
Additionally, no placebo drug will be used from extension visit Month 3 onwards 
(participants of study drug washout period) and from Month 9 onwards (all other participants 
of extension phase).
3.5
Purpose and timing of interim analyses/design adaptations
Interim analyses (IA) of efficacy, futility and safety will be carried out during the study in 
order to avoid exposing study patients to ineffective treatment or undue risks or to allow study 
discontinuation in case of overwhelming efficacy. Two interim analyses of efficacy will be 
performed when approximately 50% of the target number of patients with primary endpoints 
have been accumulated and the second one when approximately 75% of the planned number 
of patients with primary endpoints are available.
Interim analyses for futility will be conducted simultaneously with the analyses of efficacy, 
and one additional futility analysis may also be performed earlier than the first planned 
efficacy IA (at approximately 50% primary events), but only after a sufficient number of 
primary events are accrued, i.e., >25%.  The criteria for formal statistical significance at the 
interim analyses are specified in the data analysis section of the protocol, but details on futility 
boundaries and stopping rules will be pre-specified in the charter of the Data Monitoring 
Committee (DMC). The timing and number of safety analyses will also be specified in DMC 
charter, but these are estimated to occur on a six-month basis (full committee) and on a three-
month basis (chair only).
The unblinded results of the interim analyses will be reviewed by the DMC. Investigators, 
Novartis, and others who are involved in the conduct of the trial, in the analysis of the final 
trial results, or who have contact with study centers, will remain blinded to the treatment 
codes and interim analysis results until all monitoring decisions have been made and the 
database has been locked for final analysis.
4
Population
Participants eligible for this trial will include male and non-child-bearing potential female 
patients age 18 years and older who (a) have suffered a documented acute myocardial 
infarction at least 30 days before randomization and (b) have persistent evidence of systemic 
inflammation on the basis of an hsCRP > 2 mg/L despite the use of standard of care post-MI 
medical therapies. Standard of care post-MI background therapy includes, but is not limited to, 
lipid lowering, anti-hypertensive, beta blockers, and anti-platelet therapy as appropriate. 
In data from the PROVE IT – TIMI 22 trial, 43 percent of a post-MI population screened at 
30 days had hsCRP >2 mg/L despite maximal therapy including high-dose statin (Ridker et al 
2005).
In previous registries and studies of post-MI patients, approximately 25 percent are likely to 
have a diagnosis of T2DM, 35 percent are likely to be pre-diabetic, and 40 percent are likely 
to be normoglycemic patients. In this trial the following definitions of pre-diabetes and type 2 
diabetes at randomizations will be used:

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Definition of randomization Pre-Diabetes 

At visit 1 OR 2 HbA1c of 5.7-6.4% or FPG 100-125 mg/dL (5.6-6.9 mmol/L) (ADA 2010 
Clinical Practice Recommendations)
Definition of randomization Type 2 Diabetes

At Visit 1 (screening) and Visit 2 (Randomization/Baseline) any patient with:

Medical history of type 2 diabetes and any patient currently on concomitant anti-
diabetic medication
or 

HbA1c ≥6.5% (visit 1 and visit 2)
or

FPG ≥ 126 mg/dL (≥7.0 mmol/L) (visit 1 and visit 2).
or

Combination of FPG ≥ 126 mg/dL (≥7.0 mmol/L) and HbA1c ≥6.5% (visit 1 and visit 
2)
Definition of Prediabetes at the End of Study Visit

At randomization and at the EOS visit of the pivotal phase (based on the last available 
HbA1c and FPG measurement prior to the EOS visit) having prediabetes as defined by 
HbA1c of 5.7-6.4% or FPG 100-125 mg/dL (5.6-6.9 mmol/L) (ADA 2010 Clinical 
Practice Recommendations)
The pivotal phase will be an event-driven global trial conducted in the outpatient setting. It is 
anticipated that approximately 1,400 patients with adjudication committee confirmed 
cardiovascular endpoints will accrue during the course of the pivotal phase (see Section 9.7
for Power Calculations). To accomplish this goal, it is expected that approximately 17,000 
patients will need to be screened in order to randomize approximately 10,000 patients. All 
participants of the pivotal phase who continue to be eligible to receive study drug will be 
offered the option to enter the extension phase.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed. 
2. Male, or Female of non-child-bearing potential 
3. Age ≥ 18 years at Visit 1.
4. Documented spontaneous MI (diagnosed according to the universal MI criteria with or 
without evidence of ST segment elevation) at least 30 days before randomization. 
(Thygesen et al 2007)

Diagnosis of the qualifying MI should be based on medical history of clinical 
symptoms consistent with myocardial ischemia associated with elevation of cardiac 
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OR development of new pathological Q waves regardless of symptoms. For details, 
refer to the Universal Definition of MI (Thygesen et al 2007).

Please see below for documentation requirements.
a.
Acute MI (hospitalization records): requires documentation of a rise and/or fall of 
cardiac biomarkers (preferably troponin) with at least one value above the 99th 
percentile of the upper reference limit (URL) or above criteria diagnostic for 
MIAND evidence of myocardial ischemia as demonstrated by at least one of the 
following :
i. Symptoms of ischemia
i. ECG changes indicative of new ischemia (new ST-T changes or new LBBB)
ii. Development of pathologic Q waves (please see appendix 3 for definitions of 
pathological Q waves)
iii. Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality
b. Prior MI (no hospital records for acute event available): requires documentation 
of any one of the following :
i. Development of pathological Q waves  with or without symptoms (please see 
appendix 3 for definitions of pathological Q waves)
ii. Imaging evidence of a region of loss of viable myocardium that is thinned and 
fails to contract, in the absence of a non-ischemic cause
iii. Pathologic findings of a healed or healing MI

Patients with MI resulting from PCI or CABG will not be eligible
5.
Have an hsCRP ≥ 2 mg/L (collected less than 60 days prior to Visit 2 and performed at 
the central laboratory, which is a minimum of 28 days after qualifying MI or after any PCI 
performed separately from qualifying MI) on stable (at least 4 weeks) long term 
(cardiovascular) medications. 
4.2
Exclusion criteria
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test 
2. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, UNLESS they are
a. 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) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone or partial or total hysterectomy, 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.
[For Croatia only]

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[In Croatia, women who are < 50 years of age must have >2 years of amenorrhea or 
minimum of 1 year of amenorrhea with FSH levels of ≥40 IU determined on 2 or 
more occasions at least one month apart]
3. Any of the following concomitant conditions or diseases:
a. Planned  coronary revascularization (PCI or CABG) or any other major surgical 
procedure.
b. Major non-cardiac surgical or major endoscopic procedure within the past 6 months 
prior to Visit 1
c. Multi-vessel CABG surgery within the past 3 years 
d. Symptomatic patients with Class IV heart failure (HF) (New York Heart Association). 
e. Uncontrolled hypertension (defined as an average SBP >160 mmHg or an average   
diastolic blood pressure (DBP) >100 mmHg at Visit 1. Patients are allowed to be re-
evaluated, at the discretion of investigator for this criterion if anti-hypertensive 
therapy has been started or increased as a result of initial screening blood pressure 
above these limits (Mancia et al 2009).
f.
Uncontrolled diabetes as defined by the investigator
g. Nephrotic syndrome or eGFR < 30 mL/min/1.73 m2 per MDRD formula or kidney 
transplant (regardless of renal function), at Visit 1
h. Known active or recurrent hepatic disorder (including cirrhosis, hepatitis B and 
hepatitis C (positive or indeterminate central laboratory results), or alanine 
aminotransferase/ aspartate aminotransferase (ALT/AST) levels > 3 times ULN or 
total bilirubin > 2 times ULN) atVisit 1
i.
Prior malignancy other than basal cell skin carcinoma 
4. A history of alcohol and/or substance abuse that could interfere with the conduct of the 
trial
5. History or evidence of tuberculosis (TB) (active or latent) infection or one of the risk 
factors for tuberculosis such as but not limited or exclusive to:
a. History of any of the following: residence in a congregate setting (e.g. jail or prison, 
homeless shelter, or chronic care facility), substance abuse (e.g. injection or non-
injection) health-care workers with unprotected exposure to patients who are at high 
risk of TB or patients with TB disease before the identification and correct airborne 
precautions of the patient 
b. Close contact (i.e. share the same air space in a household or other enclosed 
environment for a prolonged period (days or weeks, not minutes or hours)) with a 
person with active pulmonary TB disease within the last 12 months. 
c. Evidence of TB infection (active or latent), at Visit 1, determined by purified protein 
derivative (PPD) skin test and/or QuantiFERON®-TB Gold (QFT-g) assay  as defined 
by country guidelines (refer to Determination of Tuberculosis Status, p.39). 
i.
If presence of TB (active or latent) is established then treatment (according to 
country guidelines for TB treatment or TB treatment with immunomodulating 
drugs) must have been initiated or completed prior to randomization per country 
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ii.
In the absence of country TB (active or latent) guidelines, the following has been 
demonstrated: TB has been treated adequately with antibiotics, cure can be 
demonstrated, and risk factors resulting in TB exposure and contracting TB have 
been removed (e.g. the patient does not live anymore in high TB exposure 
setting). 
6. History of ongoing, chronic or recurrent infectious disease 
7. Patients with suspected or proven immunocompromised state, including (a) those with 
evidence of Human Immunodeficiency Virus (HIV) infection; Patients on anti-retroviral 
therapy are excluded (b) those with any other medical condition which in the opinion of 
the investigator places the patient at unacceptable risk for participation in 
immunomodulatory therapy; or (c) those requiring systemic or local treatment with any 
immune modulating agent in doses with systemic effects e.g. high dose oral or intravenous  
steroids (> 20 mg prednisone orally daily for > 14 days, > 5 mg prednisone orally daily or 
equivalent dose of intravenous steroid) or high dose methotrexate (> 15 mg weekly).
Topical, inhaled, local steroid use in doses that are not considered to cause systemic 
effects are permitted.
8. Live vaccinations within 3 months prior to the randomization visit or live vaccinations 
planned during the trial.
9. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.
10. Patients who have received an investigational drug or device within 30 days (inclusive) of 
Visit 1, or who are expected to participate in any other investigational drug or device 
study during the conduct of this trial, except for patients who have an investigational drug 
eluting stent (DES), provided that they have completed the DES trial.  FDA/country-
specific drug regulatory authority approved DES devices are permitted.
11. Any biologic drugs targeting the immune system (for example, TNF blockers, anakinra, 
rituximab, abatacept, tocilizumab) 
12. Any life threatening condition with life expectancy < 5 years, other than vascular disease 
that might prevent the patient from completing the study
Determination of tuberculosis status
Determination of tuberculosis (active or latent) status, either by performing the PPD skin test 
or the QFT-g assay will be required before administration of study drug and should be 
performed as defined by country guidelines. Patients need to have given written informed 
consent before any of these assessments are initiated. Patients who have had a negative PPD 
skin test or negative QFT-g assay performed within 30 days of screening (Visit 1) will not 
need repeat testing performed to determine eligibility. All other patients will need tuberculosis 
(active or latent) status determined at Visit 1.
Any significant findings will be recorded in the “Medical History” section of the eCRF as 
necessary.
Patients with either a positive PPD or positive or indeterminate QFT-g test may still 
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1. Treatment of tuberculosis (active or latent) (according to country guidelines) has been 
initiated or completed prior to randomization
or
2. Patients with a history of TB who were treated must demonstrate that treatment has 
been received and further work up (according to country practice/guidelines) establishes 
conclusively that the patient has no evidence of active tuberculosis.
or
3. The repeat QFT-g test is negative in patients with an indeterminate QFT-g  result at 
Visit 1.     
PPD skin test
A PPD skin test may be initiated to evaluate for an occult infection with TB. The test dose is 
bioequivalent to 5 tuberculin units (or as according to local standard practice) of standard PPD 
usually injected intradermally into the volar surface of the forearm. The injection site will be 
cleansed and the PPD extract will then be injected into the most superficial layer under the 
skin. If given correctly, the injection should raise a small wheal of about 5 mm, which 
resolves within 10-15 minutes.
A reaction will be measured in millimeters of indurations (hard swelling) after 48h – 72h. A 
PPD skin induration > 5 mm is interpreted as positive result. This will determine whether the 
patients have had a significant reaction to the PPD skin test.  In case of a positive PPD skin 
test, the patient may be further screened for latent TB infection by performing the QFT-g test.
The investigator will either obtain PPD skin tests on his own and be reimbursed by Novartis 
for its cost or be supplied with them by the Novartis affiliate, depending on the local Novartis 
policy.
QuantiFERON-TB Gold Assay
A QuantiFERON®-TB Gold (QFT-g) assay may be performed to assess the TB (active or 
latent) status at baseline on patients as needed.
This blood-based assay is specific for Mycobacterium tuberculosis and is not influenced by 
previous Bacillus Calmette-Guérin (BCG) vaccination or exposure to other Mycobacteria 
species. This test, in contrast to the PPD skin test, is also insensitive to a booster effect since 
the patient is  not exposed to the vaccine. The assay measures the production of interferon-
gamma and puts it into relation to a negative and a positive control sample.
Details about QFT-g sample processing are described in the central laboratory manual.
Chest x-ray
A chest x-ray may be performed if required by country regulations in case of positive PPD 
skin test or positive QFT-g assay but will not be part of eligibility assessment.
If in line with country guidelines, a chest x-ray will be sufficient to check eligibility with 
respect to active TB status prior to randomization. This x-ray should be no more than 30 days 
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Tuberculosis status will not be re-assessed during the extension phase.
5
Treatment
5.1
Investigational and control treatment
Canakinumab (ACZ885) or matching placebo solution for injection will be provided by 
Novartis as ready-to-use pre-filled syringes. The sites will receive their first shipment of study 
treatment only after the first screened patient has been registered in the IVRS/IWRS. 
Two strengths and respective corresponding matching placebos will be supplied:
Canakinumab 50 mg in 0.5 mL solution for injection and one placebo formulation 
matching to this active drug formulation. 
Canakinumab 150 mg in 1 mL solution for injection and one placebo formulation 
matching to this active drug formulation. 
The study drug will be given as subcutaneous injections at randomization, week 2 (month 0.5), 
and then quarterly beginning at week 12 (month 3). All injections (double dummy design, two 
syringes of 1 mL for patients randomized to randomization plan A, one syringe of 1ml and 
one syringe of 0.5 ml for patients randomized to randomization plan B) will be administered 
at study sites by trained site staff, facilitating both compliance and long-term follow-up for 
both safety and efficacy outcomes. Please see Table 5-1 below for planned canakinumab 
injections at study visits. Study treatment and/or placebo will be given in addition to local 
standards of care for post-MI patients which may include lipid lowering, anti-hypertensive, 
beta blockers and anti-platelet therapies and is determined by the responsible treating 
physician. The sites should make alternative arrangements for those patients likely to miss 
visits due to travel or other reasons.  The minimum time between dosing visits after Visit 3 is 
30 days. 
Table 5-1
Injection Description
Randomization 
Plan
Treatment 
Groups
Injections at all visits excluding 
Screening, month 0.5 and 1.5 
visits
Injections at Visit 
month 0.5
A
Canakinumab 
150 mg sc
1 x canakinumab 150 mg 
and 1 x matching placebo
2 x placebo matching 
canakinumab 150 mg
A
Canakinumab 
300 mg sc
2 x canakinumab 150 mg
2 x canakinumab 150 
mg
A
Placebo
2 x placebo matching 
canakinumab 150 mg
2 x placebo matching 
canakinumab 150 mg
B
Canakinumab 
50 mg sc
1 x canakinumab 50 mg 
and 1 x 150 mg matching placebo
1 x placebo matching 
canakinumab 50 mg
1 x placebo matching 
canakinumab 150 mg

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B
Canakinumab 
150 mg sc
1 x canakinumab 150 mg 
and 1 x 50 mg matching placebo
1 x placebo matching 
canakinumab 50 mg
1 x placebo matching 
canakinumab 150 mg
B
Placebo
1 x 50 mg matching placebo
and 1 x 150 mg matching placebo
1 x 50 mg matching 
placebo
and 1 x 150 mg 
matching placebo
In the extension phase, all participants except for those with prediabetes will remain on their 
pivotal phase randomization plan and treatment group for the first three extension phase visits 
(Month 0 to Month 6). After the database from the pivotal phase is locked, participants will be 
switched to an open-label dose of 150 mg canakinumab at their fourth scheduled extension 
visit (visit Month 9) (Figure 3-2). The patients will then start to receive one syringe of 
canakinumab 150 mg in 1 mL solution for injection.
No study drug treatment will be provided for those patients with both randomization and 
pivotal phase EOS prediabetes during the 6-month study drug washout period. This means 
that patients participating in the washout will skip two doses of their pivotal phase blinded 
assigned treatment arm. After the end of the study drug washout, participants will receive one 
dose of their assigned pivotal phase blinded treatment arm at their first visit of the subsequent
main drug dispensing period of the extension (visit Month 0) before they switch to the open-
label dose of 150 mg canakinumab at their next visit (visit Month 3) (Figure 3-3).
All participants of the extension phase will remain on the open-label dose of 150 mg 
canakinumab until the final dose of canakinumab is implemented at the study sites, based on 
the results from the pivotal phase.
5.2
Treatment arms
Following protocol Amendment 6 patients will be assigned to one of the following 4 
treatment arms in a ratio of 1.4 : 1.3 : 1.3 : 2

Canakinumab 50 mg s.c. at randomization (month 0), placebo s.c. at week 2 (month 0.5) , 
50 mg s.c. at week 12 (month 3) and thereafter 50 mg s.c. quarterly

Canakinumab 150 mg s.c. at randomization (month 0), placebo s.c. at week 2 (month 0.5), 
150 mg s.c. at week 12 (month 3) and thereafter 150 mg s.c. quarterly

Canakinumab 300 mg s.c. at randomization (month 0), week 2 (month 0.5) , week 12 
(month 3) and thereafter 300 mg s.c. quarterly 

Placebo s.c. at randomization (month 0), week 2 (month 0.5) , week 12 (month 3) and 
thereafter placebo s.c. quarterly
with allocation in a 1.3 : 0.7 : 1 ratio to 300 mg, 150 mg and placebo respectively in 
randomization plan A and 0.6 : 1.4 : 1 to 150 mg, 50 mg and placebo respectively in 
randomization plan B. All patients will be equally likely to be assigned to randomization plan 
A or B. Within each of the two randomization plans patients will have a 2:1 probability of 
being on active treatment. Prior to protocol amendment 6, patients were assigned in a 1:1:1 

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ratio to the 300 mg arm, the 150 mg arm or placebo. Across trial parts 1 and 2 this will 
approximately result in a 1:1:1:1.5 allocation to 300, 150, 50 mg and placebo, respectively. 
More precisely, given about 743 patients in trial part one and 9257 in trial part 2, the overall 
patient allocation would be approximately 2253 for both the 300 and 150 mg groups, 2160 for 
the 50 mg group and 3333 for the placebo group (a 1.01:1.01:0.97:1.5 ratio).
In the extension phase, all participants except for those with prediabetes will remain on their 
pivotal phase randomization plan and treatment arm for the first three extension phase visits 
(Month 0 to Month 6). The participants will be switched to a quarterly s.c. injection of an 
open-label dose of 150 mg canakinumab at their fourth scheduled extension visit (visit Month 
9) following database lock of the pivotal phase (Figure 3-2). Prediabetic patients participating 
in the 6-month study drug washout will remain on their pivotal phase randomization plan and 
treatment arm only until their first visit of the subsequent main drug dispensing period (visit 
Month 0) before they switch to the open-label dose of 150 mg canakinumab at their next visit 
(visit Month 3) (Figure 3-3). All participants of the extension phase will remain on the open-
label dose of 150 mg canakinumab until the final dose of canakinumab is implemented at the 
study sites, based on the results from the pivotal phase.
5.3
Treatment assignment
At pivotal phase Visit 2, all eligible patients will be randomized via Interactive Voice 
Response System /Web System (IVRS/IWRS) to one of the treatment arms. The investigator 
or his/her delegate will contact the IVRS/IWRS after confirming that the patient fulfills all the 
inclusion/exclusion criteria. The IVRS/IWRS will assign a randomization number to the 
patient, which will be used to link the patient to a treatment arm and will specify a unique 
medication number for the first package of study drug to be dispensed to the patient. The 
randomization number will not be communicated to the caller.
In trial part 1 prior to the implementation of protocol amendment 6 at each site, there was a 
single randomization plan. In trial part 2 (following protocol amendment 6) this trial has two 
randomization plans A and B. The IVRS/IWRS randomly assigns patients to plan (A and B) 
and treatment. Randomization plan A includes placebo, 150 mg and 300 mg canakinumab 
arms and therefore, is fully blinded. Patients assigned to randomization plan A will receive 
two 1 mL injections at each trial visit except at visit 3 (1.5 months). Randomization plan B 
includes placebo, 50 mg and 150 mg canakinumab arms, and is also fully blinded. Patients 
assigned to randomization plan B will receive one 1 mL and one 0.5 mL injections at each 
pivotal phase visit except at visit 3 (1.5 months). The randomization numbers will be 
generated using the following procedure to ensure that treatment assignment is unbiased and 
concealed from patients and investigator staff. A patient randomization list will be produced 
by the IVRS/IWRS provider using a validated system that automates the random assignment 
of patient numbers to randomization numbers. These randomization numbers are linked to the 
different treatment arms, which in turn are linked to medication numbers. A separate 
medication list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of medication 
numbers to study drug packs containing each of the study treatment. 
In the extension phase all participants except for those with prediabetes will remain on their 
randomization number assigned at randomization in the pivotal phase until they switch to an 

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open-label dose of 150 mg canakinumab at the fourth scheduled extension visit (visit Month 9)
(Figure 3-2). Prediabetic patients participating in the 6-month study drug washout will remain 
on their randomization number only until their first visit of the subsequent main drug 
dispensing period (visit Month 0) before they switch to the open-label dose of 150 mg 
canakinumab at their next visit (visit Month 3) (Figure 3-3).
Stratification
Randomization will be stratified by ‘time since most recent MI’ as follows:

Post MI ≥ 30 days but < 6 months

Post MI ≥6 months 
Sites will be asked to indicate the patients’ glycemic status at the Visit 3 call post 
randomization as the Visit 1 and Visit 2 lab results are needed for the following categories
(see Section 3.1 for definitions): 

Normoglycemia:  HbA1c <5.7% at V1 and V2 

Pre-Diabetes:   HbA1c 5.7 – 6.4 % or FPG 100-125 mg/dL (5.6-6.9 mmol/L) inclusive at 
V1 or V2
Note: To be included in the 6-month study drug washout, a patient must have a
prediabetic status at both randomization and the pivotal phase EOS visit, according to 
the last HbA1c and FPG measurement available at the EOS visit

T2DM: (patient needs to have one or more of the following)

HbA1c ≥ 6.5% OR FPG ≥ 126 mg/dL (≥7.0 mmol/L)  at V1 and V2 

Combination of HbA1c ≥ 6.5% and FPG ≥ 126 mg/dL (≥7.0 mmol/L) as confirmed at 
V1 and V2 

Medical history of T2DM and on a current anti-diabetic medication
At the pivotal phase EOS visit sites will be asked to indicate the patients’ glycemic status 
based on the last available lab results and based on the glycemic status at randomization. 
Patients who are determined to be prediabetic at both randomization and the pivotal phase 
EOS visit, will be included in the 6-month study drug washout (see Section 4 for definition). 
Sites are required to call the IVRS/IWRS at every visit/phone contact to: 

Prescreen: Register the prescreening visit. 

