Clinical trial NCT01327846
Conditions: Atherosclerosis
Keywords: Cardiovascular Death Myocardial Infarction Stroke Canakinumab IL-1B hsCRP
Sponsor: Novartis Pharmaceuticals
Start date: 2011-04-11; Completion date: 2019-04-14
Enrollment: 10066 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Main Study (CACZ885M2301): The purpose of the pivotal phase of this trial was to test the hypothesis that canakinumab treatment of patients with myocardial infarction (MI) at least one month prior to study entry and elevated hsCRP could prevent recurrent cardiovascular events.

The purpose of the extension phase of the main study is to collect additional long-term safety data on continued exposure to canakinumab in patients who participated in the pivotal phase.

Sub-study 1 (CACZ885M2301S1): The purpose of this sub-study was to evaluate the effect of quarterly subcutaneous canakinumab treatment for 24 months comparted with placebo on the carotid plaque burden measured by integrated vascular MRI in patients enrolled in the CACZ885M2301 study (CANTOS).

Sub-study 2 (CACZ885M2301S2): The purpose of this CANTOS sub-study was to determine whether, in patients with type 2 diabetes participating in the CANTOS main study, canakinumab compared to placebo, on top of standard of care could increase insulin secretion and insulin sensitivity.

Detailed description:
Sub-study 1 and 2 were terminated prior to data collection from subjects. However, there is an ongoing extension trial where patients are receiving open-drug label.

Arms: arm 1: Pivotal Phase:

Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care therapy.

Extension Phase:

Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy arm 2: Pivotal Phase:

Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy arm 3: Pivotal Phase:

Blinded Canakinumab 300 mg quarterly subcutaneous (with one additional dose at week 2) + standard of care therapy.

Extension phase:

Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy arm 4: Pivotal Phase:

Blinded matching placebo quarterly subcutaneous + standard of care therapy.

Extension Phase:

Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care therapy
Interventions: intervention 1: Canakinumab intervention 2: Placebo intervention 3: Standard of care
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: 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

Protocol documents:
Prot_000.pdf: 
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


Novartis
Confidential
Page 2
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 3
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 4
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 5
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 6
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 7
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 8
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 9
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 10
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 11
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 12
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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.   


Novartis
Confidential
Page 13
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 14
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
 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. 


Novartis
Confidential
Page 15
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.
 
 
 
 
 


Novartis
Confidential
Page 16
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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; 


Novartis
Confidential
Page 17
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
(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


Novartis
Confidential
Page 18
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 19
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 20
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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).


Novartis
Confidential
Page 21
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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: 


Novartis
Confidential
Page 22
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 23
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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, 


Novartis
Confidential
Page 24
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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: 


Novartis
Confidential
Page 25
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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. 


Novartis
Confidential
Page 26
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 27
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 28
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 29
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 30
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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


Novartis
Confidential
Page 31
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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:


Novartis
Confidential
Page 32
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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/ 


Novartis
Confidential
Page 33
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 34
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 35
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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. 


Novartis
Confidential
Page 36
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 37
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
§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.


Novartis
Confidential
Page 38
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
§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. 


Novartis
Confidential
Page 39
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 40
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 41
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 42
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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:


Novartis
Confidential
Page 43
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 
biomarkers above the 99th percentile of the upper reference limit (preferably troponin) 


Novartis
Confidential
Page 44
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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]


Novartis
Confidential
Page 45
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
[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 
guidelines. 


Novartis
Confidential
Page 46
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 
participate in the study if


Novartis
Confidential
Page 47
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 
old at the time of screening.


Novartis
Confidential
Page 48
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 49
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 50
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 51
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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).


Novartis
Confidential
Page 52
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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
 
 


Novartis
Confidential
Page 53
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 54
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 55
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 56
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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. 


Novartis
Confidential
Page 57
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 58
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 59
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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, 


Novartis
Confidential
Page 60
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 61
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 62
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 63
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 64
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
dispense treatment. Dispensing of medication should be the last assessment performed at each 
visit.


Novartis
Confidential
Page 65
Amended Protocol Version 09 Clean                                       
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 66
Amended Protocol Version 09 Clean                                       
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 67
Amended Protocol Version 09 Clean                                       
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 68
Amended Protocol Version 09 Clean                                       
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 69
Amended Protocol Version 09 Clean    
                  
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 70
Amended Protocol Version 09 Clean                                       
Protocol No.CACZ885M2301 
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.
 


Novartis
Confidential
Page 71
Amended Protocol Version 09 Clean                                       
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 72
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 73
Amended Protocol Version 09 Clean                                       
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 74
Amended Protocol Version 09 Clean                                       
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 75
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 76
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 77
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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)


Novartis
Confidential
Page 78
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


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 


Novartis
Confidential
Page 79
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.]


Novartis
Confidential
Page 80
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 81
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 82
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 83
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 84
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 85
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 86
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 87
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 88
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 89
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 90
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 91
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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
 
 
any cardiovascular 


Novartis
Confidential
Page 92
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 93
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 94
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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 


Novartis
Confidential
Page 95
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 

Hyperpyrexia, Hyperthermia malignant


Novartis
Confidential
Page 96
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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


Novartis
Confidential
Page 97
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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, 


Novartis
Confidential
Page 98
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 99
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 100
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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).


Novartis
Confidential
Page 101
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 
have not received study treatment.


Novartis
Confidential
Page 102
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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


Novartis
Confidential
Page 103
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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 


Novartis
Confidential
Page 104
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 105
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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.


Novartis
Confidential
Page 106
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 107
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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. 


Novartis
Confidential
Page 108
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 109
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 110
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 111
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 112
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 113
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 114
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 115
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 116
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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.


Novartis
Confidential
Page 117
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 118
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 119
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 120
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 121
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 122
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 123
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 124
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 125
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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. 


Novartis
Confidential
Page 126
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 127
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 128
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 129
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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, 


Novartis
Confidential
Page 130
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 131
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 132
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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:


Novartis
Confidential
Page 133
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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.


Novartis
Confidential
Page 134
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 

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 


Novartis
Confidential
Page 135
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 136
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 137
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 138
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 139
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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 


Novartis
Confidential
Page 140
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 141
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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


Novartis
Confidential
Page 142
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 143
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 144
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 


Novartis
Confidential
Page 145
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 146
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.


Novartis
Confidential
Page 147
Amended Protocol Version 09 Clean
Protocol No.CACZ885M2301 
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.