Visit 1: Register the screening visit. The first shipment of study treatment will ONLY be 
sent once the site registers their first screened patient.

Visit 2: Register Screen Failures or randomize a patient.  For randomization, enter 
patient’s stratification as the time from the index MI to the date of randomization.

Visit 3: Register the occurrence of the visit and provide glycemic status.

Obtain medication numbers for randomization (month 0), week 2 (month 0.5), week 12 
(month 3), and quarterly dispensing of study treatment thereafter..

Register a patient who has died or withdrawn consent (pivotal phase).

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
Register a patient who has completed the pivotal phase (this will only occur when the 
study has been deemed complete by the DMC or Novartis and the patient returns for the 
pivotal phase EOS visit); register pivotal phase EOS visit as non-dispensing visit.

Register a patient who has a glycemic status of “randomization and pivotal phase EOS 
prediabetes” and transitions into the 6-month study drug washout.

End of Prediabetes Washout Visit 199: register a patient who has completed the 6-month 
study drug washout.

Extension phase Visit 201 (Month 0): Register a patient who consented to participate in 
the extension phase. 
Register a drug dispensing visit, obtain medication numbers and provide study drug as per 
pivotal phase treatment arm assignment / randomization number. Note 1: The patients will 
remain on their assigned pivotal phase treatment arm until Visit 203 (Month 6) (Figure 3-
2), except for prediabetic patients participating in the 6-month study drug washout. Such 
patients will remain on their assigned pivotal phase treatment arm only until Visit 201 
(Month 0) (Figure 3-3). Note 2, for patients not participating in study drug washout: In 
case the last drug administration of the pivotal phase occurred within 4 weeks before the 
pivotal phase EOS visit, the study drug administration at Visit 201 (Month 0) will be 
skipped and the first injection as part of the extension phase will be performed at Visit 202 
(Month 3). 

Extension phase Visit 202 (Month 3): prediabetic patient who completed the 6-month 
study drug washout will receive an open-label dose of 150 mg canakinumab and quarterly 
dispensing of an open-label dose of 150 mg canakinumab thereafter until the final 
canakinumab dose will be implemented at study sites based on the results from the pivotal 
phase (Figure 3-3). Patients who did not participate in the study drug washout will remain 
on their assigned pivotal phase treatment arm (Figure 3-2).

Extension phase Visit 204 (Month 9): patient will receive an open-label dose of 150 mg 
canakinumab and quarterly dispensing of an open-label dose of 150 mg canakinumab 
thereafter until the final canakinumab dose will be implemented at study sites based on the 
results from the pivotal phase (Figure 3-2). 

Register a patient who has died or withdrawn consent during the extension phase.

Register a patient who has completed the extension phase (when the patient returns for the 
extension phase EOS visit).
The randomization scheme for patients will be reviewed and approved by a member 
 
 The randomization codes will be maintained
 
 

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Figure 5-1
Transition from pivotal phase to extension phase
PFS: PreFilled Syringe, FPFV: First Patient First Visit, LPLV: Last Patient Last Visit
*for patients not participating in study drug washout: pivotal phase EOS visit and first extension phase 
visit are two different study visits that should occur on the same day. (If the last pivotal phase study 
drug injection before the EOS visit occurred within four weeks of the EOS visit, the first injection from 
the extension will be skipped). For participants of study drug washout: End of Prediabetes Washout 
visit and first visit of the main drug dispensing period of the extension phase are two different visits that 
should occur on the same day.   
5.4
Treatment blinding
Patients, investigator staff and external personnel performing the assessments will remain 
blinded to the identity of the treatment from the time of randomization until the patients 
switch to the open-label dose of 150 mg canakinumab at extension phase visit Month 3 (only 
participants of 6-month study drug washout) and visit Month 9 (all patients who did not 
participate in the study drug washout), respectively. Data analysts will remain blinded to the 
identity of the treatment from the time of randomization until pivotal phase database lock, 
using the following methods:
Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible by anyone else involved in the study with the exception of the independent 
unblinded statistician, programmer and data manager/data coordinator (and assistant as 
required) who need to have access to prepare safety and efficacy interim analysis reports for 
the DMC and the bioanalyst and pharmacokineticist (to avoid the unnecessary analysis of 
placebo samples). These personnel will not be involved in any other trial activities.
The identity of the treatments in trial part 1 and in trial part 2 within each randomization plan
(i.e., Plan A and Plan B) will be concealed by the use of double-dummy approach using study 

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drugs that are identical in packaging, labeling, schedule of administration and appearance. 
While investigators will not be blinded as to whether patients in trial part 2 are in 
randomization plan A or B, the probability of the patient being on active treatment is the same 
(2:1) in either case. Thus, it is not expected that this introduces any biases.
The study drug injections as part of the extension phase will remain blinded for the data 
analysts until pivotal phase database lock. The study drug injections received as part of the 
extension phase will remain blinded to patients, investigator staff and external personnel 
performing the assessments until patients switch to the open-label dose of 150 mg 
canakinumab at visit Month 3 (only participants of 6-month study drug washout; see Figure 3-
3) and visit Month 9 (all patients not participating in study drug washout; see Figure 3-2), 
respectively. Until the switch to the open-label dose of 150 mg canakinumab during the 
extension phase, unblinding will only occur in the case of patient emergencies (see Section 
5.5.9), at the time of interim analysis and at the conclusion of the pivotal study phase. In the 
event a patient becomes unblinded for any reason they may continue study treatment and 
assessments according to the protocol at the discretion of the investigator.
During the open-label treatment as part of the extension phase, medication with a double blind 
label will continue to be dispensed until new supplies bearing open-label sticker are available 
at site. The dispensation of the open-label canakinumab dose during the extension phase with 
kits bearing a double blind label will be managed by the IVRS/IWRS. 
 hsCRP (from baseline) and canakinumab 
antibody results will be blinded to the sites and Novartis but will be available unblinded for 
the DMC analyses to assure patient safety.
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified in the study by a Patient Number. A center number is also 
assigned by Novartis to the investigative site. Upon signing the informed consent form, the 
patient is assigned the next sequential patient number by the investigator. The investigator or 
his/her staff will contact the IVRS/IWRS and provide the requested identifying information 
for the patient to register them into the IVRS/IWRS. In the electronic data capture (EDC) 
system, there will be blank CRF books available labeled with a Patient Number. The site 
should select the CRF book with a matching Patient Number to enter data. 
Once assigned to a patient, the Patient Number will not be reused. If the patient fails to be 
randomized for any reason, the IVRS/IWRS should be notified within 2 days that the patient 
was not randomized. The reason for not being randomized will be entered on the Screening 
Period Phase Disposition eCRF.
The assigned patient numbers will be kept also during the extension phase.

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5.5.2
Dispensing the study treatment
Each study site will be supplied by Novartis with study treatment in packaging of identical 
appearance per product volume. The first shipment of study treatment will occur once the site 
has registered their first screened patient in the IVRS/IWRS. All injections should be 
administered by the site staff only. 
The study treatment packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the four formulations provided (2 active 
and 2 corresponding placebo forms). Investigator staff will identify the two study treatment 
packages for the patient at each dispensing visit by contacting the IVRS/IWRS and obtaining 
the medication numbers. Immediately before administering the study treatment, the, 
investigator staff will detach the outer parts of the labels from the packaging and affix them to 
the source document (Drug Label Form) for that patient’s unique patient number. 
For the main drug dispensing period of the extension phase, there will be a transition time.  
This transition time will be divided into three parts:

First part from first visit (visit Month 0) until switch to open-label treatment with 150 mg 
canakinumab (i.e. visit Month 3 for participants of 6-month study drug washout (Figure 3-
3), and visit Month 9 for all other patients (Figure 3-2)): Patients will continue to receive 
their double-blind treatment. The medication dispensing will be managed via IWRS/IVRS. 

Second part from first 150 mg canakinumab open-label treatment (i.e. visit Month 3 for 
participants of 6-month study drug washout and visit Month 9 for all other patients, 
respectively) until the final dose is implemented at study sites based on the results from 
the pivotal phase: Patients will receive 150 mg/1 ml canakinumab in an open-label fashion 
but with a double-blinded sticker until kits with the 150 mg dose are available at study 
sites with an open-label sticker. The medication dispensation will be managed via 
IWRS/IVRS.

Third part from implementation of the final canakinumab dose at study sites until end of 
study: Patients will receive the final canakinumab dose with double-blinded sticker until
kits with the appropriate dose are available at study sites with an open-label sticker. The 
medication dispensation will be managed via IWRS/IVRS.
5.5.3
Supply, storage and tracking 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 assistants have access. Upon receipt, all study treatment should be stored in the 
refrigerator at 2-8 degrees C (36-46 degrees F). Study treatment temperature should be 
verified and documented daily (business days) with a minimal / maximum thermometer or 
another equivalent temperature recording tool. Clinical supplies are to be dispensed only in 
accordance with the protocol.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug and no information about the 
patient.

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The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability ledger. Monitoring of drug accountability will be performed 
by the field monitor during site visits and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the Novartis 
monitor will arrange the return of all unused, damaged or expired study treatment and a copy 
of the completed drug accountability ledger to Novartis. 
The above will also apply for the extension phase.
5.5.4
Instructions for prescribing and taking study treatment
All randomized patients will receive two subcutaneous injections per visit, beginning at 
randomization (month 0), week 2 (month 0.5) and then quarterly beginning at week 12 (month 
3). 
Patients will receive either one injection of canakinumab and one injection of placebo, or two 
injections of placebo or two injections of canakinumab. Injections will be given after all other 
study assessments have been completed for the visit. All dosages prescribed and dispensed to 
the patient and all dose changes during the study must be recorded on the Dosage 
Administration Record eCRF. All drug kits assigned by the IVRS/IWRS will be 
recorded/databased in the IVRS/IWRS. The investigator should promote compliance by 
informing the patient that compliance is necessary for the patient’s safety and the validity of 
the study. 
Principal investigator or trained staff will select injection site(s) for the study injections, 
which may be administered subcutaneously in the abdomen and/or extremities. 
Instructions for use of the safety syringe can be found in Appendix 4.
During the extension phase, all participants except for those with prediabetes will remain on 
their pivotal phase assigned treatment arm for the first three visits (Month 0 to Month 6). The 
participants will be switched to an open-label dose of 150 mg canakinumab at the fourth 
scheduled extension visit (visit Month 9) (Figure 3-2) until the final dose of canakinumab is 
implemented at the study sites based on the results from the pivotal phase. During the open-
label treatment with a dose of 150 mg canakinumab, only one injection will be administered
per visit. Prediabetic participants of the 6-month study drug washout will receive one dose of 
their assigned pivotal phase blinded treatment arm at their first visit of the subsequent main 
drug dispensing period of the extension (visit Month 0) before they switch to the open-label 
dose of 150 mg canakinumab at their next visit (visit Month 3) (Figure 3-3) until the final 
dose of canakinumab is implemented at the study sites based on the results from the pivotal 
phase.
5.5.5
Permitted interruptions of study treatment
For patients who are unable to tolerate the protocol-specified dosing scheme, dose 
interruptions are permitted in order to keep the patient on study treatment. Patients are 
encouraged to continue study treatment; however, patients are allowed to interrupt and restart 
medication at any time during the study at the discretion of the investigator. 

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These changes must be recorded on the Dosage Administration Record CRF (eCRF).This will 
also apply for the extension phase.
5.5.6
Concomitant treatment
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after signing the informed consent. All medications and significant non-drug 
therapies (including physical therapy and blood transfusions) taken within 30 days of 
screening and administered after the patient has signed informed consent must be listed on the 
appropriate Concomitant Medications and or Procedures and Significant Non-Drug Therapies 
eCRF. Prior treatment for TB infection should be listed on the Concomitant Medications 
eCRF. Influenza vaccines administered two years prior to study start and pneumococcal 
vaccines administered five years prior to study start should be recorded on the Prior Influenza 
Vaccine eCRF and Prior Pneumococcal Vaccine eCRF, respectively. Vaccinations taken 
during the trial should be reported on the Concomitant Vaccination eCRF.  
Patients who are on warfarin or warfarin like treatment with narrow therapeutic index should 
have their international normalized ratio (INR) measured locally and warfarin or warfarin like 
treatment dose adjusted accordingly within one month from starting study treatment. This is a 
general precautionary measure because canakinumab is not expected to interact with warfarin.
Also for the extension phase the investigator should instruct the patient to notify the study site 
about any new medications he/she takes after signing informed consent.
5.5.7
Prohibited treatment
Use of any treatments below is NOT allowed after the start of study treatment due to potential 
increase in immunosuppressant related concomitant conditions. They are prohibited for the 
duration of the study and for at least 90 days after discontinuation of study treatment. This 
will also apply to the extension phase. 
If a patient chooses to continue one of the medications below, they would still be required to 
be followed as per protocol to assess for any potential study endpoints during the pivotal 
phase. During the extension phase, patients would still be required to be followed as per 
protocol to assess for any adverse events. If a patient stops taking any of the below prohibited 
medications they are eligible to restart study treatment 90 days after stopping the prohibited 
medication, at the discretion of the investigator.

Any anti retro-virals and / or any biologic drugs targeting the immune system (e.g., TNF
blockers, anakinra, rituximab, abatacept, tocilizumab) 

immune suppressive drugs: e.g. high dose systemic oral or intravenous steroids ( > 20 mg 
prednisone orally daily for >14 days, > 5 mg orally prednisone daily, or equivalent dose of 
intravenous steroid) or high dose methotrexate (> 15 mg weekly). (Topical, inhaled, local 
steroid use in doses that are not considered to cause systemic effects are permitted.)

Live vaccines within 90 days of study treatment. 
If a patient receives a live vaccine during this trial the next scheduled study treatment will 
be administered no earlier than 90 days from the administration of the live vaccine.

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5.5.8
Interruption and Discontinuation of study treatment and premature 
patient withdrawal
The investigator should interrupt or discontinue study treatment for a given patient if, on 
balance, he/she believes that continuation of study treatment would be detrimental to the 
patient’s well-being. If any patient interrupts or discontinues study treatment, the site is 
required to follow the patient, as per the study assessment schedule (either by phone or on site 
visits) until the site has been notified by Novartis that the study has been deemed complete. 
This will also apply to the extension phase.
Study treatment must be discontinued under the following circumstances; 

Withdrawal of informed consent. Study treatment may only be resumed if the patient has 
re-consented to participation and if the Investigator deems it appropriate to re-initiate 
study treatment.  After the patient re-signs the ICF but prior to restarting study treatment, 
the Investigator must perform a thorough review of new medical histories and 
concomitant medication changes from the time corresponding to when the patient left the 
trial until he/she rejoined.  New medical histories must be added to the Adverse Event 
eCRF and medication changes to the Concomitant Medication eCRF. Additionally, serum 
chemistry and hematology laboratory evaluations must be reviewed prior to resuming 
study treatment (Note: if serum chemistry and hematology results were obtained within 6 
months prior to resuming study treatment, they do not need to be repeated at the central 
laboratory; if they are not available within 6 months a blood sample must be drawn and 
results reviewed by the Investigator prior to dosing the patient).    

Pregnancy. Patients must discontinue study treatment if pregnant; however, study 
treatment can be resumed in the future after consultation with the Sponsor providing the 
patient has stopped breast-feeding, has an appropriate clinical profile (i.e. safety 
laboratories, medical history, adverse events, concomitant medications) and there is 
documented evidence in the patient chart that the patient is of post-menopausal status per 
Section 4.2 Exclusion 2. 

Use of prohibited treatment as per Section 5.5.7 

Presence of any malignancy, other than excised basal cell skin carcinoma 

Any other protocol deviation that results in a significant risk to the patient’s safety
Any of the following laboratory abnormalities
Clinical Symptoms as noted below, without regard to Liver Function Test’s (LFT)

A jaundice like event 

Any serious adverse event (SAE) indicative of fatal or non-fatal hepatitis, liver failure 
or its complications
LFT elevations and Clinical Symptoms

ALT or AST > 3X ULN

Clinical symptoms suggestive of hepatic dysfunction – such as general malaise, 
fatigue, abdominal pain, nausea, vomiting or rash with eosinophilia 
Asymptomatic elevations of ALT / AST /T. Bilirubin

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
ALT or AST > 3x ULN with a T. Bilirubin > = 2x ULN but with no notable increase 
in ALP to > 2 X ULN 
Asymptomatic isolation of elevations of ALT or AST

ALT or AST > 8 x ULN discontinue study treatment if elevation persists > 48 hrs

ALT or AST ≥ 5x ULN ≤8x ULN discontinue study treatment if elevation persists > 
2wks. 