SAP_001.pdf: 
Clinical Development and Medical Affairs
CACZ885M2301/canakinumab / NCT01327846
Canakinumab Anti-inflammatory Thrombosis Outcomes Study 
(CANTOS) - 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
Detailed Statistical Methodology
Author(s):
 
 
 
 
 
Document type:
Analysis Plan Documentation
Document status:
Final; Amendment 4
Release date:
14 April 2017
Number of pages:
89
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
RAP Module 3
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................4
List of figures ......................................................................................................................4
List of acronyms ..................................................................................................................6
1
Introduction .......................................................................................................................12
2
Definitions .........................................................................................................................12
2.1
Analysis sets ..........................................................................................................12
2.2
Subgroup definitions..............................................................................................14
2.3
Assessment windows, baseline and post baseline definitions, missing data 
handling .................................................................................................................20
2.3.1
Assessment windows and visit mapping...............................................20
2.3.2
Baseline definition ................................................................................21
2.3.3
Post-baseline definition.........................................................................21
2.3.4
On treatment definition .........................................................................21
2.3.5
Visit mapping for the study completion visit........................................21
2.3.6
Data from unplanned visits and unscheduled visits ..............................22
2.3.7
Time window for post stroke assessments............................................23
2.3.8
Close-out procedure ..............................................................................23
2.3.9
Missing data handling ...........................................................................25
2.4
Key trial design aspects relevant to trial analysis..................................................26
3
Patient disposition, background and demographic characteristics....................................29
3.1
Patient disposition..................................................................................................29
3.2
Background and demographic characteristics .......................................................30
3.3
Medical History .....................................................................................................32
4
Study medication...............................................................................................................33
5
Concomitant medication....................................................................................................33
6
Efficacy evaluation............................................................................................................36
6.1
Variables................................................................................................................36
6.1.1
Endpoint adjudication process ..............................................................37
6.1.2
Primary efficacy variable ......................................................................38
6.1.3
Key secondary efficacy variables..........................................................40
6.1.4
Other secondary efficacy variables .......................................................40
6.2
Summarizing results across centers, countries and regions...................................40
6.3
Statistical hypothesis, model, and method of analysis ..........................................40
6.3.1
Primary variable....................................................................................41


Novartis
Confidential
Page 3
RAP Module 3
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
6.3.2
Key secondary efficacy variables..........................................................48
6.3.3
Other secondary efficacy variables .......................................................51
51
55
56
57
58
59
60
60
61
6.4
Kaplan-Meier type analyses and graphs ................................................................62
6.4.1
Overall Kaplan-Meier type graphs across trial parts.............................62
6.4.2
Kaplan-Meier graphs for each trial part and general principles............64
6.4.3
Calculation of number needed to treat ..................................................65
6.5
Methodology for dose response evaluation ...........................................................65
7
Safety evaluation ...............................................................................................................66
7.1
Safety assessment approach accounting for multiplicity.......................................67
7.2
Statistical models used in multiple safety contexts ...............................................67
7.3
Other safety evaluation..........................................................................................69
7.3.1
Adverse Events......................................................................................69
7.3.2
Laboratory data .....................................................................................72
7.3.3
Vital signs..............................................................................................75
7.3.4
Electrocardiogram (ECG) .....................................................................75
7.4
Safety topics of interest .........................................................................................76
7.4.1
Infections / opportunistic infections......................................................77
7.4.2
Hepatic safety data ................................................................................79
7.4.3
Malignancy............................................................................................81
7.4.4
Thrombocytopenia ................................................................................82
7.4.5
Neutropenia...........................................................................................82
83
7.4.7
Disorders of lipoprotein metabolism.....................................................83
7.4.8
Hypoglycemia .......................................................................................84
7.4.9
Autoimmunity .......................................................................................84
7.4.10
Injection site reactions...........................................................................84
7.4.11
Vertigo/dizziness...................................................................................84


Novartis
Confidential
Page 4
RAP Module 3
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
7.4.12
Other safety topics.................................................................................84
8
Interim analyses.................................................................................................................84
9
Sample size and power considerations..............................................................................85
Appendix 1: Post-stroke functional assessment sub-study.......................................................85
10 References .........................................................................................................................86
List of tables
Table 2-1
Definition of dose received at a visit....................................................12
Table 2.2
Criteria leading to exclusions from analysis sets ..................................14
Table 2.3-1
Subgroup analyses for the primary major adverse cardiovascular 
event (MACE) endpoint and other key efficacy outcomes...................15
Table 2.3-2
Standard safety subgroups.....................................................................16
Table 2.3-3
Additional subgroups needed only for specific analyses ......................18
Table 2.3-4
Regional/country subgroups to support regional/local submissions, 
for which selected tables have to be repeated .......................................19
Table 2-4
Time windows for endpoints based on HbA1c, FPG, standard 
hematology, biochemistry or fasting lipid profile.................................23
Table 2-5
Time windows for urinalysis based endpoints......................................23
Table 5-1
Conversion table for statin doses ..........................................................35
Table 6-1
Primary, key secondary and secondary variables for CANTOS...........36
Table 7-1
Clinical notable criteria for selected laboratory tests............................73
Table 7-2
NIH CTC version 4.0 grades for Chronic kidney disease, which 
can be assessed in this trial....................................................................74
Table 7-3
Clinically notable changes in vital signs...............................................75
Table 7-4
List of safety topics of interest..............................................................76
Table 7-5
Higher Risk Subgroups .........................................................................78
Table 7-6
Hepatic events .......................................................................................79
Table 7-7
NIH CTC version 4.0 grades for platelets.............................................82
Table 7-8
NIH CTC version 4.0 grades for neutrophils ........................................82
List of figures
Figure 2-1
Assessment windows ............................................................................20
Figure 2-2
Overview of close-out procedure..........................................................24
Figure 2-3
Patient allocation to treatment arms prior and after protocol 
amendment 6 including reduced patient numbers following 
protocol amendment 8...........................................................................27
Figure 6-1
Simplified overview of the adjudication process..................................38
Figure 6-2
Illustrative examples of events counting for the primary analysis.......39
Figure 6-3
Possible closed testing procedure if Dunnett test had not been used...42


Novartis
Confidential
Page 5
RAP Module 3
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Figure 6-4
Closed testing procedure for primary and key secondary endpoints ...43
Figure 6-5
Closed testing procedure with full details of testing of key 
secondary endpoints..............................................................................49
Figure 6-6
Candidate dose response patterns..........................................................66