ALT or AST≥ 3x ULN <5 ULN discontinue medication at the discretion of the 
investigator 
Asymptomatic isolation elevation of T. Bilirubin 

T. Bilirubin ≥ 3x ULN discontinue if elevation persists > 48 hours 
Study treatment may be restarted at the discretion of the investigator, if the reason for 
withdrawal of study treatment has resolved. Every effort should be made to restart study 
treatment, if deemed appropriate by the investigator(s).  If subjects are rechallenged due liver 
function laboratory evaluations, they should be followed closely. The subject should be made 
aware of the potential risk, and consent to the rechallenge, and the Institutional Review Board 
(IRB) consulted.
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently 
for any reason. This will also apply for the extension phase until patients switch to open-label 
administration of canakinumab starting at visit Month 3 (participants of 6-month study drug 
washout) and visit Month 9 (all patients not participating in study drug washout), respectively. 
Patient Status
Patients may voluntarily withdraw from the study for any reason at any time; however, they 
must be reminded that the site will attempt to obtain a vital status yearly and at the conclusion 
of the pivotal phase to assess for any potential study endpoints. The site will also attempt to 
obtain a vital status yearly during the extension phase. The patient contact information should 
be reviewed with the patient at every scheduled study visit to ensure it is up to date.  If local 
regulations permit, the patient should be asked to provide the contact information for a friend 
or relative as well as their primary care physician (PCP).
Study Treatment Discontinuation: If premature discontinuation of study treatment occurs 
for any reason, the investigator must make every effort to determine the primary reason for a 
patient’s premature discontinuation from treatment. Patients who discontinue study treatment 
should NOT be considered withdrawn from the study. For any patient who chooses to 
discontinue study treatment, the site must capture this information on the Drug Accountability 
Record eCRF and the patient should not be registered as discontinued in IVRS/IWRS unless 
they have withdrawn consent from all study follow-up. The patient should be encouraged to 
return for scheduled visits after discontinuation of study medication.  If the patient refuses 
onsite visits, the patient, at minimum, should be encouraged to be followed by telephone per 
the assessment schedule, as every effort must be made by sites staff to follow patients for 
cardiovascular events and health status. For telephone visits, as much information should be 
collected as possible (vital status, study endpoints, adverse events, etc).  If, at the end of study, 

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contact is made to the patient (or on site visit) to assess a health status; the patient will be 
deemed “completed”.  
Lost to-Follow-up: Sites must make every effort to reach patients who fail to return for visits, 
or become lost to follow-up for any reason, as all patients must be accounted for, at the EOS, 
to assess for study endpoints. The investigator must show "due diligence" by documenting in 
the source documents the steps taken to contact patients who are lost to follow-up (i.e. those 
patients whose life or death status is unclear because they fail to appear for study visits 
without stating an intention to withdraw). Steps taken include dates of telephone calls, 
registered letter confirmations, and etc. Sites will be requested to complete the Visit 
Information eCRF at the regularly scheduled study time points to document the attempts made 
to contact a person. “Lost to Follow Up” information will be captured on the Study Phase 
Completion eCRF only if sites are unable to obtain a status on a patient at the end of the study. 
It is permissible for a patient to contact the site to return for a scheduled clinic visit, at which 
time their status should then be updated in the systems appropriately. Patient will maintain the 
previously provided Patient Number and resume study activities based upon their original 
randomization date.
Withdraw Consent: Any patient who withdraws their consent to participation of study 
procedures, including telephone contacts to assess health status, will have this information 
captured on the Study Phase Completion eCRF, which will prompt annual completion of the 
Survival Information eCRF. To complete the Survival Information page, sites will be asked to 
check public registries on an annual basis to try and obtain a health status on their patients. 
Patients may re-consent at any time to resume their participation in the trial. Patients will 
maintain the previously provided Patient Number and resume study activities based upon their 
original randomization date. Patients who discontinue study treatment prematurely will not be 
replaced by an equal number of newly enrolled patients.
The following will apply to the extension phase: 
Patients may voluntarily withdraw from the study for any reason at any time. The patient 
contact information should be reviewed with the patient at every scheduled study visit to 
ensure it is up to date.  If local regulations permit, the patient should be asked to provide the 
contact information for a friend or relative as well as their primary care physician (PCP).
Study Treatment Discontinuation: If premature discontinuation of study treatment occurs 
for any reason, the investigator must make every effort to determine the primary reason for a 
patient’s premature discontinuation from treatment. Patients who discontinue study treatment 
should NOT be considered withdrawn from the study. For any patient who chooses to 
discontinue study treatment, the site must capture this information on the Drug Accountability 
Record eCRF and the patient should not be registered as discontinued in IVRS/IWRS unless 
they have withdrawn consent from all study follow-up. The patient should be encouraged to 
return for scheduled visits after discontinuation of study medication. If the patient refuses 
onsite visits, the patient, at minimum, should be encouraged to be followed by telephone per 
the assessment schedule, as every effort must be made by sites staff to follow patients for 
health status. 
Lost to-Follow-up: Sites must make every effort to reach patients who fail to return for visits, 
or become lost to follow-up for any reason, as all patients must be accounted for. The 

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investigator must show "due diligence" by documenting in the source documents the steps 
taken to contact patients who are lost to follow-up (i.e. those patients whose life or death 
status is unclear because they fail to appear for study visits without stating an intention to 
withdraw). Steps taken include dates of telephone calls, registered letter confirmations, and 
etc. Sites will be requested to complete the Visit Information eCRF at the regularly scheduled 
study time points to document the attempts made to contact a person. “Lost to Follow Up” 
information will be captured on the Study Phase Completion eCRF only if sites are unable to 
obtain a status on a patient at the end of the study. It is permissible for a patient to contact the 
site to return for a scheduled clinic visit, at which time their status should then be updated in 
the systems appropriately. Patient will maintain the previously provided Patient Number and 
resume study activities based upon their original randomization date.
Withdraw Consent: Any patient who withdraws their consent to participation of study 
procedures, including telephone contacts to assess health status, will have this information 
captured on the Study Phase Completion eCRF, which will prompt annual completion of the 
Survival Information eCRF. To complete the Survival Information page, sites will be asked to 
check public registries on an annual basis to try and obtain a health status on their patients.
5.5.9
Emergency unblinding of treatment assignment
Emergency unblinding should only be undertaken when it is essential to treat the patient 
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency code breaks are performed using the IVRS/IWRS. When 
the investigator contacts the system to unblind a patient, he/she must provide the requested 
patient identifying information and confirm the necessity to unblind the patient. The 
investigator will then receive details of the drug treatment for the specified patient and a fax 
or email confirming this information. The system will automatically inform the Novartis 
monitor for the site and the Clinical Trial Head that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IVRS/IWRS at any time in case of emergency. The investigator will 
provide:

protocol number

study drug name

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in case of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time.
Any patient who is unblinded will continue in the study and may continue receiving study 
medication as per protocol. This also applies for the extension phase while patients are still on 
their assigned blinded treatment arm.
5.5.10
Study completion and post-study treatment
The study closeout will be initiated once the study has reached its primary endpoint of 1,400 
patients with primary CV events. At this time point sites will be notified to bring back all 

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study patients for a pivotal phase EOS visit. At this time patients who have pivotal phase EOS 
status obtained will be deemed completed for the pivotal phase. At this time, any patient who 
has signed the informed consent, but has not been randomized into the trial will not be eligible 
to proceed to randomization and should be registered as a screen failure.
Once the pivotal phase is deemed successfully completed (1,400 primary CV events reached) 
or is stopped by the DMC recommendation of overwhelming efficacy (prior to 1,400 primary 
CV events reached) or by Novartis the following will take place

All patients with a glycemic status of prediabetes from both randomization and pivotal 
phase EOS visit will proceed into the 6-month study drug washout  

All other patients who continue to be eligible to receive study drug and consent to 
participate in the extension phase will continue study drug treatment. The extension phase 
will continue in an individual country for a minimum of two years from the date of the 
first patients enrolled in that country. The maximum duration of the extension phase will 
be 2.5 years from the date of the first patient enrolled in that country or until marketed 
product is available in that country, whichever comes first. The extension phase is then 
deemed complete while safety follow-up is anticipated to be continued in registries 
following study results and discussion with Health Authorities.

All patients with a glycemic status of prediabetes who completed the 6-month study drug 
washout and consent to participate in the main drug dispensing period of the extension 
phase will continue with the extension as noted above and restart study drug treatment. 
5.5.11
Early study termination
Novartis is committed to follow the IHC Harmonized Tripartite Guidelines for Good Clinical 
Practice (GCP) in implementation of this trial. The sponsor can terminate the study prior to 
completion of the trial in the case of a probable negative risk-benefit balance. Furthermore,
the study can be terminated at any time for any reason by Novartis. Should this be necessary, 
patients should be seen as soon as possible and treated as described in Section 6. 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 patient’s interests. The investigator 
will be responsible for informing IRBs and/or ECs of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments of the pivotal phase and indicates with an “x” when the 
visits are performed. Patients should be seen for all visits on the designated day or as close to 
it as possible. The study assessment schedule below outlines all procedures performed on 
patients at scheduled visits. The administration of study treatment is performed as per the visit 
assessment schedule at study sites by trained site staff after the completion of all other 
assessments. 
The visit assessments listed below are for the estimated timeframe a patient would participate 
in the study. This is an event driven trial and will be stopped when the target number of 
primary cardiovascular endpoints have been accrued (please see Section 9 for details). All 
patients will continue study treatments and visits until the event target has been reached. 
Patients who complete the 36 months will still be required to return to the clinic every 6 

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months for study assessments and quarterly for study treatment until notified by the site staff 
of pivotal phase completion. Only when the site staff has been notified of the pivotal phase
completion by Novartis will the patients with a glycemic status of prediabetes from both
randomization and pivotal phase EOS visit be asked to enter the 6-month study drug washout 
at their pivotal phase EOS visit. 
Patients should attend visits, where labs are drawn, in a fasting state of 10 hours.
Pre-screening is a key element to successfully identifying the correct patients to be screened 
for this clinical study. All patients should have an available hsCRP value prior to the time of 
screening (Visit 1). The available hsCRP value should be at least 28 days after a 
cardiovascular event or procedure or major surgical procedure, and must be less than 60 
calendar days prior to screening (Note: centrally-performed hsCRP results must be obtained 
less than 60 calendar days prior to Visit 2 to be used to evaluate Inclusion criterion 5, Section 
4.1). The Pre-screening visit should be used after review of the patient’s charts to determine 
patient’s eligibility and to obtain an hsCRP value. Patients with a prescreen hsCRP ≥ 2 mg/L 
from the central laboratory do not require a second hsCRP at Visit 1, providing the prescreen 
hsCRP blood sample is drawn less than 60 days prior Visit 2 and the patient is on a stable (at 
least 4 weeks) long term (cardiovascular) medications. 
Converting to T2DM: Any patient who is reported as having an elevated HbA1c and/or FPG as 
defined in Section 4, will need to have an unscheduled visit within 6 weeks following the first 
elevated HbA1c and/or FPG result to assess for conversion from pre-diabetes to T2DM.
Discontinuation of study treatment: It is highly encouraged that patients who discontinue 
study treatment still attend regularly scheduled clinic visits. If the patient does not attend the 
scheduled visit, site staff are required to make a telephone contact with the patient according 
to the visit schedule (i.e., every 3 months) to assess for any potential study endpoints and 
record as appropriately in the eCRFs. 
For patients whose treatment is stopped as a result of a data monitoring committee 
recommendation to suspend treatment in one dose group, follow-up for cardiovascular (CV) 
and safety events will continue. Since these patients will not receive further study medication, 
less frequent follow-up will be conducted every 6 months. 
Withdrawal of consent or Lost to Follow-Up: Sites are required to provide an annual update in 
the eCRF’s for any patient who has a status of Withdrawal of consent. Please see Section 
5.5.8 for any patient who fails to appear for on site visits the study staff will be required to 
complete the Visit Information eCRF.
For any patients who suffer from a stroke during the pivotal phase please see Section 6.6.5 for 
details
Sites are required to call the IVRS/IWRS at the prescreening and screening visit and at each 
visit to register their patient’s status and if applicable, receive the medication numbers to 

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dispense treatment. Dispensing of medication should be the last assessment performed at each 
visit.

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Table 6-1
Assessment schedule of pivotal phase
Visit
Pre-
Screen
1
2
2.5
3
4
5
6
7
8
9
10
11
12,16, 
20,248
13,17, 
21, 258
14,18, 
22,268
15,19, 
23,278
End of Study 
(EOS)
Month
-1 0
0.5
1.5 3
6
9 12
15
18
21
24
27,39, 
51,63…
30,42, 
54, 66…
33,45, 
57,69…
36,48, 
60,72…
event driven
Obtain informed consent
X
Prescreening Informed Consent
X
Height
X
Inclusion/Exclusion
X
Labs for entry criteria only:, HIV 
Screen, HBsAg and HCV antibody
[For Japan only] [In Japan, HBc 
antibody and HBs antibody are 
additionally included]
X
Hs-CRP
X10
X7 X
X
X
X
X
X
X
X
X
X
X
X
Determination of tuberculosis status1
X
Demography
Demography
X
History of CV Disease
X
Medical History/Current Conditions
X
Family History of CV disease
X
Smoking & Alcohol History
X
Treatment Assessments
Call IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior & Concomitant Antidiabetic & CVD 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Visit
Pre-
Screen
1
2
2.5
3
4
5
6
7
8
9
10
11
12,16, 
20,248
13,17, 
21, 258
14,18, 
22,268
15,19, 
23,278
End of Study 
(EOS)
Month
-1 0
0.5
1.5 3
6
9 12
15
18
21
24
27,39, 
51,63…
30,42, 
54, 66…
33,45, 
57,69…
36,48, 
60,72…
event driven
Efficacy Assessments
Potential endpoint assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c & FPG (all patients)2
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
Physical Exam 
X
X
X
X
X
Vitals (includes BMI, weight, waist 
circumference)
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
Standard Hematology & Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Lipid Profile3 
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunological (e.g. ANA) Screen
X
X12
AE (prompting for infections)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test in women9
X
X

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Visit
Pre-
Screen
1
2
2.5
3
4
5
6
7
8
9
10
11
12,16, 
20,248
13,17, 
21, 258
14,18, 
22,268
15,19, 
23,278
End of Study 
(EOS)
Month
-1 0
0.5
1.5 3
6
9 12
15
18
21
24
27,39, 
51,63…
30,42, 
54, 66…
33,45, 
57,69…
36,48, 
60,72…
event driven
Other

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Visit
Pre-
Screen
1
2
2.5
3
4
5
6
7
8
9
10
11
12,16, 
20,248
13,17, 
21, 258
14,18, 
22,268
15,19, 
23,278
End of Study 
(EOS)
Month
-1 0
0.5
1.5 3
6
9 12
15
18
21
24
27,39, 
51,63…
30,42, 
54, 66…
33,45, 
57,69…
36,48, 
60,72…
event driven
1 Please see protocol Section 4.2 Determination of tuberculosis status for details.
2 Diagnosis of diabetes 
 based on HbA1c data (and/or FPG for diagnosis of diabetes) should be verified by a 
repeat HbA1c and FPG within 6 weeks of the initial observation.
3 Patient must have fasted 10 hours for this test. Triglycerides (TG), total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol and 
non-HDL cholesterol. LDL Cholesterol, VLDL cholesterol and non-HDL cholesterol will be calculated unless triglycerides > 400 mg/dL in which 
case a direct LDL cholesterol assay will be employed.
 
5 Please see Section 6.6.4 and Section 6.6.5 for administration of the questionnaires in addition to the use of the modified Rankin 
questionnaire. 
 
  
7 Patients with a prescreen hsCRP ≥ 2 mg/L from the central laboratory do not require an hsCRP at Visit 1, providing the centrally-performed 
prescreen hsCRP is less than 60 days prior Visit 2 and the patient is on stable (at least 4 weeks) long term (cardiovascular) medication.  
8 This sequence of visits will repeat until the study is deemed complete and sites are notified by the Sponsor to have all patient return for the 
EOS assessments
9 Mandatory for all women, regardless of menopause or surgical history.
10 The pre-screening hs-CRP value should be noted in the patient chart. 
11 Includes prior treatment for tuberculosis as well as prior flu and pneumococcal vaccinations and all concomitant vaccinations (Section 5.5.6)
12 Upon approval by Novartis, the Investigator (in select countries) may collect EOS frozen blood samples prior (ideally within 3 months) to the 
scheduled EOS visit.

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Table 6-2 lists all of the assessments of the extension phase for patients not participating in 
the 6-month study drug washout. The table indicates with an “X” when the visits are 
performed. Patients should be seen for all visits on the designated day or as close to it as 
possible. The study assessment schedule below outlines all procedures performed on patients 
at scheduled visits. The administration of study treatment is performed as per the visit 
assessment schedule at study sites by trained site staff after the completion of all other 
assessments. The first drug administration as part of the extension phase will be performed at 
the first visit of the extension phase. The first visit of extension phase at Month 0 (visit 201) 
should occur on the same day as the pivotal phase EOS visit (Figure 3-2). In case the last drug 
administration of the pivotal phase occurred within 4 weeks before the pivotal phase EOS 
visit, the study drug administration at the extension phase Month 0 visit will be skipped and 
the first injection as part of the extension phase will be performed at the Month 3 visit (visit 
202). If the pivotal phase EOS visit and the first visit of the extension phase cannot occur on 
the same day, the Investigator must perform a thorough review of new medical histories and 
concomitant medication changes from the time of the last trial visit until the first visit of the 
extension phase. New medical histories must be added to the Adverse Event eCRF and 
medication changes to the Concomitant Medication eCRF. After signing the ICF, the patient 
should enter the extension phase at the visit number corresponding to the visit that would be 
scheduled if the pivotal phase EOS visit and first visit of the extension phase occurred on the 
same day. However, if this visit number is greater than Month 9 (Visit 204), the patient should 
enter the extension phase at visit Month 9 (Visit 204). The first visit of the extension phase 
should occur within 18 months of the last visit of the pivotal phase. The visit assessments 
listed below are for the estimated timeframe a patient would participate in the study. The 
extension phase will continue in an individual country for a minimum of two years from the 
date of the first patients enrolled in that country. The maximum duration of the extension 
phase will be 2.5 years from the date of the first patient enrolled in that country or until 
marketed product is available in that country, whichever comes first.
Discontinuation of study treatment: It is highly encouraged that patients who discontinue 
study treatment still attend regularly scheduled clinic visits. If the patient does not attend the 
scheduled visit, site staff are required to make a telephone contact with the patient according 
to the visit schedule (i.e. every 3 months) to assess for any adverse event and record as 
appropriately in the eCRFs. 
Sites are required to call the IVRS/IWRS at each visit to register their patient’s status and if 
applicable, receive the medication numbers to dispense treatment. Dispensing of medication 
should be the last assessment performed at each visit.

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Table 6-2
Assessment schedule of extension epoch for patients not participating in study drug washout
Visit Number
2012
202
203
2045
205
206
207
208
209
210
299
(End of 
extension1)
Month
02
3
6
9
12
15
18
21
24
27
301
Obtain informed consent
X
Pregnancy test in women3
X7
X
Call IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
Prior & Concomitant Antidiabetic & CVD 
Medications
X6,7
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X6,7
X
X
X
X
X
X
X
X
X
X
AE (prompting for infections, malignancies, 
CV events)8
X6,7
X
X
X
X
X
X
X
X
X
X
Drug administration
X2
X
X
X5
X
X
X
X
X
X
Study phase completion form
X
Vitals (includes BMI, weight, waist 
circumference)
X
X
X
1 The extension phase will continue in an individual country for a minimum of two years from the date of the first patients enrolled in that 
country. The maximum duration of the extension phase will be 2.5 years from the date of the first patient enrolled in that country or until 
marketed product is available in that country, whichever comes first.
2 First visit of extension phase at Month 0 (Visit 201) should occur on the same day as the pivotal phase EOS visit. In case the last drug 
administration of the pivotal phase occurred within 4 weeks before the pivotal phase EOS visit, the study drug administration at the extension 
phase visit 201 (Month 0) will be skipped and the first injection as part of the extension phase will be performed at visit 202 (Month 3). Prior & 
Concomitant Antidiabetic & CVD Medications, Concomitant Medications, Vitals and AE assessment are not required at first visit of extension 
phase (Month 0, Visit 201) if they are performed as part of the pivotal phase EOS visit.
3 Mandatory for all women, regardless of menopause or surgical history. Pregnancy test to be performed locally.
 

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5 Visit 204 (Month 9) will be the first scheduled visit at which an open-label dose of 150 mg canakinumab will be administered. The 
intermediate dose of 150 mg canakinumab will be administered until the final dose of canakinumab is implemented at the study sites based on 
the results from the pivotal phase.
6 Adverse Events and Concomitant Medications ongoing from the pivotal phase EOS visit must be re-entered into the extension phase visit 
Month 0 (Visit 201) Adverse Event eCRF and Concomitant Medication eCRF, respectively.
7 Adverse Events, Concomitant Medications and a urine pregnancy test will be newly assessed for patients who do not have the pivotal phase
EOS visit on same day as the first visit of the extension phase.
8 New medical histories must be added to the Adverse Event eCRF.

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Table 6-3 lists all of the assessments of the extension phase for patients with prediabetic status 
at both randomization and pivotal phase EOS visit who participate in the 6-month study drug 
washout with no study drug administration. The table indicates with an “X” when the visits 
are performed. Patients should be seen for all visits on the designated day or as close to it as 
possible. The study assessment schedule below outlines all procedures performed on patients 
at scheduled visits. The administration of study treatment is performed as per the visit 
assessment schedule at study sites by trained site staff after the completion of all other 
assessments. During the study drug washout, prediabetic patients will skip two doses of their 
pivotal phase blinded assigned treatment arm. The pivotal phase EOS glycemic status will be 
assessed based on the last HbA1c and FPG data available at the EOS visit. If no HbA1c value 
is available from the End of Prediabetes Washout visit or if a diabetes diagnosis is only based 
on one FPG value of ≥ 126 mg/dL (≥ 7 mmol/L) from the End of Prediabetes Washout visit, 
an unscheduled visit should be conducted within 6 weeks. At their first visit of the subsequent 
main drug dispensing period of the extension phase (visit Month 0) study drug washout 
participants receive one dose of their assigned pivotal phase blinded treatment arm before 
they switch to the open-label dose of 150 mg canakinumab at their next visit (visit Month 3). 
The first visit of the main drug dispensing period of the extension phase (Month 0, Visit 201) 
should occur on the same day as the End of Prediabetes Washout visit (Visit 199) (Figure 3-3). 
If the End of Prediabetes Washout visit and the first visit of the main drug dispensing period 
of the extension phase cannot occur on the same day, the Investigator must perform a 
thorough review of new medical histories and concomitant medication changes from the time 
of the last attended trial visit until the first attended visit of the main drug dispending period 
of the extension phase. New medical histories must be added to the Adverse Event eCRF and 
medication changes to the Concomitant Medication eCRF. After signing the ICF, the patient 
should enter the main drug dispensing period of the extension phase at the visit number 
corresponding to the visit that would be scheduled if the End of Prediabetes Washout visit and 
first visit of the main drug dispensing period of the extension phase occurred on the same day.
However, if this visit number is greater than Month 3 (Visit 202), the patient should enter the 
extension phase at visit Month 3 (Visit 202). The first visit of the main drug dispensing period
of the extension phase should occur within 18 months of the last visit of the pivotal phase. 
The visit assessments listed below are for the estimated timeframe a patient would participate 
in the study. The extension phase will continue in an individual country for a minimum of two 
years from the date of the first patients enrolled in that country. The maximum duration of the 
extension phase will be 2.5 years from the date of the first patient enrolled in that country or 
until marketed product is available in that country, whichever comes first.
Discontinuation of study treatment: It is highly encouraged that patients who discontinue 
study treatment still attend regularly scheduled clinic visits. If the patient does not attend the 
scheduled visit, site staff are required to make a telephone contact with the patient according 
to the visit schedule (i.e. every 3 months) to assess for any adverse event and record as 
appropriately in the eCRFs. 
Sites are required to call the IVRS/IWRS at each visit to register their patient’s status and if 
applicable, receive the medication numbers to dispense treatment. Dispensing of medication 
should be the last assessment performed at each visit.