Novartis
Confidential
Page 6
RAP Module 3
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
List of acronyms
AE
Adverse event
AHD
Antihyperglycemic drug
ALP 
Alkaline phosphatase
ALT 
Alanine aminotransferase (SGPT)
AST 
Aspartate aminotransferase 
ATC
Anatomical Therapeutic Chemical classification system
BCa
Bias-corrected and accelerated bootstrap
BMI
Body Mass Index
BNP
Brain Natriuretic Peptide
CABG
Coronary Artery Bypass Graft
CAD
Coronary artery disease
CANTOS
Canakinumab Anti-inflammatory Thrombosis Outcomes Study
CCU 
critical care unit 
CDBL
Clinical Database Log
CEC
Clinical Events Committee
CHD
Coronary Heart Disease
COPD
Chronic Obstructive Pulmonary Disease
CREDI 
Novartis Clinical REsearch Documentation and Information system
CRF
Case Report Form
CRS
Case Retrieval Strategy
CV
Cardiovascular
DBL 
Conjugated (direct) bilirubin
DBP
Diastolic Blood Pressure
DHP
Data Handling Plan
DILI 
Drug-induced liver injury
DMC
Data Monitoring Committee 
ECG
Electrocardiogram
eGFR
estimated Glomerular Filtration Rate
FAS
Full Analysis Set
FPG
Fasting Plasma Glucose
HbA1c
Glycosylated hemoglobin 
HDL
High Density Lipoprotein
HR
Heart Rate
hsCRP
high sensitivity C-reactive protein
ICU 
intensive care unit
IDL
Intermediate density lipoprotein
Il-1β / Il-6
Interleukin-1β, Interleukin-6
IRT
Interactive Response Technology 
IP
Investigational Product
IVRS
Interactive Voice Response System
LAD
Left Anterior Descending artery
LCX
left circumflex artery
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LLN
Lower Limit of the Normal range
LPLV
Last Patient Last Visit
MACE
Major Adverse Cardiovascular Events (CV death, MI or stroke)
MAR
Missing At Random


Novartis
Confidential
Page 7
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
MCMC
Markov chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
NMQ
Novartis MedDRA Query
NOD
New Onset Diabetes
NovDTD
Novartis Drug/Therapy Dictionary 
NT-proBNP
N-terminal pro-Brain Natriuretic Peptide
OC/RDC
Novartis Oracle Clinical/Remote Data Capture system
PCI
Percutaneous Coronary Intervention
PD
Protocol Deviation or Pharmacodynamics
 
 
 
PPS
Per-Protocol Set
PT
MedDRA Preferred Term
QTc
heart rate-corrected QT interval
QTcB
QTc (Bazett’s correction)
QTcF
QTc (Fridericia’s correction)
RAAS
Renin-angiotensin-aldosterone system
RCA
Right coronary artery
RMP
Novartis Risk Management Plan
SAE
Serious Adverse Event
SAF
Safety Set
SBP
Systolic Blood Pressure
SMQ
Standardized MedDRA query
SOC
(primary) System Organ Class
SPP
Novartis Safety Profiling Plan
T1DM
Type 1 Diabetes Mellitus
T2DM
Type 2 Diabetes Mellitus
TBL 
Total bilirubin
TIA
Transient Ischemic Attack
TNF
Tumor necrosis factors
 
VLDL
Very low-density lipoprotein


Novartis
Confidential
Page 8
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Document History – Changes compared to previous versions of RAP module 3
Amendment 4, April 14, 2017
Section
Changes
2.1
Table 2-1: Addition of PD for site closure due to GCP non-compliance
2.2
Table 2.3-1 Age subgroup categories clarified to make clear that these are two 
separate subgroup variables
2.2
Table 2.3-1: Added subgroup as requested by FDA (presence of MI prior to index 
MI – yes/no)
2.2
Table 2.3-2 Change made Age subgroup categories to clarify this is two separate 
subgroup variables (consistent with Table 2.3-1)
2.3.1
Added text to highlight different terminology used in the protocol
2.3.8
Amended to reflect that the LPLV date will be used as the cut-off date since all 
events are planned to be adjudicated up to the last patients’ visit
5
Removed Table 5-1. Revised text referencing table 5-1 to state that summaries 
should be based on the protocol visit schedule. Updated references to Table 5-2 
due to table re-numbering.
Amendment 3, July 19, 2016
Section
Changes
Various
Various changes to text are made to clarify the intent.  Minor changes are not 
reflected below.  Changes that result in a change from what was originally 
intended are explained below.
1
Changed wording to reflect that the data from the washout and extension phases 
of the study will be addressed in a separate analysis plan and study report.
2.2
Table 2.3-3: removed subgroup related to patients entering washout who had 
stopped medication prior to final main trial assessment.
2.3.8
Clarifying that the analysis cutoff date could be earlier than the LPLV.  In this case, 
events will only be considered as investigator reported.
2.3.9
-
Removed planned sensitivity analyses for examining the assumption of non-
informative censoring. This will be investigated, but not generally included in the 
study report.
-
Clarified that censoring date may not be the same for all time to event
endpoints. 
2.4
Figure 2-3 updated to match corresponding figure in study protocol.
5
Definitions of medication categories updated.
6
Removing the text about “post treatment phase” as it was resulting in confusion as 
to what was intended.  Clarified main analyses will be based events occurring in 
the double blind phase.
6.1.2
Updated censoring algorithm to align with use of the cutoff date.
6.3.1
-
Covariate adjusted analysis of primary endpoint changed to “may be 
considered.” This is an exploratory analysis and not planned to be part of the 
study report.  
-
Added that the association between hsCRP changes and outcomes will be 
explored, this is already mentioned in the current protocol.
6.3.2
-
Added supportive analyses for diabetes related time to event endpoints.
-
Removed reference to analysis of washout period data.
-
Added statement that washout period data will be analyzed in a separate study 


Novartis
Confidential
Page 9
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Section
Changes
report or an addendum to the study report.
6.5
Dose response model approach revised to reflect current plan for dose response 
modelling. 
7
-
Removed text related to summarizing data by trial part to avoid confusion 
between the main AE tables, which are pooled across trial parts and some 
specific analyses that present data separately by trial part. 
-
Revised categories used for by-time-period analyses.
7.3.1
-
Clarified on-treatment definition for AEs.
-
Removed plan for time-to-event analysis or AEs.
7.3.2
-
Updated notable criteria in Table 7-1.
-
Added detailed description for analysis of long term effects on kidney function.
7.4
Updated list of adverse events of special interest to align with current safety 
profiling plan.
7.4.1
-
Added by-time-period analyses for infections to align with other adverse event 
analyses.
-
Model for analysis of infections is revised to align with model for other adverse 
event analyses.
-
Analysis of duration of infections revised to only present a descriptive summary. 
Negative binomial model analysis is removed.
7.4.2
Removed ordinal regression analysis of LFT parameters; results are summarized 
using frequency tables.
7.4.3
Additional summary tables added to align with other adverse event analyses.
7.4.4
Removed summary of early drops in platelet counts.
7.4.8 – 7.4.12
-
Topic of long term effects on kidney function was moved into Section 7.4.12  
(Other safety topics).  Analysis description is covered in section 7.3.2.  
(Laboratory data).
-
Topic of QT prolongation was moved into section 7.4.12  (Other Safety topics) 
and will be analyzed under section 7.3.4 (ECG).
-
Section on Hypoglycemia reordered to section 7.4.8.
-
Added new sections 7.4.9-7.4.11 (Autoimmunity reactions; Injection site 
reactions; Vertigo/dizziness).
-
Section on “Other safety topics” reordred to section 7.4.12. Section title 
changed to clarify that this section addresses other adverse events that are not 
part of the adverse events of special interest.
10
Removed; this will be addressed in a separate analysis plan and report.
11
Removed; this will be addressed in a separate analysis plan and report.
Appendix 1
Removed; this will be addressed in a separate analysis plan and report.
Appendix 2
Renumbered to Appendix 1.
Amendment 2, April 13, 2016
Section 
Changes
Throughout
Editorial changes.
2.1 (Table 2-2)
Updated Per protocol criteria. 
2.2 (Table 2.3-1)
-
Detail added on the region subgroups.


Novartis
Confidential
Page 10
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Section 
Changes
-
Clarified analyses would be done in all tables by region subgroup.
-
Updated definition of Pre-diabetic and Diabetic.
2.2 (Table 2.3-3)
-
Details added to basis for diabetes diagnosis subgroups
-
Baseline HbA1c/FPG categories subgroups updated.
2.3.4
On-treatment definition added.
2.3.9 
(previously 2.3.8)
-
Added missing date imputation rules.
-
Amended time to event section.
-
MACE endpoint (and all individual components) censoring rules updated.
3.1
Changed the calculation of patient’s age to be from date of start of screening 
instead of date of informed consent.
3.2
Updated sub-level categories. 
5
-
Added PCSK9 inhibitors to the list of non-statins.
-
Added SGLT2 inhibitors to the list of other oral hypoglycemic agents.
-
Added rules for the summary of statin use for the determination of the daily 
dose for each patient.
6.3.2
-
Updated the definition of new onset diabetes.
-
Updated the second set of criteria for determining new onset diabetes.
 
7.3.1
Amended the cut off for common events from 1% to 2%.
7.3.3 (Table 7-2)
Amended clinically notable changes in vital signs criteria.
7.4
Inserted table 7-3 with an updated list of AEs of special interest.
7.4.2
-
Clarified baseline glycemic and abnormal LFT subgroup analyses.
-
Updated the covariates in the ordinal regression.
7.4.3
Amended the identification of malignancy. 
12
Added references.
Amendment 1, June 26, 2014
Section
Changes
2.2
Updates to the per-protocol analysis sets.
2.2
Updates to the subgroup definitions.
2.3.2
Clarification of the hsCRP the baseline value. 
3
Minor updates and clarifications to patient disposition, demographics, and medical 
history.
6.1.1
New section 6.1.1 was added for endpoint adjudication process. 
6.3.1
-
Addition of an additional early futility analysis to be performed at approximately 
30% of the target number of 1400 patients have experienced CEC confirmed 
MACE, as per protocol amendment 8. 
-
Clarification that in case one active arm is stopped, the target number of 
patients with a MACE that is still to be collected has to be adjusted. For patients 
whose treatment arm is stopped per DMC recommendation, follow-up for 
cardiovascular (CV) and safety events will continue.


Novartis
Confidential
Page 11
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Section
Changes
-
A sensitivity analysis will be performed by performing the primary analysis 
excluding all patients who were unblinded during the double blind phase of the 
study.
-
Change from baseline to the last hsCRP prior to the 1st confirmed MACE will be 
summarized by treatment. 
6.3.2
-
Clarification added that all identified cases of new onset of diabetes will be 
confirmed by the adjudication committee.
-
Clarifications on subgroup analyses for the key secondary new onset of 
diabetes endpoint.
7
Several minor updates and clarifications.
8
Protocol amendment 8 introduced an additional early futility analysis to be 
performed at approximately 30% of the target number of 1400 patients have 
experienced CEC confirmed MACE. 
12
Added new reference.


Novartis
Confidential
Page 12
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
1
Introduction
The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS; Novartis 
study code CACZ885M2301) is 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.
This document outlines the agreements for the Statistical Analysis Plan for CANTOS based 
on the discussions between 
 and Novartis. The detailed 
statistical analysis plan including additional supportive/
, table shells and 
data set specifications will be prepared on this basis.
It is planned that after the end of the core study visit patients will be followed for safety in an 
extension study.  Data collected after the end of the core study visit will not be part of the 
main CANTOS clinical database and analyses using data from this extension study will not be 
specified in this document.
2
Definitions
2.1
Analysis sets 
The following analysis sets 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 drug 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 the two 
injections constituting the treatment assignment at randomization.
For patients who cannot be assigned in this manner, the most frequent dose at an 
individual visit (as defined in table 2-1) will be considered the treatment received. In 
the case of more than one equally frequent dose (ties), the highest most frequent dos e 
will be assigned. 
Note: Any patient who did not receive any injection of study drug during the study is 
automatically excluded from the safety set, due to the lack of at least one dose of study 
medication.
Table 2-1
Definition of dose received at a visit
Sum of injection doses* [mg]
Dose at the visit
0 (meaning ≥ 1 placebo injections, but 
not even a partial canakinumab 
injection)
Placebo


Novartis
Confidential
Page 13
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Sum of injection doses* [mg]
Dose at the visit
> 0 to ≤ 50 mg of canakinumab
Canakinumab 50 mg
> 50 to ≤ 150 mg of canakinumab
Canakinumab 150 mg
> 150 of canakinumab
Canakinumab 300 mg
* Placebo injections counted as 0 mg