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Table 6-3
Assessment schedule of extension epoch for prediabetic patients participating in 6-month study drug washout
Visit Number
1991
(End of 
Prediabetes 
Washout)
2013
2028
203
204
205
206
207
208
299
(End of 
extension2)
Month
Pivotal 
phase EOS + 
6 months
0
3
6
9
12
15
18
21
242
Obtain informed consent
X
Pregnancy test in women4
X
X
Call IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
Prior & Concomitant Antidiabetic & CVD 
Medications
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X9,10
X
X
X
X
X
X
X
X
AE (prompting for infections, malignancies, 
CV events)11
X
X9,10
X
X
X
X
X
X
X
X
Drug administration
X
X8
X
X
X
X
X
X
Study phase completion form
X
X
Vitals (includes BMI, weight, waist 
circumference)
X
X
X
X
Physical Exam
X
ECG
X
hsCRP
X
HbA1c & FPG
X7
Standard Hematology & Chemistry
X
Fasting Lipid Profile6
X

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1 Patients with prediabetic status as defined by HbA1c/FPG lab values of HbA1c of 5.7 – 6.4% or FPG of 100 – 125 mg/dL (= 5.6 – 6.9 
mmol/L) at both pivotal phase randomization and pivotal phase EOS will participate in study drug washout before they restart study drug 
administration as part of the extension phase at visit 201 (Month 0), provided they sign the Informed Consent Form.
2 The extension phase will continue in an individual country for a minimum of two years from the date of the first patients enrolled in that 
country. The maximum duration of the extension phase will be 2.5 years from the date of the first patient enrolled in that country or until 
marketed product is available in that country, whichever comes first.
3 The first visit of the main drug dispensing period of the extension phase at Month 0 (Visit 201) should occur on the same day as the End of 
Prediabetes Washout visit (Visit 199). Prior & Concomitant Antidiabetic & CVD Medications, Concomitant Medications, Vitals and AE 
assessment are not required at visit Month 0 (Visit 201) if they are performed as part of the End of Prediabetes Washout visit (Visit 199).
4 Mandatory for all women, regardless of menopause or surgical history. Urine pregnancy test to be performed locally.
 
6 Patient must have fasted 10 hours for this test. Triglycerides (TG), total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol and 
non-HDL cholesterol. LDL Cholesterol, VLDL cholesterol and non-HDL cholesterol will be calculated unless triglycerides > 400 mg/dL in which 
case a direct LDL cholesterol assay will be employed.
7 An unscheduled visit will be conducted within 6 weeks if no HbA1c value is available from the End of Prediabetes Washout visit (visit 199) or 
if a diabetes diagnosis is only based on one FPG value of ≥ 126 mg/dL (≥ 7 mmol/L) at the End of Prediabetes Washout visit.
8 Visit 202 (Month 3) will be the first scheduled visit at which an open-label dose of 150 mg canakinumab will be administered. The 
intermediate dose of 150 mg canakinumab will be administered until the final dose of canakinumab is implemented at the study sites based on 
the results from the pivotal phase.
9 Adverse Events and Concomitant Medications ongoing from the End of Prediabetes Washout visit must be re-entered into the extension 
phase visit Month 0 (Visit 201) Adverse Event eCRF and Concomitant Medication eCRF, respectively.
10 Adverse Events and Concomitant Medications will be newly assessed for patients who do not have their End of Prediabetes Washout visit 
on the same day as the first visit of the main drug dispensing period of the extension phase.
11 New medical histories must be added to the Adverse Event eCRF.

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6.1
Information to be collected on screening failures
All patients where informed consent has been given for the pivotal phase (including screening 
failures), will have the Screening Phase Disposition, Demographics, Inclusion / Exclusion, 
Informed Consent and Adverse Event (if SAE data has been collected) eCRFs completed. 
For screened patients who signed informed consent but are not randomized or entered into the 
next period of the study (usually starting at visit 1) will have adverse events that are not SAEs   
followed by the investigator and collected only in the source data. 
For all patients who signed the informed consent and are randomized, or who are entered into 
the next period of the study, will have all adverse events occurring after informed consent 
recorded on the Adverse Event eCRF page, with the exception of all study endpoints. 
The investigator will have the discretion to record abnormal test findings on the Medical 
History eCRF whenever, in their judgment the test abnormality occurred prior to the informed 
consent signature. For example: an investigator can determine that an ECG abnormality that 
was seen on an ECG conducted after informed consent was obtained was a pre-existing 
condition. This pre-existing condition is then recorded on the Medical History eCRF and not 
as an adverse event.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: 
information on date of birth (if allowable), age, sex, race and ethnicity.
Relevant medical history/current medical conditions present before signing informed consent 
will be collected at Visit 1 of the pivotal phase. General medical history will include: HEENT, 
Neoplastic and Hematological Disorders, Cardiovascular history, including MI history, prior 
events or disease, hypertension, hyperlipidemia, smoking history, Respiratory, Kidneys and 
Urinary Tract, Gastrointestinal, Immunological and infectious, Endocrine and Metabolic 
including history and diagnosis of diabetes and it’s complications, CNS including psychiatric 
disorders. Relevant medical history/current medical condition data includes data until signing 
of informed consent. Where possible, diagnoses and not symptoms will be recorded. Family 
history for cardiovascular diseases will be collected.
6.3
Treatment exposure and compliance
Study treatment will be administered at the clinic under the supervision of the investigative 
staff with the dosing record captured within each visit on the Drug Accountability eCRF. 
Any medications taken within 30 days prior to the date of screening and after will be recorded 
on the appropriate Concomitant Medications and or Procedures and Significant Non-drug 
Therapies eCRF. 
This will also apply for the extension phase.

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6.4
Efficacy
6.4.1
Primary Efficacy assessment (primary objective)
The primary endpoint is defined as the time to the first adjudication committee confirmed 
major adverse cardiovascular event (MACE) occurring during the double-blind treatment 
period of the pivotal phase, which is a composite of CV death, non-fatal MI, and stroke. 
An independent adjudication committee that is blinded to treatment assignments will review 
and adjudicate all clinical events that constitute the primary composite endpoint and 
secondary endpoints. 
In the extension phase no endpoints will be collected. MACE will be recorded as adverse 
events, using the Adverse Event eCRF. No adjudication of events will be performed during 
the extension phase. Reporting of Adverse Events is described in Section 7.
6.4.2
Secondary efficacy assessment (secondary objectives)
All the listed secondary efficacy assessments are for the pivotal phase only unless specified 
otherwise. Key secondary efficacy assessments will comprise:

Time to the first occurrence of the adjudication committee confirmed composite 
cardiovascular endpoint consisting of primary endpoint, and hospitalization for unstable 
angina requiring unplanned revascularization 

Time to adjudication committee confirmed new onset of type 2 diabetes among those with 
pre-diabetes at randomization (defined in Section 4) (time to NOD) 
Other secondary efficacy assessments will comprise 

Time to first event of, non-fatal MI, stroke and all-cause mortality composite

Time to all-cause mortality

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6.4.3
Appropriateness of efficacy assessments 
Time to major adverse cardiovascular events and progression to diabetes (new onset diabetes) 
are well defined and standard clinical events in clinical trials aimed at demonstrating primary 
and secondary efficacy of investigational agents on clinical endpoints. Secondary endpoints 
are widely used clinical efficacy endpoints in cardiovascular clinical endpoint trials. 
6.5
Safety
Safety and Tolerability Assessments

Laboratory evaluations (performed during pivotal phase and prediabetes washout)

Height, weight and waist circumference (performed throughout full study)

Adverse events and serious adverse events, including cardiovascular events, malignancies, 
and infections (performed throughout full study)

Discontinuation due to AEs (performed throughout full study)

Hypoglycemia events  (performed throughout full study)

Injection site reactions (assessed throughout full study)

Physical Exam (performed during pivotal phase and prediabetes washout)

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

Vitals (assessed throughout full study)

ECG (performed during pivotal phase and prediabetes washout)
Serious allergies/immunological events (e.g. Anti-canakinumab antibodies), serious infections, 
and malignancies adverse events will be monitored carefully using adverse/serious adverse 
events procedure described in Section 7.1 Adverse events and Section 7.2 Serious adverse 
event reporting during this trial because these adverse events represent hypothetical 
mechanism of action related risks of canakinumab therapy. During the pivotal phase, these 
adverse events will be adjudicated by an expert adjudication committee to strengthen data 
quality and safety conclusions. No adjudication of events will be performed during the 
extension phase.
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to signing of informed consent must be 
included in the relevant Medical History/Current Medical Conditions eCRF. Significant 
findings after the signing of informed consent, which meet the definition of an Adverse Event, 
must be recorded on the Adverse Event screen of the patient’s eCRF.
Physical examination will also be performed during prediabetes washout but not during main 
drug dispensing period of the extension phase.
6.5.2
Vital signs
Vital signs including BP (3 measurements with the average of all three used for inclusion) and 
pulse measurements will be assessed per the assessment schedule. In general blood pressure 
should be taken after the patient has been sitting for five minutes, with back supported and 
both feet placed on the floor. Systolic and diastolic blood pressure should be measured three 
times using an automated validated device with an appropriately sized cuff. The repeat sitting 
measurements should be made at 1 to 2 minute intervals and the mean of the last three 
measurements will be used. If using the automated devise and current cuff sizes available are 
not large enough for the patient's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used.
Vital signs will also be performed during the extension phase.
Clinically notable vital signs are defined in Appendix 1.
6.5.3
Height, weight and waist circumference
Height in centimeters (cm) or inches and body weight (to the nearest 0.1 kilogram [kg] or 
pound [lb] in indoor clothing, but without shoes) will be measured. Body Mass Index (BMI) 
will be calculated as the weight in kg divided by the height in meters squared. Waist 

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circumference should be measured with a flexible tape. For consistency among sites, the 
position for measuring waist circumference will be at the uppermost border of the right iliac 
crest (or at the umbilicus if landmarks cannot be palpated). The measure should be recorded 
while the patient is in the expiratory phase of respiration. 
Height, weight and waist circumference will also be performed during the extension phase.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. All patients should be fasting for at least 
10 hours prior to having the labs drawn at the scheduled time-points. All screening labs must 
be reviewed for completeness prior to randomization.  Lab results that are missing or 
unavailable must be repeated prior to randomization.  
 
 
Laboratory evaluations will also be performed during prediabetes washout but not during 
main drug dispensing period of the extension phase.
6.5.4.1
Hematology
The following tests are included in the hematology but are not limited to: HbA1c, 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured. 
Hematology will also be assessed during prediabetes washout but not during main drug 
dispensing period of the extension phase.
6.5.4.2
Clinical chemistry
The following tests are included in the chemistry but are not limited to: hsCRP, eGFR, 
Estradiol, Fasting Plasma glucose, Blood urea nitrogen, creatinine, CK (CK-MB and 
troponin-I if CK is >2ULN and there is no underlying etiology for the increase in CK), total 
bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, chloride, calcium, 
phosphorous, total protein, albumin, and uric acid will be measured. FSH, HIV screen, 
HBsAg and HCV antibody will only be measured at Visit 1 for eligibility purposes. 
Clinical chemistry will also be assessed during prediabetes washout but not during main drug 
dispensing period of the extension phase.
[For Japan only]
[In Japan, HBc antibody and HBs antibody will also be measured for Visit 1 eligibility 
purposes. This is not applicable for the extension phase.]

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6.5.4.2.1 Fasting Lipid profile
The following tests are included in the fasting lipid profile but are not limited to triglycerides, 
total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol and non-HDL 
cholesterol. LDL cholesterol, VLDL cholesterol and non-HDL cholesterol will be calculated 
unless triglycerides > 400 mg/dL in which case only a direct LDL cholesterol assay will be 
employed. 
Fasting Lipid profile will also be performed during the prediabetes washout but not during 
main drug dispensing period of the extension phase.
6.5.5
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed at baseline (Visit 2), yearly visits, and at the end of 
study visit. ECG’s will be read by a central vendor. Each ECG tracing should be labeled with 
the study number, patient initials (if applicable), patient number, date, and kept in the source 
documents at the study site. Clinically significant abnormalities should also be recorded on 
medical history/ adverse events eCRF page. Any potential endpoints should be recorded on 
the Clinical Study Endpoint Tracking Form eCRF.
ECG will also be performed during the prediabetes washout but not during main drug 
dispensing period of the extension phase.
6.5.6
Pregnancy and assessments of fertility
Neither the pivotal phase nor the extension phase include women of child bearing potential 
and therefore pregnancy test should be performed on all female study participants to detect 
unexpected pregnancies. A positive urine pregnancy test requires immediate interruption of 
study treatment until serum β-hCG is performed and found to be negative. If the serum β-hCG 
is positive, the patient must be discontinued from study treatment but should continue follow 
up in the trial. Study treatment can be restarted after completion or termination of pregnancy 
following discussion with the Sponsor. 
6.5.7
Appropriateness of safety measurements
Safety endpoints used in this trial are standard endpoints in demonstrating safety of 
investigational agents in clinical trials. Safety events of special interest, in the following 
categories, serious infections and malignancies, will be adjudicated by two expert 
adjudication committees during the pivotal phase. No adjudication of events will be 
performed during the extension phase. Additionally, canakinumab and canakinumab antibody 

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concentrations will be measured during the pivotal phase due to the hypothetical risk of 
immune response to the study treatment. These safety events of special interest represent 
hypothetical risks of canakinumab treatment.

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7
Safety monitoring
7.1
Adverse events
An adverse event is the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s) occurring after signing informed consent.  
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them.  
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 or they require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study  
Adverse events also may be detected when they are volunteered by the patient during or 
between visits or through physical examination, laboratory test, or other assessments. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values, which are considered to be non-typical in patient with 
underlying disease 
During the pivotal phase all adverse events, which are no protocol endpoints, must be 
recorded on the Adverse Events CRF with the below listed information. During the extension 

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phase ALL adverse events must be recorded on the Adverse Events CRF with the following 
information:
1. the severity grade [mild, moderate, severe]
2. The relationship to the study treatment (Reasonable possibility that the AE is related: No, 
Yes)
3. Its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported at the time of the end of the study
4. whether it constitutes a serious adverse event (SAE) 
5. the action taken regarding study treatment 
6.
whether medication or therapies taken (no concomitant medication/non-drug therapy,    
concomitant medication/non-drug therapy)
7. the outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown)
An SAE is defined as any adverse events (appearance of or worsening of any pre-existing 
condition, undesirable sign(s), symptom(s) or medical condition, which are not protocol 
endpoints, that meet the following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above

In CACZ885M2301, malignancies are considered medically significant. This 
classification will aid in the data collection on these events.
Study-specific adaption of the standard definition of AEs and SAEs
 
 
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event sent for adjudication as a potential study endpoint or reported as a non-adjudicated 
cardiovascular endpoint by the investigator will not be reported as an adverse event /serious 
adverse event but will be captured on the Clinical Endpoint Form eCRF. Only if the 
adjudication committee determines that the event is not a study endpoint, will this event be 
reported as an adverse / serious adverse event following procedures described in Section 7.2
Serious adverse event reporting. 
The study specific exemption does not apply to the extension phase. During the extension 
phase ALL adverse events will be reported as AEs following the procedures described in 
Section 7.1 and Section 7.2. No adjudication of events will take place during the extension 
phase.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.
All adverse events should be treated appropriately. Action taken may include one or more of 
the following: no action taken (i.e. further observation only); study drug dosage temporarily 
interrupted; study drug permanently discontinued; concomitant medication given; non-drug 
therapy given. The action taken to treat the adverse event should be recorded on the Adverse 
Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent. - Assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, suspected relationship to the study treatment, 
interventions required to treat it, and outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
The investigator should also instruct each patient to report any new Adverse Experiences 
(beyond the protocol observation period) that the patient, or the patient’s personal physician, 
believes might reasonably be related to study treatment. This information should be recorded 
in the investigator’s source documents, and if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse event reporting
To ensure patient safety, every SAE, regardless of suspected causality, except for those being 
adjudicated as endpoints or are reported as non-adjudicated cardiovascular endpoint by the 
investigator during the pivotal phase, which occur after the patient has provided informed 
consent and until 90 days after the last study visit (following the last administration of study 
treatment if there are post-treatment follow-up visits) must be reported to Novartis within 24 
hours of learning of the occurrence. Any SAEs experienced after this 90 day period should 
only be reported to Novartis if the investigator suspects a causal relationship to the study drug. 
Hypoglycemia events, which require hospitalization or the assistance of another person 
to treat must, be reported as an SAE.

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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to study drug(s), 
complete the SAE Report Form in English and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for 
signature are to be found in the investigator folder provided to each site.
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
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 Novartis study drug, a Drug Safety and 
Epidemiology 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 drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
Reporting of events (including coincidental cardiovascular events) that are 
both study endpoints and AE’s / SAE during pivotal phase
The integrity of the pivotal phase may be compromised if cardiovascular events that are study 
endpoints are systematically unblinded in order to fulfill European SUSAR reporting 
requirements for SAE (European Commission ENTR/CT12 Guideline (2006)). Therefore, in 
the pivotal  phase, potential study endpoints are excluded from the definition of AE’s and 
SAE’s and are not to be captured as AE and SAE’s but only on the relevant study endpoint 
CRF. During the pivotal phase, these events are therefore NOT to be reported to Novartis 
within 24 hours on SAE forms and will not be reported to regulatory agencies or investigators 
other than as a study endpoint in the Clinical Study Report. Reporting to IRB’s should follow 
local guidelines.
The following pre-defined study endpoints are excluded from the definition of AEs and 
SAE’s in the pivotal phase: 

CV and non-CV Deaths (please see section Reporting of Deaths for specific exceptions for 
selected non-CV deaths that must be reported as both endpoints AND SAEs )

Fatal and non-fatal MI

Fatal and non-fatal Stroke (e.g. hemorrhagic stroke, ischemic stroke)



Hospitalization or prolongation of hospitalization for heart failure 

Critical Limb ischemia

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
Limb amputation

Transient Ischemia Attack (TIA)

New onset type 2 diabetes (NOD)


Coronary angiography / Coronary Revascularization (PCI or CABG) 


The Data Monitoring Committee (DMC) will review these endpoint data throughout the 
pivotal phase in an unblinded manner. Should the DMC make recommendations on the 
conduct of the pivotal phase that are considered to have significant bearing on the benefit risk 
of the trial, these will be communicated to competent authorities, IRBs/IECs and investigators 
and the ECs by Novartis in an appropriate timescale. 
Any event that is not listed under the pre-specified endpoints above should be reported as an 
SAE. If it meets SUSAR criteria, the event will be unblinded; a report to competent 
authorities and relevant ethics committees and issuance of an IND Investigator Safety Letter 
will occur per local regulatory requirements. 
Should an investigator during the pivotal phase consider that the character and the severity of 
the above listed events is not consistent with the expected presentation or course of that 
endpoint and the investigator considers that the study drug may have contributed to this 
abnormal presentation, then this event should be reported as an SAE and an endpoint. 
Should an investigator report an SAE during the pivotal phase that is considered by Novartis 
to be potentially consistent with a study endpoint, Novartis will request confirmation from the 
investigator that this event is indeed an SAE and not an endpoint. The investigator should 
respond immediately to these requests in order to minimize the risk that such an event may 
require unblinding for regulatory reporting of SUSARs. Should the investigator, following 
this request for review, consider the event to be an endpoint the event must be included as an 
endpoint and confirmation sent to Novartis DS&E that the event should no longer be 
considered an SAE. Should the investigator either fail to reply in the necessary timeframe, or 
confirm that the event is an SAE and not an endpoint, the event will be handled as an SAE.
Events that following data review and adjudication are deemed not to be endpoints for this 
study will be reported as AEs and SAEs, as soon as adjudication process has been completed, 
following standard reporting guidelines. 
During the extension phase, endpoints will no longer be collected. The above described 
protocol exemption does not apply for the extension phase. During the extension phase ALL 
SAEs must be reported to Novartis within 24 hours of learning of the occurrence as outlined 
in Section 7.2.
[For Japan only]
[In Japan, the following pre-defined study endpoints must be reported to Novartis Pharma 
K.K within 24 hours of learning of the occurrence, using the “Japan Pre-defined Study 

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Endpoints Reporting Form”. The detail of cases that need to be reported to Novartis Pharma 
K.K. and procedures for reporting are described in a separate document.