Full analysis set (FAS) – All randomized patients. This is the primary efficacy 
population applied in all efficacy variables. 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 
have 
not 
received 
study 
drug. 
(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 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; e.g., serious Good Clinical Practice violations).
Per protocol set 1 (PPS1) – 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 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. Data from patients discontinuing treatment will 
be censored a quarter year + 28 days after their last study drug injection.
All cases of prospectively defined protocol deviations will be identified prior to clinical 
database lock / unblinding and entered into a dedicated data panel as part of the locked 
database. Certain deviations may stipulate that only data up to the time of infraction will be 
included in the PP analysis, i.e. for analyses of the PP set data beyond this time -point will be 
ignored. This supplemental efficacy population is used to assess robustness of the primary 
analysis results. All exceptional cases and problems and the final decisions on the allocation 
of patients to populations will be fully defined and documented before data base lock (in 
particular before breaking the blind where applicable) and will be fully identified and 
summarized in the clinical study report as per the harmonized International Conference on 
Harmonization of technical requirements for registration of pharmaceuticals for human use 
tripartite guideline on statistical principles for clinical trials.
Criteria defining protocol deviations are provided in the Data Handling Plan (DHP). Protocol 
deviations will not lead to patient withdrawal from the study unless they indicate a significant 
risk to the patient’s safety.
For the purpose of summarizing major protocol deviations, these will be considered to be 
those protocol deviations that lead to the exclusion from an analysis set. The current draft list 
of criteria leading to exclusions from analysis sets is shown in Table 2.2. Other currently 


Novartis
Confidential
Page 14
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
foreseen protocol deviations will be reported in the clinical study report, but these will not 
lead to an exclusion from any analysis set. It is not currently foreseen that any criteria would 
lead to an exclusion from PPS from date of deviation.
Table 2.2
Criteria leading to exclusions from analysis sets
Analysis set
Criteria that cause a screened patient to be excluded
Screened
none
Safety (SAF)
Patients not receiving any dose of double-blind study medication
Randomized
Patient without a randomization number
Patient was not randomized but took study drug (covered by the above)
Full Analysis Set (FAS)
Patient mis-randomized
Patient without a randomization number
Patient was not randomized but took study drug
Site closed for GCP non-compliance (data integrity was impacted)
Per Protocol set 1 
(PPS1)
Patient mis-randomized
Patient without a randomization number
Patient was not randomized but took study drug
Patients not receiving any dose of double-blind study medication
Patient participates in any other investigational drug or device study or 
patient has received an investigational drug or device <= 30days of Visit 1 
except for previous DES trial on countries with approved DES devices          
Patient received study drug, and was later discontinued due to not 
meeting the entry criteria 
Major surgical procedure including PCI or CABG performed during the 
study but planned prior to randomization.
CABG < 3 years prior to visit 1
Patient is currently (i.e. at randomization) taking a biological drug targeting 
the immune system (ie: TNF blockers, anakinra, rituximab, abatacept, 
tocilizumab)
Documented MI does not meet entry criteria or Date of most recent MI = 
blank but there is a visit 2
Screening hsCRP  < 2 mg/L or = blank
Qualifying hsCRP measurement  date < 28 days after date of prior PCI or    
Qualifying hsCRP measurement  date < 28 days after date of qualifying MI
Exclusion of data from 
PPS from date onwards
Data from patients discontinuing treatment will be censored a quarter year 
+ 28 days after their last study drug injection.
2.2
Subgroup definitions
Generally subgroup analyses within a trial should be kept to a minimum. However, subgroup 
analyses need to be presented in submission documents like Summary of Clinical Efficacy, 
Summary of Clinical Safety, and Risk Management Plan and the clinical study report for the 
CANTOS trial will likely at least fulfill the first two of these roles.


Novartis
Confidential
Page 15
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
The objective of the subgroup analyses is to evaluate the consistency of treatment effects 
across a wide variety of patient groups.
The primary composite (MACE) endpoint of CV death, nonfatal MI and nonfatal stroke, the 
key secondary variables and potentially other important efficacy variables will be analyzed for 
the subgroups shown in the Table 2.3-1.
Table 2.3-1
Subgroup analyses for the primary major adverse cardiovascular 
event (MACE) endpoint and other key efficacy outcomes
Subgroups
Definition
Age (at study start)
<65, ≥65 years ;
<75, ≥75 years
Sex
male, female
Race
Asian, Black, Caucasian, Other 
Ethnicity
Hispanic / Latino, Asian, Other, Unknown
Type of qualifying MI
STEMI, non-STEMI, unknown
BMI at baseline
< 25, ≥ 25 & < 30, ≥ 30 kg/m2 ; < 35, ≥ 35 kg/m2
Region

Asia: China, India, Japan, South Korea, Taiwan

Western Europe: Austria, Belgium, Germany, Greece, 
Iceland, Italy, Netherlands, Norway, Sweden, United 
Kingdom

Central Europe: Bulgaria, Croatia, Czech Republic, Estonia, , 
Hungary, Latvia, Lithuania, Poland, Romania, Russian 
Federation, Serbia, Slovakia, Slovenia, Turkey

Latin America: Argentina, Brazil, Colombia, Guatemala, 
Mexico, Peru

North America: Canada, United States

Others: Australia, South Africa
In addition to the above regions in all tables by region subgroup, 
an analysis for Japan (and Japan plus Korea) will also be 
presented separate regardless the size of enrollment in these 
countries to meet Japanese regulatory requests.
Glycemic status at baseline
Normoglycemic, pre-diabetic, diabetic
Pre-diabetic is defined by one of the followings

HbA1c  ≥5.7% & <6.5% 

FPG ≥100 & <126 mg/dl

FPG ≥ 126 mg/dl at either Visit 1 or Visit 2 (or any 
unscheduled visit between, but only occurring on one visit)

HbA1c ≥ 6.5% at either Visit 1 or Visit 2 (or any 
unscheduled visit between, but only occurring on one visit)
Diabetic is defined by one of the followings

FPG ≥ 126 mg/dl at Visit 1 and Visit 2 (or any unscheduled 
visit between)


Novartis
Confidential
Page 16
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Subgroups
Definition

HbA1c ≥ 6.5% at Visit 1 and Visit 2 (or any unscheduled 
visit between)

Combination of FPG ≥ 126 mg/dl  and  HbA1c ≥ 6.5% as 
confirmed at Visit 1 and Visit 2 (or any unscheduled visit 
between)

Medical history of Type I or Type II diabetes mellitus

Anti-diabetic medication use
Smoking status at baseline 
Never, current, former 
Baseline hsCRP level
≤ 4, > 4 mg/L  
Baseline LDL-C level
< 70 mg/dL, >= 70 mg/dL;  Tertiles of baseline LDL-C (This will 
be done using the  calculated LDL-C unless triglycerides > 400 
mg/dL in which case a direct (i.e. measured) LDL-C will be 
used)
Baseline SBP level
< 130 mmHg, ≥ 130 mmHg
Baseline DBP level
< 80 mmHg, ≥ 80 mmHg
Baseline statin dose level
No, low, moderate, and high 
Baseline aspirin usage/dose
Yes / No 
Medical history of gout
Yes / No
Cardiovascular risk factors
Hypertension
Yes / No 
Dyslipidemia 
Yes / No 
Prior PCI 
Yes / No
Prior CABG 
Yes / No 
Prior TIA/stroke 
Yes / No 
History of heart failure
Chronic Heart Failure occurrence (yes/no) 
eGFR  MDRD
< 60, ≥ 60 & < 90, ≥ 90  mL/min/1.73m2
Time since index MI
< 6 vs. ≥ 6 months ; < 12 vs. ≥ 12 months
Presence of MI prior to index MI
Yes / No
A set of standard safety subgroups shown in Table 2.3-2 will by default be looked at for 
selected safety analyses (see section 7).
Table 2.3-2
Standard safety subgroups
Subgroup
Definition
Age
<65, ≥65 years;  
<75, ≥75 years
Sex
male, female


Novartis
Confidential
Page 17
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Subgroup
Definition
Race
The same as above 
Ethnicity
The same as above
Region
The same as above 
Time since index MI
< 6 months vs. ≥ 6 months 
BMI
The same as above 
Medical history of gout 
Yes / No 
Co-existing medical conditions of interest: T2DM
Yes / No
Baseline hsCRP level
The same as above 
In addition to the two preceding sets of subgroups those specified in Table 2.3-3 will be used 
in some analyses as stated in the relevant analysis plan sections. They are shown here 
irrespective of what kind of analysis they will be used for to highlight that they needed to be 
included in analysis datasets.


Novartis
Confidential
Page 18
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Table 2.3-3
Additional subgroups needed only for specific analyses
Subgroups
Duration of diabetes
< 3, ≥ 3 & < 10, ≥ 10 years 
Basis for diabetes diagnosis

Medical History of Type I or Type II diabetes mellitus

Medical History and Anti-diabetic medication

Medical History and Baseline HbA1c/FPG

Medical History and Anti-diabetic medication and Baseline 
HbA1c/FPG

Anti-diabetic medication

Anti-diabetic medication and Baseline HbA1c/FPG

Baseline HbA1c/FPG
Baseline HbA1c categories

HbA1c < 7% at randomization for deterioration of glycemic 
control analyses (HbA1c ≥ 7.5% at 6 month visit or beyond, 
confirmed by a second/unscheduled HbA1c measurement 
within 6 weeks) [i.e.  Among those randomization diabetic 
patients, we look at the sub-group of patients with HbA1c < 
7% at visit 2. Then we would analyze how many of those 
patients experience a deterioration of glycemic control as 
documented by an increase of HbA1c to >= 7.5% at 6 
months or beyond, confirmed within 6 weeks.]

For HbA1c benefit analysis in diabetics (HbA1c < 8%, ≥ 8%) 
[i.e. analysis of mean HbA1c change from baseline in T2D 
patients with baseline HbA1c < 8% and >= 8%.]
History of macular degeneration
Medical history or use of relevant medications
Baseline neutrophil levels
Abs neutrophils < 1.5 , ≥ 1.5 x 109 /L
.
Baseline use of antithrombotic 
medications
Yes/No 
key drugs for the trial population 
affected by CYP450 with a narrow 
therapeutic index (e.g. warfarin and 
amiodarone)
Yes/No 
•
Vaccines
Yes/No   
Medical history of gout, rheumatoid 
arthritis or other inflammatory 
diseases such as lupus or psoriatic 
arthritis
Yes/No
History of malignancy 
Yes/No - Yes will correspond to patients with SMQ “Malignant or 
unspecified tumors” in Medical history
Baseline QTcF 
Elevated or normal


Novartis
Confidential
Page 19
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Subgroups
Normal
•
≤ 430 msec for men, ≤ 450 msec for women  
Elevated
•
> 430 msec for men, > 450 msec for women.
Baseline heart rate
< 55 bpm versus ≥ 55 bpm
Alcohol history
Yes / No 
Baseline platelet counts
< 150, ≥ 150  x 109 /L
Early drops in platelet counts (or 
thrombocytopenia) Ordinal 
< 25, ≥ 25 - <50, ≥ 50 - <75, ≥ 75 - < LLN, >=LLN at visit 3. 
Repeat at visit 4; 
Early drops in platelet counts (or 
thrombocytopenia) defined by % 
change from baseline
< 20% and ≥ 20% drop from baseline to visit 3. Repeat at visit 4
Early drops in neutrophils (or 
neutropenia)
<0.5, ≥0.5 - <1.0, ≥1.0 - <1.5, ≥1.5 - <LLN at visit 3. Repeat at 
visit 4
Early drops in neutrophils (or 
neutropenia) defined by % change 
from baseline
< 20% and ≥ 20% drop from baseline to visit 3. Repeat at visit 4
baseline neutropenia
CTC >=3 (yes/no)
To support regional submission activities and health authority interactions, at a minimum the 
subgroups shown in table 2.3-4 are needed. 
Table 2.3-4
Regional/country subgroups to support regional/local submissions, 
for which selected tables have to be repeated
Preliminary* list of variable(s) / analyses to be repeated
Regional/country subgroup
On FAS
Disposition/Demography/Patient and disease characteristics 
Incidence of primary endpoint
Incidence of key secondary endpoints
Incidence of secondary endpoints (includes death)
Analyses of other selected efficacy variables (e.g. hsCRP)
Medical environment (e.g. prior/concomitant medications including 
statin dose, revascularization/stenting/etc. for index MI)
On SAF
Adverse events by system organ class and preferred term
Serious adverse events by system organ class and preferred term
Deaths
Standardized MedDRA queries
1. Japan
2. Japan and Korea
3. Mainland China 
4. Mainland China + Taiwan 
5. Asian patients: Japan, China, 
Taiwan, and Korea
6. India
7. Russia