Hospitalization or prolongation of hospitalization for heart failure 

Critical Limb ischemia

Limb amputation

Transient Ischemia Attack (TIA)

New onset type 2 diabetes (NOD)


Coronary angiography / Coronary Revascularization (PCI or CABG) 


This will not apply to the extension phase.]
Reporting of deaths
It is important to note that ALL deaths (deaths considered by the investigator to be CV and 
non-CV causes) must be reported as predefined study endpoints during the pivotal phase and 
the investigator must send all documentation for adjudication. 
The following SAEs have been causally associated with non-CV deaths due to various 
medications in the past. Therefore, if a patient during the pivotal phase, is considered to have 
died as a result of any of the following events, the death must be reported as both an endpoint 
AND as SAE. The SAE must be reported to Novartis as per SAE reporting guidelines.
NON-CV FATAL EVENTS THAT ARE REPORTED AS BOTH DEATH ENDPOINTS 
AND SAEs DURING PIVOTAL PHASE

Allergy events: Anaphylaxis, Angioedema, Laryngeal edema

Serious hepatic events including hepatic failure, hepatic necrosis, Hy’s law case, acute 
yellow liver atrophy

Serious cutaneous skin reactions including: Stevens-Johnson syndrome, Toxic epidermal 
necrolysis, Erythema multiforme

Drug induced hematological syndromes (including agranulocytosis, aplastic anemia, bone 
marrow failure, pancytopenia and bicytopenia)

Inflammatory lung disorders (including allergic, fibrosing, and necrotising alveolitis,  
eosinophilic pneumonia and interstitial lung disease)

Autoimmune myocarditis

Suicide including drug overdose

Malignant hypertension

Pulmonary hypertension

Renal failure (acute and chronic) including tubulointerstitial nephritis 

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
Opportunistic infections 

Systemic lupus erythematosus

Hypoglycemia

Torsade de pointes, Long QT syndrome

Pancreatitis

Drug interaction

Rhabdomyolysis

Seizure

Guillain-Barre syndrome

Progressive multifocal leukoencephalopathy (PML)
In case the cause of the death event is not listed above it will be reported as study endpoint 
only. If the death event is adjudicated as a non-CV death, the death event will be reported as 
serious adverse event. 
Reporting of adverse events during extension phase
During the extension phase, endpoints will no longer be collected. The above described 
protocol exemption does not apply for the extension phase. Therefore ALL adverse events are 
collected as SAE’s, as described in Section 7.2. During the extension phase ALL SAEs must 
be reported to Novartis within 24 hours of learning of the occurrence.
7.3
Reporting of study treatment errors including misuse/abuse
This section applies to the extension phase only.
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (European Medicines Agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE.
Treatment error 
type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE

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Treatment error 
type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Misuse/Abuse
Yes
Yes,
Yes, even if not associated 
with a SAE
7.4
Pregnancies
Women of child-bearing potential are excluded from this study (pivotal and the extension 
phases); however, in the event a woman became pregnant we must ensure patient safety. Each 
pregnancy in a patient on study treatment must be reported to Novartis within 24 hours of 
learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the Novartis study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
7.5
Data Monitoring Committee
An external and independent DMC will be formed for the pivotal phase to periodically review 
safety information, and to evaluate the interim results relative to pre-defined statistical criteria 
to see if the trial has reached standards allowing stopping for proof of efficacy or for futility.
The DMC will include experts in cardiovascular and cerebrovascular disease, T2DM, large 
scale clinical trials and statistics; the members will review the results confidentially and will 
have no other roles in the study. 
The membership of the DMC and the responsibilities of the DMC and Novartis will be 
defined in a separate document entitled the “Data Monitoring Committee Charter.” The DMC 
Charter will include information about the data flow, purpose, timing of DMC meetings, 
guidance in the decision-making process, communication strategy, procedures for ensuring 
confidentiality, procedures to address conflicts of interest, and statistical monitoring 
guidelines.
For the extension phase the DMC will not be utilized.
7.6
Adjudication Committees
There will be three separate adjudication committees for the pivotal phase. There will be no 
adjudication committees utilized for the extension phase.
7.6.1
Cardiovascular clinical events adjudication committee
During the pivotal phase, cardiovascular clinical events will be adjudicated under blind by an 
adjudication committee, composed of reviewers who are experts on cardiovascular and 
cerebrovascular disease and T2DM. This measure is designed to ensure the objectivity, 

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reliability and validity of the event classification. The procedures for reporting and case 
definitions are detailed in a separate charter document. The following primary and secondary 
endpoints will be adjudicated:

All death 

Non fatal MI 

Stroke (e.g. hemorrhagic stroke, ischemic stroke) 

Unstable angina requiring unplanned coronary revascularization

New onset type 2 diabetes mellitus
Definitions of clinical endpoints are described in Appendix 3.
The primary endpoint will be assessed based on MACE adjudicated to have occurred between 
a patient’s randomization and either 
1. the patient’s entry into the prediabetes drug washout period,
2. or the patient’s entry into the main drug dispensing period of the extension phase,
3. or for those patients not proceeding to neither prediabetes washout nor the main drug 
dispensing period of the extension phase, the patient’s pivotal phase end of study visit, but 
only if it occurred during the pivotal close-out period,
4. or otherwise the end of the pivotal close-out period (analysis cut-off).
Thus, events occurring after informed consent but before randomization do not need to be 
adjudicated and should instead be reported as adverse or serious adverse events. Events 
occurring in the  extension phase (including the prediabetes washout) should be reported as 
adverse events, as specified in Section 7.1 and Section 7.2.
Baseline and yearly ECG will be obtained during pivotal phase to assess interval ECG 
changes for study patients. Myocardial infarctions detected as interval ECG changes without 
clinical sequelae (“silent myocardial infarction”) will be reported as endpoint. Interpretation 
of all scheduled ECGs will be done by a central ECG vendor (eRT, Philadelphia, PA) using 
qualified expert physicians. 
The diagnosis New MI should be used when an ECG shows an MI that was not present on 
previous ECGs for the study patient. Previous ECGs must be available. This diagnosis should 
be used the first time the new MI is seen, but not for subsequent ECGs. 
All unplanned hospitalizations except those related to planned procedures that are non-CV 
related will be reviewed for adjudication and adjudicated when data allows adjudication.
No cardiovascular clinical events adjudication committee will be utilized for the extension 
phase.
7.6.2
Infection Adjudication Committee
An independent Infection Adjudication Committee (IAC) has been formed on a program level 
and will review pertinent data from this pivotal trial.
The mission of the IAC is to independently and blindly review, evaluate and categorize new 
reports of pre-defined infections as they become available during the conduct of this trial.
Members from the IAC may also adjudicate reports of serious allergies.

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The members, detailed mission and procedures of the IAC are detailed in the IAC charter.
The IAC will not adjudicate cases from the extension phase. 
7.6.3
Malignancy Adjudication Committee 
An independent Malignancy Adjudication Committee (MAC) has been formed on a program 
level and will review pertinent data from this trial.
The mission of the MAC is to independently and blindly review, evaluate and categorize 
reports of malignancy events across all potential indications and therapeutic areas in the 
canakinumab development program.  Members from the MAC may also adjudicate reports of 
serious allergies.
The members, detailed mission and procedures of the MAC are detailed in the MAC Charter.
The MAC will not adjudicate cases from the extension phase.
8
Data review and database management
8.1
Site monitoring
Before pivotal phase initiation, at an investigator’s meeting and/or a site initiation visit, a 
Novartis or study team representative will review the protocol and (e)CRFs with the 
investigators and their staff. This review will not be repeated for the extension phase. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site regularly to check 
the completeness of patient records, the accuracy of entries on the (e)CRFs, the adherence to 
the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that 
study treatment is being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. Continuous 
remote monitoring of each site’s data may be performed by a centralized Novartis CRA 
organization. Additionally, a central analytics organization may analyse data & identify risks 
& trends for site operational parameters, and provide reports to Novartis Clinical Teams to 
assist with trial oversight.
The investigator must maintain source documents for each patient 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 (e)CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the (e)CRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the (e)CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.

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8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Oracle 
Clinical/Remote Data Capture (OC/RDC) system. Designated investigator site staff will not 
be given access to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify on a 
regular basis that the data entered into the electronic Case Report Forms are complete and 
accurate. After database lock, the investigator will receive copies of the patient data (either 
paper or CD-ROM) for archiving at the investigational site.
This will also apply for the extension phase.
The pivotal phase data and the extension phase data will be collected in two separate 
databases in order to avoid any risk of unblinding of pivotal phase data and in order to 
guarantee a secure pivotal phase database lock while the extension phase is ongoing. The 
name of the extension phase database and of some extension phase related documents will 
contain an identifier added to the study number CACZ885M2301.
8.3
Database management and quality control
Novartis staff review the data entered into the eCRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff who will 
make the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.
Concomitant medications entered into the database will be coded. Medical history/current 
medical conditions and adverse events will be coded using the Medical dictionary for 
regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). Beyond the assessments during the study drug washout in 
prediabetic patients, no laboratory samples will be generated during the extension phase.
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). Beyond the assessments during the study drug washout in 
prediabetic patients, no ECG will be generated during the extension phase.
Randomization codes and data about all study drug dispensed to the patient will be tracked 
using an Interactive Voice Response System (IVRS/IWRS). The system will be supplied by a 
vendor, who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO).

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The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete for the pivotal phase  (i.e. 
excluding the extension phase with the study drug washout in prediabetic patients, which will 
be reported separately) and accurate, it will be locked and the treatment codes will be 
unblinded and made available for data analysis. Any changes to the database after that time 
can only be made by joint written agreement between the Clinical Science Unit Head 
 
Each occurrence of a code break via IVRS/IWRS will be reported to the clinical team and 
monitor. The code break functionality will remain available until study shut down or upon 
request of Novartis.This will also apply for the extension phase until patients switch to the 
open-label canakinumab dose.
9
Data analysis
9.1
Analysis sets
The following analysis populations will be defined for statistical analysis:

Screened set – All patients who signed the informed consent.

Randomized set – All patients who received a randomization number, regardless of 
receiving trial medication.

Safety set (SAF) – All patients who received at least one dose of study treatment and have 
at least one post-baseline safety assessment. Of note, the statement that a patient had no 
adverse events also constitutes a safety assessment. Patients will be analyzed according to 
treatment received. Treatment received will be considered identical to the randomized 
treatment if the patient has during at least one visit received at least one (of the two) 
injections constituting the treatment assignment at randomization and no wrongly 
administered injections constituting a different treatment group.

Full analysis set (FAS) – All randomized patients. This is the primary efficacy population 
applied in all efficacy endpoints. Following the intent-to-treat principle, patients are 
analyzed according to the treatment they have been assigned to at the randomization. 
However, patients who have not been qualified for randomization and who have been 
inadvertently randomized into the study are excluded from FAS, provided these patients 
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
Per protocol set (PPS) – a subset of the FAS, consists of all randomized patients in FAS 
who take at least one dose of study medication and have no major protocol deviations 
affecting the primary endpoint analyses. Major protocol deviations leading to exclusion 
from PPS will be specified prior to database lock on a blinded basis and documented in a 
separate document.
Note: The last part of the definition of the FAS is what is often referred to as misrandomized 
patients; i.e. patients for whom IVRS/IWRS calls were made by the site either prematurely or 
inappropriately prior to confirmation of the patient’s final randomization eligibility and 
double-blind medication was not administered to the patient. These patients would 
subsequently not continue to take part in the study or be followed-up. Misrandomized patients 
will not be included in the FAS, but they will be included in the Randomized Set. Further 
exclusions from the FAS may only be justified in exceptional circumstances.
Analyses will take into account the changes in randomization between trial part 1 and  trial 
part 2 (e.g. by stratifying analyses by trial part) and that patients in trial part 2 were not 
recruited concurrently with those in trial part 1. This ensure no biases arise e.g. due to 
differences over time (and thus between the two trial parts) in the recruited patient population 
or background medical care. Unless otherwise specified, patients randomized to the same 
treatment arm under randomization plan A or B will be analyzed together. This is not believed 
to introduce any biases with respect to the assessment of endpoints and the standard or care 
provided to patients, because patients have an equal 2:1 chance of being on an active 
treatment group under either randomization plan. Thus, it is not considered necessary to also 
stratify analyses in this respect.
9.2
Patient demographics and other baseline characteristics
The number of patients screened, randomized and included in FAS will be presented by 
treatment group and overall for the screened set, as well as by trial part. In addition, the 
reasons of screen failures will be provided for screened set as well. The number and 
percentage of patients in the randomized set who completed the study, who discontinued the 
study and the reason for discontinuation will be presented for each treatment group and all 
patients, as well as by trial part. The frequency (%) of patients with major protocol deviations 
as well as the criteria leading to analysis sets will be presented in separate tables for the 
randomized set. Finally, the number of enrolled and randomized patients by region as well as 
the number of patients enrolled and randomized per region and country will be presented 
descriptively for the randomized set overall and by trial part.
Baseline value is defined as the last non-missing assessment prior to the first dose of 
randomized study medication unless specified otherwise.
The following common background and demographic variables will be summarized by trial 
part using descriptive summary statistics (for continuous variables mean, median, standard 
deviation, Q1 (25th percentile), Q3 (75th percentile), minimum and maximum and for 
categorical variables frequency and percentage):

Age [years]

Sex

Race

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Ethnicity

Height [cm]

Weight [kg]

Body mass index [kg/m2] calculated as weight [kg]/ height2 [m2]

Waist circumference [cm]

Sitting pulse [bpm]

Mean sitting SBP [mmHg]

Mean sitting DBP [mmHg]

Smoking history

Alcohol history

Region (Country) of enrollment

Cardiovascular risk factors and other co-morbidities including but not limited to following:

Diabetes mellitus, complications of diabetes

Hypertension

Dyslipidemia/Hyperlipidemia

 




Prior repeated MI (multiple MIs in medical history)

Prior PCI

Prior stent implantation (incl. drug eluding stent or bare metal stent)

Prior CABG

Prior TIA/stroke

Congestive heart failure

Medical history of gout

Post MI index group

hsCRP [mg/L (two values available with the mean of these two used in analysis)]

HbA1c [%]

FPG [mmol/L]

Lipid profile

Glycemic status: T2DM, pre-diabetes, normoglycemic

Level of exercise

Family history of MI, stroke or diabetes

Highest degree of education
Treatment group comparability will be examined using the Cochran-Mantel-Haenszel test 
stratified by trial part and time since index MI for the categorical variables and the F-test for 
the continuous variables as appropriate. These p-values will be provided for descriptive 

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purposes and will not be considered to define any formal basis for determining factors that 
should be included in statistical models. If imbalances between treatment groups with respect 
to some variables occur, additional supplemental analyses may be performed to assess the 
impact of these imbalances as appropriate.
9.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Study drug
The duration of the randomized treatment received during the double-blind pivotal phase will 
be computed as the time from the first injection to the first out of 
1. the last injection date plus a quarter year (91 days), 
2. the patient’s death 
3. or the patient’s pivotal phase completion visit during the pivotal phase close-out period.
This algorithm reflects the planned treatment schedule and the long half-life of the study drug. 
The duration of the treatment period will be summarized for the full analysis set and safety set 
by trial part and treatment group descriptively including by duration categories. The overall 
patient-years of treatment will be computed as the sum of patient years of double-blind 
treatment for all patients.
Duration of exposure to study treatment excluding interruptions will be computed and 
summarized as above, but not counting periods during which the last injection was more than 
a quarter year ago.
Prior and concomitant therapies
Prior or concomitant medications will be summarized for the safety set and full analysis set in 
separate tabulations by trial part based on the coding dictionary used. Medications will be 
presented in alphabetical order, by preferred terms and grouped by anatomical main group. 
Tables will show the overall number and percent of patients receiving at least one drug of a 
particular preferred term and at least one drug in a particular anatomical main group.
Prior medications and significant non-drug therapies are defined as any medications and 
significant non-drug therapies taken prior to the randomization visit. Concomitant 
medications and significant non-drug therapies are defined as those used during the double-
blind period. Concomitant medications that were prohibited as per protocol and given during 
the conduct of the study as well as significant non-drug therapies will be summarized.
Furthermore, the following classes of medications to be precisely defined in the statistical 
analysis plan, at time of randomization and during the double-blind period, which are relevant 
to program indication, will be summarized separately:

Anti-ischemic agents

Beta blockers

Intravenous or oral nitrates

Calcium channel blockers

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
Anti-platelet agents

Acetylsalicylic acid (aspirin)

Non-aspirin oral anti-platelet agents (like P2Y12 inhibitors clopidogrel and prasugrel)

ACE inhibitors (like ramipril) 

ARBs

Lipid-lowering agents

Statins

Non-statins (like fibrates, binding resins and nicotinic acid)

Diuretics

Thiazide diuretics

Anti-diabetic medications

Insulin

Thiazolidinediones

Other oral hypoglycemic agents

Proton pump inhibitors

Anticoagulants
9.4
Analysis of the primary variable(s)
The primary analysis and all analyses of secondary/
 will use the Full 
Analysis Set (FAS), which reflects the intention-to-treat principle.
Unless otherwise specified all time-to-event analyses will be based on events occurring during 
the double-blind period of the pivotal phase. This means that only events between a patient’s 
randomization and the first of either 
1. the patient’s entry into the prediabetes washout period for prediabetic patients,
2. or the patient’s entry into the main drug dispensing period of the extension phase,
3. or for those patients proceeding to neither washout nor main drug dispensing period of the 
extension phase, the patient’s end of pivotal phase visit, but only if it occurred during the 
pivotal phase close-out period,
4. or otherwise the end of the pivotal phase close-out period (analysis cut-off) will be 
counted in these analyses.
9.4.1
Variable
The primary efficacy variable is the time to first occurrence of a major adverse cardiovascular 
event (MACE), which is a composite endpoint consisting of cardiovascular death, non-fatal 
MI, and stroke. An independent adjudication committee will review and adjudicate all clinical 
events that constitute the composite of the primary endpoints on a blinded basis. 
The time-to-event is computed as the number of days from randomization to the onset of the 
primary endpoint event in the pivotal phase. Data on patients who do not reach the primary 
endpoint by the study end date will be censored at the latest date they are known to be at risk 
in the pivotal phase.