Novartis
Confidential
Page 20
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Preliminary* list of variable(s) / analyses to be repeated
Regional/country subgroup
Adverse events of special interest
* subject to changes dependent on local requirements
2.3
Assessment windows, baseline and post baseline definitions, 
missing data handling
2.3.1
Assessment windows and visit mapping
Figure 2-1
Assessment windows
Screening phase
The screening phase is defined as the period prior and up to randomization. After obtaining 
written informed consent, the patient will be evaluated for eligibility to participate in to the 
study.
Double-blind phase
The double-blind phase includes double-blind treatment phase and post-treatment phase. It 
does not include the washout phase or any long-term follow-up after the completion of this 
trial. The double-blind phase defined here is the same as the double-blind treatment period 
defined in the study protocol.
Double-blind treatment phase
The double-blind treatment phase refers to the time period during which patients actually 
receive treatment (or are still expected to have significant PK exposure).
The double-blind treatment phase begins at the time of randomization and ends with the 
earliest of the last trial drug intake plus a quarter year (91 days), the death of the patient or the 
last study assessment in the main part of the trial (i.e. excluding the washout). During the 
double-blind treatment phase, patients will return for scheduled clinic visits.
Post-treatment phase
The post-treatment phase refers to the time period during which patients no longer receive 
treatment and no longer have significant PK exposure up to the end of the study visit for the 
      Randomization
1st of last intake plus a quarter,
    Death or end of 
  Death or last
death or end of core study visit
     core study visit
  washout
  assessment
Washout 
phase
Double-blind phase
Double-blind treatment phase
Post-treatment phase
Screening 
phase


Novartis
Confidential
Page 21
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
core study. As this is an outcome study, patients should nevertheless be followed-up during 
this phase until the end of the core study, in order to assess the occurrence of trial endpoints.
The 
post-treatment 
phase 
(after 
unscheduled 
drug 
discontinuation 
or 
study 
completion/termination) begins after last study drug intake plus a quarter year (91 days) + 1 
day and ends with the date of the end of core study visit or the death of the patient. During the 
post-treatment phase, patients should also continue to return for scheduled clinic visits.
The distinction between double-blind treatment phase and post-treatment phase does not 
affect the primary intention-to-treat analysis, but affects e.g. the supportive on-treatment 
sensitivity analysis.
2.3.2
Baseline definition
Baseline is defined as the last available measurement during the screening phase, i.e. prior and 
up to randomization. That means that if the measurement at the baseline visit is missing, then 
the previous measurement preceding baseline will be used as the baseline measurement.
For hsCRP the baseline value will be the mean of the available hsCRP values within 60 days 
prior and up to randomization.
2.3.3
Post-baseline definition
Post-baseline is defined as any assessment after randomization including treatments and 
outcomes that occur after but on the same day as randomization. On the other hand, 
measurements and laboratory samples taken on the day of randomization during the 
randomization visit (at the end of which a patient is randomized) are considered baseline 
assessments.
2.3.4
On treatment definition
As baseline is relative to randomization, it is necessary to confirm where events/assessments 
occur relative to intake of dose. Any event/assessment occurring on or after the time of the 
first intake of IP and up to 119 days after the last treatment intake for those patients who 
discontinued treatment will be deemed to have occurred whilst “on treatment”. 
Scheduled Assessments: For scheduled assessments, both date and time are expected to be 
recorded in the database. However in the instance that only the date is recorded for an 
assessment, then the assessment will be deemed to have occurred prior to treatment. This is 
justified as protocol indicates injections will be given after all other study assessments have 
been completed for each visit.
Events: Should an event occur on the same day as first intake of IP, then the most 
conservative approach is to consider this to be on treatment.
2.3.5
Visit mapping for the study completion visit
As the core study completion visit will occur after a different length of follow-up for different 
patients, it needs to be defined for which scheduled timepoint assessments at the study 
completion visit are counted. I.e. it needs to be defined when e.g. plotting the quarterly/bi -


Novartis
Confidential
Page 22
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
yearly hsCRP values over time, whether the study completion hsCRP should count for the 
0.25 year visit, the 0.5 year visit, the 0.75 year visit, the 1 year visit etc., which will be based 
on when it occurred.
When showing values over time, study completion visit assessments will be displayed as if 
they had occurred at the next scheduled timepoint for that assessment. For example, if a 
patient has a regular month 45 visit and then the study completion visit occurs 2 months later, 
then the study completion visit would be considered to provide the patient’s values for month 
48.
2.3.6
Data from unplanned visits and unscheduled visits
Data from unplanned visits and unscheduled visits will not be re-mapped to other visits for the 
purpose of displaying variables over time except for laboratory data.  For laboratory data, a 
time window will be used to identify the assessment closest to the target day within the 
window over time.  The unplanned and unscheduled visits will be used in the analysis of 
event endpoints (e.g. new onset diabetes), and will be counted towards shift tables or other 
analyses regarding the worst observed values for patients. 


Novartis
Confidential
Page 23
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Table 2-4
Time windows for endpoints based on HbA1c, FPG, standard 
hematology, biochemistry or fasting lipid profile
Time window
Start of time window (study days)
End of time window (study days)
Week 2 visit
1, but only after the laboratory assessment  of 
the baseline visit
28
Month 1.5 visit
29
68
Month 3 visit
69
137
Month 6 visit
138
228
Month 9 visit
229
320
Month 12 visit
321
457
Month X visit 
(where X≥18 is a 
multiple of 6)
Rounded [ ( 365.25 / 12 ) * ( X – 3 ) ] + 1
Rounded [( 365.25 / 12 ) * ( X + 3 ) ]
Table 2-5
Time windows for urinalysis based endpoints
Time window
Start of time window (study days)
End of time window (study days)
Month 3 visit
1, but only after the laboratory assessment  of 
the baseline visit
228
Month 12 visit
229
639
Month 30 visit
640
1096
Month 42 visit
1097
1461
Month X visit 
(where X≥42 is a 
multiple of 12 
added to 30)
Rounded [ ( 365.25 / 12 ) * ( X – 6 ) ] + 1
Rounded [( 365.25 / 12 ) * ( X + 6 ) ]
2.3.8
Close-out procedure
CANTOS is designed as an event driven trial with the aim to finish the core study when 
approximately 1,400 patients had a confirmed primary endpoint. A close-out procedure will 
be initiated with a timing appropriate to achieve this.