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9.4.2
Statistical model, hypothesis, and method of analysis
The primary statistical null hypotheses are

H11: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 
300 mg dose group is greater than or equal to the hazard rate of the placebo group

H21: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 
150 mg dose group is greater than or equal to the hazard rate of the placebo group

H31: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 
50 mg dose group is greater than or equal to the hazard rate of the placebo group.
Each null hypothesis is tested against the one-sided alternative that the hazard rate is smaller 
for the respective active dose group than for the placebo group.
These hypotheses will be tested by comparing each dose to placebo with a log-rank test 
stratified by time since index MI (30 days to < 6 months and ≥ 6 months) and by trial part 
using exact method for handling ties on the full analysis set (FAS) according to the intent-to-
treat principle. The stratification according to trial part entails some statistical inefficiency 
compared to a trial that would have had 4 treatment groups from the start, especially for the 
50 mg dose. However, this approach ensures that no biases arise e.g. due to differences over 
time between the two trial parts in the recruited patient population or background medical care. 
While investigators are not blinded to the assignment of patients to randomization plan A or B, 
this is not believed to introduce any biases with respect to the assessment of the primary 
endpoint and the standard or care provided to patients, because patients have an equal chance 
of being on an active treatment group under either randomization plan. Thus, it was not 
considered necessary to also stratify the analysis in this respect, but a sensitivity analysis will 
be conducted. A sensitivity with respect to the consistency of treatment effects in the two 
parts of the trial will also be performed.
The family-wise error rate will be controlled at the two interim analyses and the final analysis 
using the closed testing procedure shown in Figure 9-1 using the graphical method of Bretz et 
al. (Bretz, et al. 2009); however, in intersection null hypotheses involving the primary null 
hypotheses for the 300 mg, 150 mg or 50 mg doses these primary null hypotheses will be 
tested using a weighted version of Dunnett’s test (Dunnett 1955). Specifically this means that 
for any intersection hypothesis from the full closure that contains at least two of H11, H21 and 
H31, a weighted Dunnett test amongst the primary null hypotheses is performed with the 
overall significance level for that test and the weighting chosen according to the weights 
assigned to these null hypotheses by the update algorithm of the graphical method. The 
nominal adjusted significance levels based on the weighted Dunnett test are always slightly 
larger than the corresponding Bonferroni levels would be. For example the mvtnorm package 
in R (Genz and Bretz 2009) calculates the nominal Dunnett significance levels at the final 
analysis for the 300 mg, 150 mg and 50 mg doses versus placebo in the test of the global null 
hypothesis to be 0.5500504%, 1.1001008% and 1.1001008%, respectively, as compared to 
Bonferroni levels of 0.49%, 0.98% and 0.98%. If other non-primary null hypotheses in such 
an intersection hypothesis have non-zero weight on the basis of Figure 9-1, the intersection 
null hypothesis will be rejected if either (a) these other null hypotheses can be rejected at a 
Bonferroni significance level based on that weight or (b) the primary null hypotheses can be 
rejected based on the weighted Dunnett test. All other intersection hypotheses are tested with 

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a weighted Bonferroni test. Protection of the family–wise error rate at level alpha is still 
guaranteed when the transition weights on the directed edges are chosen as in Figure 9-1 (see 
comment below) and all the tests on secondary variables are performed at the level resulting 
from the graphical procedure. The consonance of the test procedure (Brannath and Bretz 2010) 
has also been ensured as described below.
The testing procedure in Figure 9-1 initially splits the entire available significance level (at the 
final analysis 2.45%) between the three primary null hypotheses relating to the three doses (at 
the final analysis 20% of 2.45% = 0.49% for the primary null hypothesis of the 300 mg dose, 
40% of 2.45% = 0.98% for that of the 150 mg dose and 40% of 2.45% = 0.98% for that of the 
50 mg dose). These weights were chosen by balancing the prior expectations about the 
efficacy dose response relationship versus the potential for a better risk benefit ratio with 
lower doses. In particular, one aim was to ensure that there would be at least 80% power for 
the 50 mg dose to become significant assuming a 20% relative risk reduction for all doses. In 
the process of ensuring this, the weight for the 300 mg dose was reduced more than that of the 
150 mg, because a higher dose is only of interest if it demonstrates a better efficacy than 
lower doses. This means that when the other doses are not effective the 300 mg dose would 
only become significant with a relative risk reduction that is at least in the region of 17.5%, 
while for the 150 mg dose this would already be the case with relative risk reductions below 
16%. However, this was considered acceptable in order to ensure the desired operating 
characteristics for the 150 mg and 50 mg dose.
Key secondary endpoints for a dose are tested using a weighted Bonferroni-Holm procedure
(Holm 1979) only after successful rejection of the primary null hypothesis for that dose. In 
that case, a higher fraction of the local significance level that is passed from the primary null 
hypothesis for a dose to the key secondary endpoints for the same dose is assigned to the 
secondary CV composite endpoint (90%) than to the new onset of diabetes endpoint (10%).
Note that if the primary endpoint for the 300 mg dose (null hypothesis H11) is rejected 45% of 
the local significance level assigned to that null hypothesis is shifted to the primary endpoint 
for the 150 mg dose (null hypothesis H21) and 25% to the primary endpoint for the 50 mg dose 
(null hypothesis H31). This reflects the possibility that lower doses could potentially have a 
better safety profile than higher doses; hence, it would be desirable to demonstrate the 
efficacy of lower doses even after demonstrating the efficacy of a higher dose. In contrast, the 
main reason why some of the local significance level assigned to lower doses is shifted to 
higher doses is to preserve the consonance of the test procedure; i.e. to avoid a situation in 
which e.g. the primary null hypothesis for the 300 mg would be rejected by the weighted 
Dunnett test, but could not be rejected by the chosen closed testing procedure due to 
insufficient alpha being assigned to some intersection null hypotheses. 

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Figure 9-1
Closed testing procedure for primary and key secondary endpoints
When the primary null hypothesis for a dose is rejected, some of the local significance level assigned to that primary null 
hypothesis is passed to the key secondary null hypotheses for the same dose. These are then tested using a weighted 
Bonferroni-Holm procedure at the available local significance level with weights of 90% for the key secondary CV composite and 
10% for the key secondary new onset of diabetes endpoint. Only if both key secondary null hypotheses for a dose are rejected, 
will any of the local significance level assigned to these null hypotheses be passed on to null hypotheses for other doses.
Two efficacy interim analyses, at which the trial could be stopped for demonstrated efficacy 
or one or both active arms could be stopped for futility will be performed respectively after 
50% and 75% of the target number of 1,400 patients have experienced a primary endpoint. 
Futility criteria and the criteria other than purely formal statistical significance required for 
stopping the trial for demonstrated efficacy will be specified in the Data Monitoring 
Committee charter. An additional futility analysis may also be conducted by the DMC prior to 
the first planned efficacy IA (at approximately 50% primary events), but only after a 
sufficient number of primary events are accrued, i.e, >25%.
A fixed Bonferroni split of the one sided significance level will be used to account for the two 
efficacy interim analyses and the final analysis, with a significance level of 0.01% for the first 
and 0.04% for the second efficacy interim analysis. I.e. the closed testing procedure will be 
performed with a one-sided significance level of 0.01% at the first efficacy interim analysis, 
with a one-sided significance level of 0.04% at the second efficacy interim analysis and with a 
one-sided significance level of 2.45% at the final analysis. In this fashion the familywise type 
I error rate will be controlled at the overall (one-sided) significance level α = 2.5%. This 
constitutes an equivalent level of evidence as the two-sided 5% level. Multiplicity adjusted p-
values will be calculated for each null hypothesis as the smallest significance level at which 
one can reject that null hypothesis. Both one-sided and two-sided p-values will be reported. 
To obtain the latter, the same test procedure as shown in Figure 9-1 will also be conducted in 
a one-sided fashion on the 2.5% significance level to test for the superiority of placebo over 
each test arm.
The hazard ratios and their associated confidence intervals will be estimated by means of a
(Cox 1972) proportional-hazards model stratified by time since index MI (< 6 months, ≥ 6 
months) and by trial part using treatment (canakinumab doses and placebo) as a factor in the 
model using exact method for handling ties. Kaplan-Meier type plots will be presented to 
summarize the time to first event in the composite endpoint, by presenting the time-dependent 

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cumulative frequency and percentage of patients who reach the primary composite endpoint 
by treatment group. Appropriate methods for plotting the overall data from both trial parts 
together will be pre-specified in the statistical analysis plan. Separate Kaplan-Meier plots by 
trial part will also be provided.
Should one of the three active arms be stopped due to safety reasons or futility, then thereafter 
the pre-specified testing procedure will be performed for the other arm treating all null 
hypotheses for the stopped arm as non-rejected. For patients whose treatment is stopped as a 
result of a data monitoring committee recommendation to suspend treatment in one dose 
group, follow-up for cardiovascular (CV) and safety events will continue. Since these patients 
will not receive further study medication, less frequent follow-up will be conducted every 6 
months. Continued follow-up would likely enhance understanding of the safety of the other 
dose groups as well. Follow-up will simply continue in all scenarios until 1,400 patients have 
had a primary endpoint and the only difference to the pre-planned study conduct will be that 
the patients in the stopped treatment arms are not being treated after the DMC decision point.
9.4.3
Handling of missing values/censoring/discontinuations
Regarding time-to-event endpoints only observed events will be used in the analysis and in 
the primary analysis censoring of non-observed events will be assumed to be non-informative. 
Sensitivity analyses with respect to this assumption will be performed. Incomplete dates of 
events and censoring dates will be imputed as described below.
In the primary analysis, all patients, including those who discontinue study therapy due to lack 
of efficacy, adverse events or abnormal laboratory values will be followed until death or the 
end of the pivotal phase. Information of patients discontinuing study drug or participation in 
trial visits will be collected whenever possible and will be used in the analysis. In patients 
who could not be followed up for primary outcome events, it is aimed to at least determine the 
vital status of the patients at the final pivotal phase visit.
The following rules will be applied separately for the composite MACE endpoint and for all 
its individual components. Patients who have not experienced the respective endpoint will be 
censored on the date of the last follow-up in the following way:

for patients who die, the censoring date will be the date of death unless the patient 
withdrew his consent for the collection of follow-up information,

for patients who attend a final visit during pivotal phase close out, the censoring date will 
be the final visit date,

otherwise the censoring date will be based on the last pivotal phase visit at which the 
investigator reported that it was known whether the patient experienced any clinical events 
since the last visit (i.e. answer of “yes” or “no” to this question, not “unknown”. The last 
known date the patient was reported alive at that pivotal phase visit will be used, if the last 
known date the patient was alive is missing the date of the last pivotal phase visit at which 
it was known whether the patient experienced any clinical events since the last pivotal 
phase visit will be used.
Should the censoring date lie after the chosen analysis cut-off date, it will be set to the 
analysis cut-off date.

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If the date of a MACE endpoint or of censoring is not known or is incomplete following all 
attempts to get an approximate date, a day will be imputed using the following algorithm:

If only the month of the event is known, then the 15th day of this month will be imputed.

If only the year of the event is known, then the 1st July will be imputed.

If year, month and day are unknown, the randomization date will be imputed.

If this imputation rule leads to a date before the randomization date or after a patient’s last 
pivotal phase visit or after a patient’s death, but before the imputation the date could have 
been on one of these dates, then the date will be imputed as that date.
9.4.4
Supportive analyses
The components of the composite primary efficacy endpoint (CV death, fatal or non-fatal MI, 
fatal or stroke) will also be analyzed individually in order to evaluate their contributions to the 
overall treatment effect.
The primary endpoint will also be analyzed on the PPS. Additionally in an on-treatment 
analysis on the FAS patients will be considered censored at the latest one quarter year + 28 
days (119 days) after the last study injection. Besides adjudicated endpoints investigator 
reported outcomes will also be analyzed.
The three pooled canakinumab doses will be compared to placebo on the primary composite 
endpoint and its components, because in case of similar efficacy on all three doses this would 
be the most powerful test of the scientific hypothesis addressed by this trial. Additionally, 
when all three doses have similar efficacy such a pooled analysis approach may be able to 
provide the most precise information on the effects in subgroups. Methods to evaluate dose 
response in terms of cardiovascular events will also be pre-specified in the detailed statistical 
analysis plan.
Furthermore, pre-specified subgroup analyses will include age, sex, race, ethnicity, BMI, 
region, glycemic status, smoking status, baseline hsCRP level, LDL-C levels, SBP/DBP levels, 
statin, aspirin, gout and renal failure. Possible interactions between treatment and baseline 
variables will be evaluated with appropriate methods. Results will be presented graphically as 
forest plots. The objective of the subgroup analyses is to show the consistency of treatment 
effects across a wide variety of patient groups. Additional subgroup analyses will be 
considered and pre-specified prior to unblinding of trial database for final analysis. 
Additionally, the post-baseline subgroups of response in hsCRP response and target hsCRP 
levels achieved will be explored.
A sensitivity analysis will be conducted using randomization plan as an additional covariate 
or stratification factor in the primary model. A sensitivity with respect to the consistency of 
treatment effects in the two parts of the trial will also be performed. Finally, in order to 
achieve approximately 50% of patients < 12 months or ≥ 12 months post index-MI 
recruitment in one of these subgroups may be stopped earlier than in the other subgroup. If 
that occurs, then a sensitivity analysis stratifying the primary analysis by time since index MI 
30 days to < 6 months,  ≥ 6 months to <12 months and ≥ 12 months will be performed.

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9.5
Analysis of key secondary
 variables
Unless otherwise specified all time-to-event analyses will be based on events occurring during 
the double-blind period of the pivotal phase (see Section 9.4). Dose response in secondary 
 variables such as hsCRP will also be explored.
9.5.1
Secondary variables
Key secondary efficacy variables
The following key secondary variables will be used in the analyses:

Time to the first occurrence of an adjudication committee confirmed composite 
cardiovascular endpoint consisting of the components of the primary endpoint and 
hospitalization for unstable angina requiring unplanned revascularization 

Time to adjudication committee confirmed new onset of type 2 diabetes among those with 
pre-diabetes at randomization
The following hypotheses will be tested with respect to the key secondary variables for the 
canakinumab 300 mg dose versus placebo

H12: The hazard rate of first adjudication committee confirmed secondary composite CV 
endpoint in the canakinumab 300 mg dose group is greater than or equal to the hazard rate 
of the placebo group 

H13: The hazard rate of new onset of diabetes for pre-diabetic patients in the canakinumab 
300 mg dose group is greater than or equal to the hazard rate of the placebo group
Each null hypothesis is tested against the one-sided alternative that the hazard rate is smaller 
for the canakinumab 300 mg dose group than in the placebo group. The corresponding 
hypotheses for the comparison of the canakinumab 150 mg dose versus placebo are H22 for 
the secondary composite CV endpoint and H23 for the new onset of diabetes endpoint; the 
corresponding hypotheses for the comparison of the canakinumab 50 mg dose versus placebo 
are H32 for the secondary composite CV endpoint and H33 for the new onset of diabetes 
endpoint.
All key secondary efficacy variables will be analyzed on the FAS with a log-rank test 
stratified by time since index MI and trial part. The hazard ratios will be estimated using a 
Cox regression model stratified by time since index MI and trial part. Kaplan-Meier type plots 
showing each treatment will be provided overall and separately by trial part. The multiplicity 
adjustment used to protect the familywise type I error rate is shown in Figure 9-1. Based on 
this testing procedure, once the primary null hypothesis for a dose has been rejected the key 
secondary endpoints for that dose are tested using a weighted Bonferroni-Holm test (Holm 
1979) at the available local significance level for the key secondary endpoints for that dose. 
The weighting of this Bonferroni-Holm procedure will be 90% for the key secondary CV 
composite and 10% for the key secondary new onset of diabetes endpoint.
The secondary efficacy variable corresponding to new onset diabetes in patients with 
prediabetes at randomization will be the time from randomization to the first of repeated FPG
≥126 mg/dL (≥7.0 mmol/L) or the first of repeated HbA1c ≥ 6.5% or start of new anti-
diabetic concomitant medication(s) for glucose lowering purpose. Due to the discrete nature 

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of the time points when new onset of type 2 diabetes can be determined, events identified at 
the same pivotal phase visit time point for different patients will be considered as tied events 
and exact method for handling ties will be used. This assumes that for each of these patients 
new onset of diabetes occurred at some time point since the previous pivotal phase visit, but 
that due to the impossibility of continuous monitoring of the patients the true order in which 
each of them progressed to diabetes is unknown (Allison 1995). For this endpoint, patients 
without new onset of diabetes will be considered censored at the time of their last laboratory 
assessment.
Other secondary efficacy variables
Although all-cause mortality is considered a very important secondary endpoint due to its 
importance as both an efficacy and safety outcome, it is not part of the pre-specified testing 
procedure for primary and key secondary endpoints, because given the expected number of 
deaths in the trial it would not have been possible to adequately power the key secondary 
mortality endpoint.
All-cause death and the composite of all-cause death, stroke or MI will be analyzed on the 
FAS with a log-rank test stratified by time since index MI and trial part. The hazard ratios will 
be estimated using a Cox regression model stratified by time since index MI and trial part. 
Kaplan-Meier plots showing each treatment will be provided overall and by trial part. Patients 
who did not die will be considered censored at the last time they were reported to be alive.
Analysis of the prediabetes washout period
Data from the double-blind period of the pivotal phase and the prediabetes washout period of 
the extension phase will be combined to assess to what extent canakinumab truly delayed 
progression to diabetes and to what extent it only masked diabetes during the pivotal phase 
double-blind period. The analysis will take into account that masking of diabetes may have 
occurred in patients not diagnosed as diabetic during the pivotal phase that did not enter the 
washout period. A number of sensitivity analyses with a range of assumptions about these 
patients will be performed. These analyses will be specified in a detailed Statistical Analysis 
Plan.

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9.5.3
Safety variables
Safety will be evaluated based on the safety set (SAF). The assessment of safety will be based 
primarily on the assessment of potential and identified risks defined in the safety profiling 
plan (SPP), the frequency of adverse events, laboratory abnormalities, and serious adverse 
events suspected by the investigators to be related to study treatments. Other safety data (like 
vital signs, ECG) will be summarized as appropriate.
As appropriate overall (i.e. across the two trial parts) absolute risk differences, risk ratios, 
hazard ratios or odds ratios for each active dose versus placebo will be calculated taking into 
account the  trial part to avoid any confounding of the safety assessment through differential 
follow-up or differences in patient populations.
Adverse events between informed consent and randomization
Adverse events between informed consent and randomization will be summarized by primary 
system organ class and preferred term. This summary will include events that would qualify 
as trial endpoints if they occurred after randomization, but which are to be reported as AEs 
prior to randomization.
Adverse events (AEs) excluding trial endpoints
The incidence of treatment emergent AEs (events started on the first dose of study medication 
or events present prior to start of double-blind treatment but increased in severity based on 
preferred term) excluding trial endpoints for the pivotal phase will be summarized by primary 
system organ class (SOC), preferred term and also by severity and relationship to study 
treatment. Standardized MedDRA Queries (SMQs) may also be employed. The MedDRA 
version used for reporting the study will be clearly identified.
If a patient reported more than one AE with the same preferred term, the AE with the greatest 
severity will be presented. If a patient reported more than one AE within the same primary 
system organ class, the patient will be counted only once with the greatest severity at the 
system organ class level, where applicable.

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The number and percentage of patients reporting any AE during the double-blind period of the 
pivotal phase will be summarized by primary system organ class, preferred term and treatment, 
and also by SMQ and treatment if needed.
Separate summaries will be provided for study drug related AEs, deaths, SAEs and, other 
significant AEs leading to discontinuation.  
Similar summaries will be provided for the extension phase.
AEs of special interest
Frequencies of adjudicated immunological AEs (serious allergies/immunological events (e.g. 
immunological laboratory screen and anti-canakinumab antibodies), serious infections, and 
malignancies, whether newly detected or worsening of existing malignancies) will be reported. 
For the extension phase no adjudication of AEs will be performed.
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(Hematology, Serum chemistry and Urinalysis).
Descriptive summary statistics for the change from baseline to each study visit will be 
presented. These descriptive summaries will be presented by laboratory test and treatment 
group. Change from baseline will only be summarized for patients with both baseline and post 
baseline values.
In addition, shift tables by treatment group will be provided for all parameters (except for 
creatinine clearance, which will be calculated using the MDRD formula) in order to compare 
a patient’s baseline laboratory evaluation relative to all post-baseline values.
The frequency and percentage of patients with clinically notable laboratory results after 
baseline will be tabulated.
Liver safety
The following analyses will be performed for the pivotal phase:

The liver-related events meeting specified criteria standard table will be used to provide 
the number and percentage of patients having aspartate transaminase (AST), alanine 
transaminase (ALT) > 3, 5, 8, 10 x ULN or total bilirubin (TBL) >1.5, 2 x ULN or 
alkaline phosphatase (AP) > 2, 3 x ULN. The number and percentage of potential Hy’s 
Law cases will be presented by treatment group. Potential Hy’s Law cases are defined as 
those patients with AST or ALT >3xULN and TBL >2xULN and AP <2xULN at the same 
lab measurement.

A cross-tabulation of baseline and worst post-baseline values by below, within and above 
normal range categories will be provided. Shift tables will be provided for the parameters 
AST, ALT, TBL and AP. These summaries will be presented by laboratory test and 
treatment group.

Standard laboratory tables will be produced as for all other laboratory parameters.

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
The narrow and broad “Possible drug related hepatic disorders – comprehensive search” 
SMQ and the corresponding lower level SMQs will be presented including the respective 
preferred term frequencies covered under the SMQs.

The overall SMQ/preferred term table will be used to provide the number and percentage 
of patients with hepatic disorders.

eDISH (electronic Drug-Induced Serious Hepatotoxicity) plots will be provided 
representing the entire study population.

Narratives for any patients discontinued due to liver function abnormalities will be 
prepared.
Vital signs
Descriptive summary statistics of vital sign variables for the change from baseline to each 
post baseline visit will be presented. These descriptive summaries will be presented by vital 
sign and treatment group. Change from baseline will only be summarized for patients with 
both baseline and post-baseline values.
ECG
Based on a standard 12-lead ECG, any new or worsening clinically relevant findings will be 
recorded as AEs except for ECG changes constituting study endpoints. Therefore, no separate 
presentation of ECG findings is foreseen.

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9.6
Sample size calculation
Expected event rates in a secondary prevention trial in patients with prior MI
In spite of differences in eligibility criteria and outcome definitions, several recent trials 
provide useful information on the expected rates of the endpoint in the proposed trial, and 
support the focus on hard endpoints. The ARISE trial (Tardif et al. 2008) randomized 6,144 
patients with recent acute coronary syndrome (between 14 and 365 days before enrollment) to 
succinobucol vs. placebo and followed them for an average of 2 years. The observed 
incidence on the composite endpoint of cardiovascular death, MI, stroke or cardiac arrest 
corresponds to an incidence rate of 5.1 events per 100 person-years.
The PROVE-IT TIMI-22 trial (Cannon et al. 2004) provides an additional estimate of event 
rates in post-acute coronary syndrome patients (71% post MI), randomized within less than 10 
days post index event. Over an average follow-up of 2 years, the 2,099 patients in that trial 
randomized to receive 80 mg of atorvastatin daily had a cumulative incidence of myocardial 
infarction or death from coronary heart disease of 7.2%. This corresponds to an incidence rate 
of 3.7 events per 100 person-years. The addition of stroke and other cardiovascular deaths to 
this endpoint might be expected to increase this rate to over 4 events per 100 person-years.  
The WIZARD trial (O’Connor et al. 2003) provides an additional estimate of event rates 
based on somewhat different eligibility criteria. That trial randomized individuals with a 
history of myocardial infarction anytime in the past who also had a C pneumoniae IgG titer of 
1:16 or more to azithromycin or placebo and followed these people for an average of 14 
months. In 7,722 patients followed for the endpoint of recurrent myocardial infarction or 
death a total of 600 experienced the event with a median follow up of 14 months, 
corresponding to an incidence rate of 6.7 events per 100 person-years.
Levels of hsCRP in patients with prior myocardial infarction are powerful predictors of 
subsequent events. Rates of recurrent events are 30% to 60% higher in patients with hsCRP≥2 
mg/L relative to lower levels, regardless of the intensity of statin treatment (Ridker et al. 
1998). While aggressive lipid-lowering with statins reduces levels of hsCRP, elevations 
remain common in post-MI patients. Specifically, in the PROVE-IT TIMI-22 trial, 43% of 
patients randomized to 80 mg atorvastatin daily had on-treatment levels of hsCRP ≥ 2 mg/L 
(Ridker et al. 2005). A similar prevalence of elevated hsCRP was observed in patients treated 
with 80 mg simvastatin daily in the Aggrastat-to-Zocor trial (Morrow et al. 2006). In the 
primary prevention setting of the JUPITER trial (Ridker et al. 2008), 20 mg of rosuvastatin 
substantially reduced levels of hsCRP from a baseline median of 3.2 mg/L, but on-treatment 
median levels in the active treatment group remained above 2 mg/L at all follow-up visits. 
The event rates from these trials that have included individuals with prior myocardial 
infarction, with the additional consideration of the increased MACE rate associated with an 
elevated level of hsCRP, appear to support an estimate of the expected MACE rate of 3.25 to 
4 per 100 person-years in the placebo group. This range already takes into consideration that 
full-dose statin therapy will most likely be used by such patients. The expected risk during the 

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first year of the trial is expected to be higher for patients randomized within 30 days to 6 
months of their index MI, than for patients randomized longer after their index MI.
The observed blinded event rate at the time of protocol amendment 8 appears to be at the 
upper end of the previously expected range despite a lower than expected enrollment into the 
<6 month and <12 month post-index MI subgroups. The blinded event rate also appears to be 
stable over time into the second year of follow-up based on the current follow-up information 
(on average less than a year and up to 2.5 years in the first patients enrolled).
Needed number of patients with primary endpoints and Sample size 
As shown in Table 9-1 1,400 patients across all three trial arms with an observed major 
cardiovascular disease event (MACE) provide ≥ 90% power for demonstrating the superiority 
of at least one dose of canakinumab over placebo using the closed testing described in  
Section 9.4 Analysis of the primary variable (s) at the one-sided 2.45% level available for the 
final analysis if all doses have a true 20% net relative hazard reduction compared to placebo 
for MACEs after discounting for discontinuations of treatment. Additionally, in this case both 
the 150 mg dose and 50 mg dose have ≥ 80% power to become significant.
Table 9-1
Power at the final analysis for 1,400 patients with a MACE
True relative risk reduction 
Power [%]
300 mg 
[%]
150 mg
[%]
50 mg 
[%]
at least one 
dose significant
300 mg 
150 mg
50 mg 
all doses 
significant
25.0
25.0
25.0
99.4
93.5
96.1
96.3
89.0
22.5
22.5
22.5
97.9
85.4
90.4
91.4
76.5
20.0
20.0
20.0
93.6
72.0
80.6
80.3
56.9
17.5
17.5
17.5
83.7
54.9
65.8
63.9
35.8
22.5
22.5
0
94.9
82.3
88.1
1.9
1.9
20.0
20.0
0
87.5
67.6
77.2
1.8
1.8
22.5
17.5
10.0
89.0
81.6
64.9
24.7
20.9
Power results are based on 5,000 simulated trials per scenario. Only results for primary endpoints were simulated, therefore 
the actual power will be slightly higher as significant key secondary endpoints for one dose may make more alpha available 
for the primary endpoint of the other dose. All simulations were performed in SAS 9.2 (TS1M0) on an AIX 6.1 platform.
Depending on the exact distribution of endpoints across the three trial arms either the 150 mg 
dose would need to achieve a relative risk reduction of 15 to 16% versus placebo, or the 300 
or 50 mg dose would need to achieve a relative risk reduction of 17 to 18% versus placebo in 
order for any dose to become significant. Once that is the case relative risk reductions of 
approximately 14 to 16% may become significant for the other doses. 
A sample size of approximately 10,000 randomized patients is expected to be sufficient to 
accrue the planned number of 1,400 patients with a MACE in approximately 6 years. Given a 
20% relative risk reduction in all active treatment arms, reducing the sample size from 17,200 
patients to approximately 10,000 randomized patients reduces the expected number of patients 
with events in the 50 mg dose by less than 4% (11 patients with an event).  Thus, the impact 
of the reduction in sample size on the power for the 50 mg dose will be negligible.

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In order to achieve the planned number of events and preserve the target power of the study 
the event rate of the primary endpoint will be monitored in a blinded fashion so that 
adjustments can be made to the number of patients to be randomized and/or the duration of 
follow-up.
No sample size calculation was performed for the extension phase, because the objective of 
the extension phase is long-term safety assessment in participants of the pivotal phase.
9.7
Power for analysis of key secondary variables
The revised sample size following amendment 6 was determined solely based on the primary 
endpoint, the initial calculations for the power of the key secondary variables were therefore 
not updated.
9.8
Interim analyses
Interim analyses of efficacy, futility and safety will be carried out during the pivotal phase of 
the study. Two interim analyses of efficacy will be performed when about 50% of the target 
number of primary cardiovascular events have been accumulated and the second one when 
75% of the planned number of events are available. Criteria for the interim and final analyses 
will be determined using a fixed Bonferroni split of the alpha allocated to the interim analyses 
and to the final analyses in order to protect the overall one-sided familywise type I error rate 
across all analyses at 2.5%. The fixed total one-sided alpha allocated to both interim analyses 
of efficacy combined is 0.05%. Of this 0.01% is allocated to the first efficacy interim analysis 
and 0.04% allocated to the second efficacy interim analysis. The one-sided significance level 
for the final analysis is thus 2.45%.
Interim analyses for futility will be conducted simultaneously with the two analyses of 
efficacy.  One additional futility analysis may also be performed earlier than first planned 
efficacy IA (at approximately 50% primary events), but only after a sufficient number of 
primary events are accrued, i.e., >25%.  It should be noted that the efficacy criteria are not 
modified to “buy back” alpha based upon the presence of futility boundaries; this conservative 
approach ensures that the familywise type I error rate of the study is protected.
Full details on boundaries and stopping rules will be pre-specified in the Charter of the Data 
Monitoring Committee (DMC). Timing and number of safety analyses will also be specified 
in DMC charter.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
This will also apply for the extension phase.

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10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
 
 
 
 
 
 
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or ethics committee approval will be 
obtained.
The informed consent form will be updated to include details of the extension phase. Patients 
may only be included in the main drug dispensing period of the extension phase (Visit 201 
and beyond) after providing written (witnessed, where required by law or regulation), 
IRB/IEC-approved informed consent as described above.
10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs/REBs, and regulatory authorities as 

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required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
The above will also apply for the extension phase. The extension phase will be introduced via 
a protocol amendment. The informed consent form will be amended accordingly.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be submitted for publication and 
posted in a publicly accessible database of clinical study results regardless of study outcome.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal Standard Operating Procedures (SOPs), and are performed according to 
written Novartis processes.
This will also apply for the extension phase.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations during the 
pivotal and extension phases. Under no circumstances should the investigator contact Novartis 
or its agents, if any, monitoring the trial to request approval of a protocol deviation, as no 
authorized deviations are permitted. If the 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 it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the CSR.
11.1
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. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 

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cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days.
This will also apply for the extension phase.

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12
References
References are available on request.
Internal Reference Section
Investigator’s Brochure, Edition 15 dated 09 August 2016
External Reference Section
American Diabetes Association (2010) Summary of revisions for the 2010 Clinical Practice 
Recommendations. Diabetes Care;33:Suppl.1. 
Brannath W, Bretz F (2010) Shortcuts for locally consonant closed test procedures. J 
American Statistical Association; 105(490): 660-9.
Bretz F, Maurer W, Brannath W, et al (2009 A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine; 28(4): 586-604.
Cannon CP, Braunwald E, McCabe CH, et al (2004) Pravastatin or Atorvastatin Evaluation 
and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators : Intensive 
versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes. NEJM; 
350:1495-504.
Cox DR (1972) Regression models and life-tables (with discussion). J. R. Statist. Soc, B; 
34:187-220.
Diabetes Prevention Program Research Group (2002) Reduction in the incidence of type 2 
diabetes with lifestyle intervention or metformin. NEJM; 346:393-403.
Dinarello C, Ikejima T, Warner SJC, et al (1987) Interleukin 1 induces interleukin 1, I. 
Induction of circulating interkeukin 1in rabbits in vivo and in human mono nuclear cells in 
vitro. J. Immunol; 139: 1902-1910.
Duewell P, Kono H, Rayner KJ, et al (2010) NLRP3 inflammasomes are required for 
atherogenesis and activated by cholesterol crystals. Nature; 464(7293):1357-61.
Dunnett CW (1955) A multiple comparison procedure for comparing several treatments with 
a control. J American Statistical Association; 50:1096-1121.
European Commission : Enterprise and Industry Directorate-General (2006) Detailed 
guidance on the collection, verification and presentation of adverse reaction reports arising 
from clinical trials on medicinal products for human use.. Brussels ENTR/CT 3 Revision 2.
European Society of Hypertension (2003) European Society of Cardiology guidelines for the 
management of arterial hypertension. Journal of Hypertension; 21:1011-1053.
Holm S (1979) A simple sequentially rejective multiple test procedure. Scan J Statist 6:65–70.
Kaptoge S, Di Angeloantonio E, Lowe G et al Emerging Risk Factors Collaboration (2010) C-
reactive protein concentration and risk of coronary heart disease, stroke and mortality: an 
individual meta-analysis. Lancet; 375:132-140.

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Lan G, DeMets D (1983) Discrete sequential boundaries for clinical trials. Biometrika 
70(3):659-663.
Little RR (2010) Consensus Statement on the Worldwide Standardization of HbA1c (Internet) 
Available from <http://www.ngsp.org/contact.asp> (Accessed 22 September 2010)
Mancia G, Laurent S, Agabiti-Rosei E et al (2009) Reappraisal of European guidelines on 
hypertension management: a European Society of Hypertension Task Force document. J 
Hypertension; 27: 1-38.
McMurray JJ, Kjekshus J, Gullestad Let al (2009) Effects of statin therapy according to 
plasma high-sensitivity C- reactive protein concentration in the controlled rosuvastatin 
multinational trial in heart failure (CORONA), Circulation; 120: 2188-2196.
Morrow DA, de Lemos JA, Sabatine MS, et al (2006) Clinical relevance of C-reactive protein 
during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor trial.  
Circulation; 114: 281-288.
O’Connor CM, Dunne MW, Pfeffer MA, et al (2003) Azithromycin for the Secondary 
Prevention of Coronary Heart Disease Events: The WIZARD Study: A Randomized 
Controlled Trial. JAMA; 290(11):1459-1466.
Ridker PM, Danielson E, Fonseca FA, et al (2008) Rosuvastatin to prevent vascular events in 
men and women with elevated C-reactive protein. NEJM; 359:2195-2207. 
Ridker PM, Danielson E, Fonseca FA, et al (2009) Reduction in C-reactive protein and LDL 
cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study 
of the JUPITER trial. Lancet; 373:1175-82.
Ridker PM, Cannon CP, Morrow D, et al (2005) C-Reactive Protein Levels and Outcomes 
after Statin Therapy, NEJM; 352:20-8.
Ridker PM, Rifai N, Clearfield M, et al (2001) Measurement of C-reactive protein for the 
targeting of statin therapy in the primary prevention of acute coronary events, NEJM; 
344:1959-1965.
Ridker PM, Rifai N, Pfeffer MA, et al (1998) Inflammation, pravastatin, and the risk of 
coronary events after myocardial infarction in patients with average cholesterol levels. 
Cholesterol and Recurrent Events (CARE) Investigators. Circulation; 98:839-44.
Tardif J-C, McMurray JJV, Klug E et al (2008) Effects of succinobucol (AGI-1067) after an 
acute coronary syndrome: a randomized, double-blind, placebo-controlled trial. Lancet; 371: 
1761–8.
Thygesen, K, Alpert, JS, White, HD et al (2007). Universal Definition of Myocardial 
Infarction. Circulation; 116:2634-2653.
Warner SJC, Auger KR, and Libby P (1987a). Human interleukin 1 induces interleukin 1 gene 
expression in human vascular smooth muscle cells. J. Exp. Med; 165: 1316-1331. 

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Warner SJC, Auger KR, and Libby P (1987b) Human interleukin 1 induces interleukin 1. II. 
Recombinant human interkeukin 1 induces interleukin 1 production by adult human vascular 
endothelial cells. J. Immunol; 139: 1911-1917.
Book references 
Allison PD (1995) Survival analysis using the SAS® System: A Practical Approach, Cary, 
NC: SAS Institute Inc.
Chou’s Electrocardiography in Clinical Practice; Surawicz, B, Knilans, T; Ed. 5th Edition. 
(2001). Saunders Publishing. Literature available on request.
Genz A, Bretz F (2009). Computation of multivariate normal and t probabilities. Lecture 
Notes in Statistics, Vol. 195. Springer, Heidelberg.

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13
Appendix 1: Clinically notable laboratory values and vital 
signs
Laboratory notable range deviations will be provided in the investigator binder.
Vital sign notable range deviations
VITAL SIGNS
NOTABLE ABNORMALITIES
Pulse (beats/min)
either 120 + increase 25* or >130
either 50 + decrease 30* or < 40 
Blood pressure (mmHg)
systolic
either 180 + increase 30* or > 200
either 90 + decrease 30* or < 75
diastolic
either 105 + increase 20* or > 115
either 50 + decrease 20* or < 40
Weight
a weight change of > 10% during the study
*Refers to post-baseline value as compared to baseline value

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15
Appendix 3  Study Endpoint Definitions
15.1
Definition of Cardiovascular Death
Cardiovascular death includes sudden cardiac death, death due to acute myocardial infarction, 
death due to heart failure, death due to stroke, and death due to other cardiovascular causes.
Sudden cardiac death: A sudden death that occurs in a previously stable patient who does 
not have a prior terminal condition, such as malignancy not in remission or end-stage chronic 
lung disease. 
Established sudden cardiac death includes the following deaths:
Witnessed and instantaneous without new or worsening symptoms.
Witnessed within 60 minutes of new or worsening symptoms.
Witnessed and attributed to an identified arrhythmia (e.g., captured on ECG recording or 
witnessed on a monitor by either a medic or paramedic or unwitnessed but found on 
implantable cardioverter-defibrillator review).
After unsuccessful resuscitation from cardiac arrest
After successfully resuscitated from cardiac arrest and without identification of a non-
cardiac etiology (Post-Cardiac arrest Syndrome) 
Unwitnessed death without other cause of death
General Considerations
A patient seen alive and clinically stable 12-24 hours prior to being found dead without any 
evidence or information of a specific cause of death should be classified as an “Unwitnessed 
Death.” Typical scenarios include
• Patient well the previous day but found dead in bed the next day
• Patient found dead at home on the couch with the television on
Deaths for which there is no information beyond “Patient found dead at home” may be 
classified as “Undetermined Cause of Death”
Death due to Acute Myocardial Infarction (AMI): refers to a death within 30 days after a 
myocardial infarction (MI) related to consequences seen immediately after the myocardial 
infarction, such as progressive congestive heart failure (CHF), inadequate cardiac output, or 
recalcitrant arrhythmia. If these events occur after a “break” (e.g., a CHF and arrhythmia free 
period), they should be designated by the immediate cause. The acute myocardial infarction 
should be verified either by the diagnostic criteria outlined for acute myocardial infarction or 
by autopsy findings showing recent myocardial infarction or recent coronary thrombus, and 
there should be no conclusive evidence of another cause of death.
Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive 
of myocardial ischemia, and accompanied by presumably new ST elevation, or new LBBB 
and/or evidence of fresh thrombus by coronary angiography and/or at autopsy, but death 
occurring before blood samples could be obtained, 

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If death occurs before biochemical confirmation of myocardial necrosis can be obtained, 
adjudication should be based on clinical presentation and ECG evidence.
Death resulting from a procedure to treat myocardial ischemia or to treat a complication 
resulting from myocardial infarction should also be considered death due to acute MI.
Death due to a myocardial infarction that occurs as a direct consequence of a cardiovascular 
investigation/procedure/operation should be classified as death due to other cardiovascular 
cause.
Death due to Heart Failure or Cardiogenic Shock: refers to death occurring in the context of 
clinically worsening symptoms and/or signs of heart without evidence of another cause of 
death.
Death due to Heart Failure or Cardiogenic shock should include sudden death occurring 
during an admission for worsening heart failure as well as death from progressive heart failure 
or cardiogenic shock following implantation of a mechanical assist device.
New or worsening signs and/or symptoms of congestive heart failure (CHF) include any of 
the following: 

New or increasing symptoms and/or signs of heart failure requiring the initiation of, or an 
increase in, treatment directed at heart failure or occurring in a patient already receiving 
maximal therapy for heart failure

Heart failure symptoms or signs requiring continuous intravenous therapy or chronic 
oxygen administration for hypoxia due to pulmonary edema

Confinement to bed predominantly due to heart failure symptoms

Pulmonary edema sufficient to cause tachypnea and distress not occurring in the context 
of an acute myocardial infarction, worsening renal function, or as the consequence of an 
arrhythmia occurring in the absence of worsening heart failure

Cardiogenic shock not occurring in the context of an acute myocardial infarction or as the 
consequence of an arrhythmia occurring in the absence of worsening heart failure.
Cardiogenic shock is defined as systolic blood pressure (SBP) < 90 mm Hg for greater than 1 
hour, not responsive to fluid resuscitation and/or heart rate correction, and felt to be secondary 
to cardiac dysfunction and associated with at least one of the following signs of hypoperfusion:

Cool, clammy skin or

Oliguria (urine output < 30 mL/hour) or

Altered sensorium or

Cardiac index < 2.2 L/min/m2
Cardiogenic shock can also be defined if SBP < 90 mm Hg and increases to ≥ 90 mm Hg in 
less than 1 hour with positive inotropic or vasopressor agents alone and/or with mechanical 
support.
Death due to Stroke (intracranial hemorrhage or non-hemorrhagic stroke): refers to death 
occurring up to 30 days after a suspected stroke based on clinical signs and symptoms as well 
as neuroimaging and/or autopsy, and where there is no conclusive evidence of another cause 
of death.

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Death due to Other Cardiovascular Causes: refers to death due to a cardiovascular cause 
not included in the above categories (e.g. dysrhythmia, pulmonary embolism, cardiovascular 
intervention, aortic aneurysm rupture, or peripheral arterial disease). Mortal complications of 
cardiac surgery or non-surgical revascularization, even if “non-cardiovascular” in nature, 
should be classified as cardiovascular deaths.
Death of Undetermined Cause (presumed cardiovascular) :
All deaths not attributed to the categories of Cardiovascular Death or to a Non-cardiovascular 
cause are considered presumed cardiovascular deaths. 
15.2
Non-cardiovascular death 
Non-Cardiovascular death is defined as any death not covered by cardiac death or vascular 
death and is categorized as follows:
Pulmonary causes
Renal causes
Gastrointestinal causes
Infection (including sepsis)
Non-infectious causes
Malignancy
Accident/Trauma
Suicide
Non-cardiovascular system organ failure (e.g. Hepatic)
Hemorrhage, not intracranial
Other. Please specify.
15.3
Definition of Non-fatal Myocardial Infarction
Acute Myocardial Infarction: the term myocardial infarction (MI) should be used when there 
is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. 
Under these conditions any one of the following criteria meets the diagnosis for MI.
Spontaneous MI : Detection of rise and/or fall of cardiac biomarkers with at least one value 
above the 99th percentile of the upper reference limit (URL) together with evidence of 
myocardial ischemia with at least one of the following:

Symptoms of ischemia

ECG changes indicative of new ischemia (new ST-T changes or new LBBB)*

Development of pathological Q waves in the ECG**

Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality

*ECG manifestation of acute myocardial ischemia (in the absence of LVH and LBBB):

ST Elevation - New ST elevation at the J-point in two contiguous leads with the cut-off 
points:

≥ 0.2 mV in men or ≥ 0.15 mV in women in leads V2-V3 and/or ≥ 0.1 mV in other leads.

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
ST depression and T-wave changes – New horizontal or down-sloping ST depression ≥ 
0.05 mV in two contiguous leads; and/or T inversion ≥ 0.1 mV in two contiguous leads 
with prominent R waves or R/S ratio >1.

**Pathological Q waves:
1. Any Q-wave in leads V2-V3 ≥ 0.02 seconds or QS complex in leads V2 and V3
2. Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or 
V4-V6 an any two leads of a contiguous lead grouping (I, aVL, V6, V4-V6, II, III, 
aVF).
Percutaneous Coronary Intervention (PCI) related Myocardial Infarct ; For PCI in patients 
with normal baseline troponin values elevations of cardiac biomarkers above the 99th
percentile URL within 24 hours of the procedure are indicative of peri-procedural myocardial 
necrosis. By convention increases of biomarkers greater than 3 x 99th percentile URL are 
consistent with PCI related myocardial infarction.

If the cardiac biomarker is elevated prior to PCI a ≥ 20% increase of the value in that 
second cardiac biomarker within 24 hours of the PCI and documentation that cardiac 
biomarkers were decreasing (two samples at least 6 hours apart) prior to the suspected 
recurrent MI is also consistent with PCI related MI.

Symptoms of cardiac ischemia are not required

CABG related Myocardial Infarct : For CABG in patients with normal baseline troponin, 
elevations of cardiac biomarkers above 5 times the 99th percentile of the normal reference 
range during the first 72 hours after CABG, when associated with 
EITHER 
New pathological Q waves in at least 2 contiguous leads on the ECG that persist through 
30days or new LBBB
OR
Angiographically documented new graft or native coronary artery occlusion
OR
Imaging evidence of new loss of viable myocardium 
Is consistent with CABG related Myocardial Infarct.

If the cardiac biomarker is elevated prior to CABG a ≥ 20% increase of the value in the 
second cardiac biomarker within 72 hours of CABG AND documentation that the cardiac 
biomarkers were decreasing (2 samples at least 6 hours apart) prior to the suspected 
recurrent MI plus either new pathological Q waves in at least 2 contiguous leads on the 
ECG or new LBBB, angiographically documented new graft or native artery occlusion or 
imaging evidence or new loss of viable myocardium is consistent with a peri-procedural 
myocardial infarct after CABG.

Symptoms of cardiac ischemia are not required.
Criteria for Prior Myocardial Infarction : Any of the following criteria meets the diagnosis for 
prior myocardial infarction:

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
Development of new pathological Q waves with or without symptoms

Imaging evidence of a region of loss of viable myocardium that is thinned and fails to 
contract in the absence of a non-ischemic cause

Pathological findings of a healed or healing myocardial infarction
ECG changes associated with prior Myocardial Infarction:

Any Q wave in leads V2-V3 ≥ 0.02 seconds or QS complex in leads V2 and V3

Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-
V6 in any two leads of a contiguous lead grouping (I, aVL, V6, V4-V6, II, III, and aVF)

R-wave ≥ 0.04 seconds in V1-V2 and R/S ≥ 1 with a concordant positive T-wave in the 
absence of a conduction defect
Criterion for Reinfarction: In patients where recurrent MI is suspected from clinical signs or 
symptoms following the initial infarction, 
 
. A second sample should be obtained 3-6 hours later. Recurrent 
infarction is diagnosed if there is a ≥ 20% increase of the value in the second sample. This 
value should exceed the 99th percentile URL. 
 
, there must also be documentation of decreasing values (two 
samples at least 6 hours apart) prior to the suspected new MI. 
 
 
ECG diagnosis of reinfarction following the initial infarction : may be confounded by the 
initial evolutionary ECG changes. Reinfarction should be considered when the ST elevation ≥ 
0.1 mV reoccurs in an inpatient having a lesser degree of ST elevation or new pathognomonic 
Q-waves, in at least two contiguous leads, particularly when associated with ischemic 
symptoms for 10 minutes or longer, The re-evaluation of the ST segment can, however also 
be seen in threatening myocardial rupture and should lead to additional diagnostic work-up. 
ST depression or LBBB on their own should not be considered valid criteria for Myocardial 
Infarction.
If biomarkers are increasing or peak is not reached then there is insufficient data to diagnose 
recurrent MI.
Clinical Classification of different types of Myocardial Infarction :For each MI identified a 
Type of MI will be assigned using the following guidelines:

Type 1 – Spontaneous MI related to ischemia due to a primary coronary event such as 
plaque erosion and/or rupture, fissuring or dissection.

Type 2 – MI secondary to ischemia due to either increased oxygen demand or decreased 
supply, e.g. coronary artery spasm, anemia, hypotension, coronary embolism, arrhythmias, 
hypertension or hypotension.

Type 3 –Sudden unexpected cardiac death including cardiac arrest, often with symptoms 
suggestive of myocardial ischemia accompanied by presumably new ST elevation, or new 
LBBB, or evidence of fresh thrombus in a coronary artery by angiography and/or at 
autopsy, but death occurring before blood samples could be obtained or at a time before 
the appearance of cardiac biomarkers in the blood.

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
Type 4a –MI associated with PCI.

Type 4b –MI associated with stent thrombosis as documented by autopsy or angiography.

Type 5 –MI associated with CABG.
Silent MI
The following criteria will be used by the central ECG reading vendor to define interval 
“silent” (no clinical symptoms or signs) MI between baseline and yearly ECGs:
Criteria for MI (Surawcz, Ed : Chou’s Electrocardiography in Clinical Practice, 5th Edition, 
2001).
Myocardial infarctions are reported only on the basis of pathologic Q waves. Pathologic Q 
waves are defined as Q wave duration > 40ms and Q/R ratio = 1/3. 
Any Q wave in V1 or V2 that is followed by an R wave should be considered abnormal.
When pathologic Q waves (i.e., myocardial infarction) are present, ST elevation or T wave 
inversion may be used to classify the infraction as New or Acute. However, ST elevation or T 
wave inversion in the absence of pathologic Q waves are not sufficient criteria for diagnosis 
of myocardial infarction.

Anterolateral MI - Pathologic Q waves in leads V3-V6.

Anterior MI - Pathologic Q waves in V3 and V4.

Anteroseptal MI - Pathologic Q waves or QS in leads V1-V4.

Extensive Anterior MI - Pathologic Q waves in leads I, aVL, and V1-V6.

High lateral MI - Pathologic Q waves in leads I and aVL.

Inferior MI - Pathologic Q waves or QS in at least two of the inferior leads: aVF, III, 
II.

Lateral MI - Pathologic Q waves in leads I, aVL, and V5-V6.

Septal MI - Pathologic Q waves or QS in leads V1-V2, (V3). In the presence of 
LAHB or LVH a Q or QS in V3 is required.

Posterior MI - Initial R wave duration 40 ms in V1 or V2, and R > S and upright T 
wave; Inferior or Lateral MI are usually also present. 
New MI
These criteria for MI are more stringent than the Expert Consensus Document criteria, 
requiring Q waves to be > 0.04 sec in duration and an R/S ratio > 1/3. These criteria (drawn 
from the cardiology literature) are designed to minimize the false positive detection of MIs 
due to very small physiologic Q waves in the inferior and anterolateral leads. 
15.4
Definition of Stroke
Stroke: is defined as the rapid onset of a new persistent neurological deficit attributed to an 
obstruction in cerebral blood flow and/or cerebral hemorrhage with no apparent non-vascular 
cause (e.g. tumor, trauma, infection). Available neuroimaging studies will be considered to 
support the clinical impression and to determine if there is a demonstrable lesion compatible 

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with an acute stroke. Non-fatal strokes will be classified as ischemic, hemorrhagic or 
unknown.
For the diagnosis of Stroke, the following 4 criteria should be fulfilled:
1. Rapid onset* of a focal/global neurological deficit with at least one of the following:
Change in level of consciousness
Hemiplegia
Hemiparesis
Numbness or sensory loss affecting one side of the body
Dysphasia/aphasia
Hemianopsia
Amaurosis Fugax
Other new neurological sign/symptom(s) consistent with stroke
*if the mode of onset is uncertain, a diagnosis of stroke may be made provided that there 
are no plausible non-stroke causes for the clinical presentation.
2. Duration of a focal/global neurological deficit: 
≥ 24 hours
OR
< 24 hours if:
This is because of at least one of the following interventions
Pharmacologic (i.e. Thrombolytic drug administration)
Non-pharmacologic (i.e. Neurointerventional procedure (e.g. Intracranial angioplasty)
OR
3. Available brain imaging clearly documents a new hemorrhage infarct
OR
4. The neurological deficit results in death.
No other readily identifiable non-stroke cause for the clinical presentation (e.g. Brain tumor, 
trauma, infection, hypoglycemia, peripheral lesion)
Confirmation of the diagnosis by at least on of the following:
Neurology or neurosurgical specialist
Brain imaging procedure (at least one of the following): 
i. CT scan
ii. MRI scan
iii. Cerebral vessel angiography
Lumbar puncture (i.e. Spinal fluid analysis diagnostic of intracranial hemorrhage)
If the acute focal signs represent a worsening of a previous deficit, these signs must have 
either:

Persisted for more than one week or

Persisted for more than 24 hours and were accompanied by an appropriate new MRI or CT 
scan finding

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Strokes are sub-classified as follows:
Ischemic (non-hemorrhagic): A stroke caused by an arterial occlusion due to either a 
thrombotic) e.g. Large vessel disease/atherosclerotic or small vessel/lacunar) or embolic 
etiology
Hemorrhagic: A stroke due to a hemorrhage in the brain as documented by neuroimaging or 
autopsy. This category will include strokes due to primary intracerebral hemorrhage 
(intraparenchymal or intraventricular), ischemic strokes with hemorrhagic transformation 
(i.e.; no evidence or hemorrhage on an initial imaging study but appearance on a 
subsequent scan), subdural hematoma*, and primary subarachnoid hemorrhage.
*All subdural hematomas that develop during the clinical trial : should be recorded and 
classified as either traumatic versus non traumatic.
Unknown: the stroke type could not be determined by imaging or other means (e.g. Lumbar 
puncture, neurosurgery, or autopsy) or no imaging was performed
Stroke Disability
Stroke disability can be classified using an adaptation of the modified Rankin Scale as follows:
0: No symptoms at all
1: No significant disability despite symptoms; able to carry out all usual duties and 
activities
2: Slight disability; unable to carry out all previous activities, but able to look after own 
affairs without assistance
3: Moderate disability; requiring some help, but able to walk without assistance
4: Moderately severe disability; unable to walk without assistance and unable to attend 
to own bodily needs without assistance
5: Severe disability; bedridden, incontinent and requiring constant nursing care and 
attention
6: Dead

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15.6
Definition of Unstable Angina Requiring Unplanned 
Revascularization
Unstable Angina requiring Unplanned Revascularization is defined as :
No elevation in cardiac biomarkers
and
Clinical presentation (one of the following) with cardiac symptoms lasting ≥10 minutes and 
considered to be myocardial ischemia on final diagnosis
Rest angina or
New onset (<2 months) severe angina (CCS* classification severity ≥ III) or

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Increasing angina (in intensity, duration and/or frequency) with an increase in 
severity of at least 1 CCS class to at least CCS III
and
Severe recurrent ischemia requiring urgent revascularization: as defined by an episode of 
angina prompting the performance of coronary revascularization on the index hospitalization 
or 
An episode of recurrent angina after discharge that resulted in re-hospitalization 
during which coronary revascularization was performed.
and
At least one of the following:
New or worsening ST or T segment changes on ECG. ECG changes should satisfy 
the following criteria for AMI in the absence of LVH and LBBB
ST Elevation - New ST elevation at the J point in two anatomically contiguous leads 
with the cut-off points: ≥ 0.2 mV in men (> 0.25 mV in men < 40 years) or ≥ 
0.15 mV in women in leads V2-V3 and/or ≥ 0.1 mV in other leads.
ST depression and T-wave changes – New horizontal or down-sloping ST depression 
≥ 0.05 mV in two contiguous leads; and/or new T inversion ≥ 0.1 mV in two 
contiguous leads.
Evidence of ischemia on stress testing with cardiac imaging.
Evidence of ischemia on stress testing without cardiac imaging but with angiographic 
evidence of ≥ 70% lesion, and/or thrombus in the epicardial coronary artery or 
initiation/increased dosing of anti-anginal therapy.
Angiographic evidence of ≥ 70% lesion and/or thrombus in an epicardial coronary 
artery.
*Grading of Angina Pectoris According to Canadian Cardiovascular Society Classification

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15.7
Definition of Heart Failure requiring Hospitalization
Heart failure requiring hospitalization is defined as an event that meets the following criteria:
Requires hospitalization defined as an admission to an inpatient unit or a visit to an 
emergency department that results in at least a 12 hour stay (or a date change if the 
time of admission/discharge is not available)
AND
Clinical manifestation of heart failure including at least one of the following: New or 
worsening:
dyspnea, 
orthopnea, 
paroxysmal nocturnal dyspnea, 
edema, 
pulmonary basilar crackles, 
radiological evidence of worsening heart failure.
AND
Additional/increased therapy
Initiation of IV loop diuretic, inotrope or vasodilator therapy
Uptitration of IV therapy, if already on therapy
Initiation of mechanical or surgical intervention, or use of ultra-filtration, 
hemofiltration or dialysis that is specifically directed at the treatment of heart 
failure.
Biomarker results (e.g. brain natriuretic peptide) consistent with congestive heart failure will 
be supportive of this diagnosis.
15.8
Definition of New Onset Diabetes
The clinical definition of Type 2 diabetes consists of the following:
a.
Presence of Fasting Plasma Glucose measured on two consecutive occasions > 126 mg/dl  
(≥7.0 mmol/L) within 6 weeks (the Event Date will be the first of these two occasions)
Or
b. Presence of HbA1c measured on two consecutive occasions > 6.5 % within 6 weeks in a 
laboratory which has validated compliance of a test that conforms to the National 
Glycosylation Standards Program (Little et al 2010) reference measurement of HbA1c 
(the Event Date will be the first of these two occasions)
Or
c.
The institution and use of a diabetes medication for the purpose of glucose control by the 
patient including all oral agents, insulin, and injectable GLP-1 analogs. (the Event Date 
will be the Date noted on the prescription)
d. In the event wherein a patient has one laboratory parameter which would place them in the 
NOD category if repeated and confirmed within 6 weeks, then has a subsequent 
measurement another parameter which similarly would place them in the NOD category if 
repeated and confirmed within 6 weeks (e.g. FPG > 126 mg/ dl (≥7.0 mmol/L) followed 

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by HbA1c > 6.5%, or vice versa) will be considered to have NOD (the Event Date will be 
the first of these 2 occasions). 
15.9
Definition of Transient Ischemic Attack
A Transient Ischemic Attack is defined as change in the blood supply to a particular area of 
the brain, spinal cord, or retina, resulting in brief neurologic dysfunction that persists, by 
definition, for less than 24 hours
Symptoms and signs
New and focal neurologic sensory and/ or motor deficits, which have a rapid onset, last no 
more than 24 hours and resolve completely. Symptoms may be localized to brain, spinal cord, 
or retina, relative to the vascular supply affecting neurologic function.
Focal sensory, reflexes, and motor lesions, which are manifestations of the arterial structure 
from which the insufficiency arises. All new neurologic signs resolve completely within 24 
hours from the time of onset.

Hemiplegia/paresis

Hemianaesthesia/sensory deficit

Hemianopsia

Neglect

Isolated facial weakness/droop

Ataxia/dysmetria

Dysarthria/speech impairment

Aphasia

Other
Procedure
A CT , MRI, or MRA of the brain, which demonstrates no new pathology. A neurological or 
neurosurgical consultation may accompany the imaging study or studies, but is not required 
for the diagnosis of TIA.
15.10
Definition of Critical Limb Ischemia
Critical limb ischemia is a manifestation of occlusive peripheral arterial disease that describes 
patients with chronic occlusive disease who demonstrate ischemic rest pain or ischemic skin 
lesions (either ulcers or gangrene). 
Symptoms
Pain at rest, claudication, recurrent skin lesions are common.

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Signs
Coolness to touch and pallor of the involved extremity may be present. Diminution or absence 
of pulse to palpation or bedside Doppler examination. Ulcers of the skin may be present. 
Procedure
CT, MRI, MRA or angiography may be performed for diagnostic purposes. Angiographic or 
open revascularization may be attempted to improve arterial blood flow.
15.11
Definition of Limb Amputation due to Vascular Cause
Therapeutic resection of a limb or a portion of a limb due to a combination of vascular 
insufficiency, osteomyelitis, cellulitis / gangrene, or poor wound healing.
Symptoms
Symptoms may include claudication, rest pain, fever, recurrent infections. There may be a 
history of previous partial or complete amputations.  
Signs
Decreased arterial pulse, abnormal temperature, deformity, chronic skin ulceration 
Procedure
Therapeutic resection of the pathologic extremity. Reasons for amputation:

Vascular insufficiency

Osteomyelitis

Cellulitis

Gangrene

Poor healing post-surgical wound

Poor healing post trauma

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15.15
Definition of Coronary Angiography
Coronary angiography is an invasive procedure wherein radiocontrast dye is introduced via an 
arterial catheter into the aorta, left ventricle, and coronary arteries to examine the functional 
capacity and anatomy of these entities.
Procedure
A radiocontrast dye is administered as described above by a cardiologist or invasive 
radiologist, using peripheral access into an artery (femoral or brachial).
15.16
Definition of Coronary Revascularization
Coronary revascularization is an invasive procedure, which usually follows coronary 
angiography, wherein either Percutaneous Transluminal Intervention, followed by Stent 
Placement, Balloon Angioplasty, or CABG is performed to relieve obstructed coronary 
arteries. 
Procedure
A team of medical professionals lead by either an invasive cardiologist (Percutaneous 
Transluminal Intervention, followed by Stent Placement, Balloon Angioplasty,) or a thoracic 
surgeon (CABG), who performs the described procedures.

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16
Appendix 4  Instructions for use of the safety syringe
Before using the safety syringe, please read the following information carefully. The box 
contains pre-filled safety syringe(s) individually sealed in a plastic wrapper.
Important safety information
Caution: Keep the safety syringe out of the reach of children.
1. Do not open the sealed outer box until you are ready to use the safety syringe.
2. Do not use the safety syringe if either the seal on the outer box or the plastic wrapper is 
broken, as it may be not safe for you to use.
3. Never leave the safety syringe lying around where other might tamper it.
4. Be careful not to touch the Safety Fingers at any time. By touching them, the safety 
syringe may self-activate.
5. Do not remove the needle cap until just before you give the injection.
6. The safety syringe cannot be re-used. Dispose of the used safety syringe immediately after 
use in a sharps container OR according to the regulatory needs of your country.
Storage of the safety syringe
1. Store the safety syringe sealed in its outer box in the refrigerator between 2°C and 8°C 
(36°F and 46°F). DO NOT STORE IT IN THE FREEZER.

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2. Remember to take the safety syringe out of the refrigerator and allow it to reach room 
temperature before preparing it for injection (about 20 minutes).
3. Do not use the safety syringe after the expiration date shown on the outer box or syringe 
label. If it has expired, return the entire pack to the pharmacy.
The injection site
The injection site is the place on the body where you are going to use the safety syringe. 
ACZ885 can be injected in either the upper outer thigh, abdomen or the upper outer arm. If 
you need more than one injection at a time, repeat the injection in the opposite thigh or arm.
Preparing the safety syringe ready for use
1. Take the box containing the safety syringe out of the refrigerator and leave it unopened for 
about 20 minutes so that it reaches room temperature.
2. When you are ready to use the safety syringe, wash your hands thoroughly with soap and 
water.
3. Clean the injection site.
4. Remove the safety syringe from the outer box and take it out of the plastic wrapper.
5. Inspect the safety syringe. DO NOT USE if it is broken or if the liquid has a distinctly 
brown discoloration or contains particles. In all these cases, return the entire product pack
to the pharmacy.
How to use the safety syringe
Carefully remove the needle guard from the 
safety syringe. Discard the needle guard
Gently pinch the skin at the injection site and 
insert the needle.

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Holding onto the finger flange, slowly
depress the plunger as far as it will go. If 
some drug leaks from the injection site, insert 
the needle further.
Keep the plunger pressed fully down while 
you hold the syringe in place for 5 seconds.
Keep the plunger fully depressed while you 
carefully lift the needle straight out from the 
injection site.
Slowly release the plunger and allow the 
syringe guard to automatically cover the 
exposed needle.
Disposal instructions
Dispose the used safety syringe immediately in a sharps container.