Novartis
Confidential
Page 24
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Figure 2-2
Overview of close-out procedure
The aim of the close-out procedure will be to allow for the execution of all necessary 
activities including the core study completion visits, data cleaning, raising and resolution of 
all queries to the clinical sites, and endpoint adjudication for endpoints that occurred during 
the core study and prior to final visit/analysis cut-off, whichever occurs first.
The close-out procedure will start based on the estimated date when the confirmed target 
number of events will be reached, with final patient visits occurring until the date of the last 
visit of the last patient (LPLV),  and finish with the clinical database lock. The analysis cutoff 
date will be defined as the LPLV.
It will be attempted to follow each patient until a final study completion visit between the 
close-out start date and the analysis cut-off date unless the patient died. If a patient does not 
attend the final visit in person, there will be attempts to obtain information by other means 
between the close-out start date and the analysis cut-off date; this information will be 
available under the final study completion visit.
For patients who withdrew consent, the follow-up information such as vital status and whether 
endpoints occurred (“yes”, “no”, “unknown”) will still be collected during the close-out 
period to the maximum extent possible under local regulations.
Events occurring after the final visit, but before the analysis cut-off for patients that entered 
the long-term follow-up or the washout, will not be entered as endpoints into the database for 
the main trial.


Novartis
Confidential
Page 25
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
2.3.9
Missing data handling
Imputation of missing date
As a general approach each time it is appropriate the partially missing date reported as 
character date in the data will be imputed.

If only the month is known, then the 15th day of this month will be imputed.

If only the year is known, then the 1st July will be imputed.
As a general approach no imputation will be performed on completely missing date.
For AEs specific rules to impute partially missing start/end dates are defined in the ADAM 
specification.
For prior and concomitant medications specific rules to impute partially missing dates are 
defined in the ADAM specification. 
Time-to-event variables
Regarding time-to-event variables only observed/reported events will be used in the analysis –
i.e.  events will not be imputed for censored patients, except for specific sensitivity analyses. 
This means that in the primary analysis censoring of non-observed events will be assumed to 
be non-informative. 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 study. Information on patients discontinuing study drug or participation in trial 
visits will be collected whenever possible and will be used in the analysis. 
In general, every effort will be made to collect information about the primary outcome events 
for those patients who discontinued treatment or their participation in the trial. 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 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 defined as the earliest of:

the date of death unless the patient withdrew his consent for the collection of follow-up 
information,

the date of the last visit satisfying at least one of the following:

yes to the question of “indicates if the subject attended the scheduled visit” on the 
Visit Information CRF

yes/no to the question of  “any clinical events since last visit” on the Visit Information 
CRF


Novartis
Confidential
Page 26
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab

yes/no to the top three questions (death, myocardial infarction, stroke) on the Clinical 
Event Tracking CRF.
Should the censoring date lie after the chosen analysis cut-off date, it will be set to the 
analysis cut-off date. Note that this censoring date should be derived independently of any 
specific analysis other than all cause mortality, because it will be used to d escribe the extent 
of follow-up for (potentially multiple) cardiovascular events and for multiple different time-
to-event analyses (e.g. time to MACE, time to MI, analyses of multiple cardiovascular events). 
For all-cause death, the censoring will occur at the minimum of withdrawal of consent, last 
known alive date and analysis cut-off  date.
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 event date will be imputed as the randomization 
date and the patient will be assumed to have had a MACE event post-randomization on 
day 1 of the follow-up.

If this imputation rule leads to a date before the randomization date or after a patient’s last 
study visit or after a patient’s death, but the date could have been on one of these dates, 
then the event date will be imputed to be the one out of these dates that the incomplete 
date is consistent with. 

In the first three bullet points it will also be taken into account, whether it is known that a 
patient was event free up to a certain time. If that is the case the imputed date will be 
restricted to be after the date up to which the patient was event free, unless this is 
incompatible with the incomplete date or violates the 4th bullet point.
Date of trial drug injection
In case of missing information on the day of injection of any study medication the date of the 
corresponding dispensing visit will be used as date of injection. If that is missing the date 
foreseen for that visit in the protocol will be assumed.
Other missing data
Missing laboratory, vital signs, ECG, quality of life and other data will not be imputed for the 
purpose of summary statistics. Such summary statistics will be displayed longitudinally 
showing only those values that are available. Subsequent more in-depth analyses may explore 
other approaches and appropriate data imputation methods will be chosen for each type of 
analysis.
2.4
Key trial design aspects relevant to trial analysis
Randomization and blinding
Initially, patients were randomized in a 1:1:1 fashion to 300 mg canakinumab with induction 
dose, 150 mg without an induction dose or placebo quarterly. Following Health Authority 
feedback on the doses a lower 50 mg dose arm was added in protocol amendment 6 in order to 


Novartis
Confidential
Page 27
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
examine the dose response of canakinumab in preventing recurrent cardiovascular events, and 
to determine if a dose lower than 150 mg would have a favorable risk benefit ratio. Following 
this amendment, randomized allocation to the four trial arms was to be unbalanced in order to 
optimize power, now that three active arms were compared versus a common control arm.
Figure 2-3
Patient allocation to treatment arms prior and after protocol 
amendment 6 including reduced patient numbers following protocol 
amendment 8
Protocol amendment 6 introduced 50 mg dose.  In protocol amendment 8, the total sample size was changed from 17,200 
to10,000.  The allocation to active drug is always 2:1 (in Part I, Part IIA and IIB).
Prior to protocol amendment 6, the following two presentations of canakinumab solution for 
injection in pre-filled syringes are used in CANTOS:

Canakinumab 150 mg/1 ml, and

Placebo matching canakinumab 150 mg/1 ml
In addition, the following pre-filled syringes were available to be used for the purpose of 
implementing the 50 mg arm following amendment 6:

Canakinumab 50 mg/0.5 ml, and

Placebo matching canakinumab 50 mg/0.5 ml.
Canakinumab 50 mg/1 ml pre-filled syringes that fully match 150 mg pre-filled syringes were 
not available near the time of protocol amendment 6. Thus, in order to evaluate 300 mg, 150 
mg and 50 mg versus placebo in a fully blinded fashion, a triple-dummy design with 3 
injections per visit would have been required. As feedback from investigators indicated that 
this would constitute an unacceptable burden to patients we identified the approach shown in 
Figure 2-3 as the most appropriate solution for introducing the 50 mg dose into the CANTOS 
trial.


Novartis
Confidential
Page 28
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
For the three trial arms in Randomization Plan A, study drug will consist of two injections of 
canakinumab 150 mg/1 ml or the matching placebo, while the three trial arms in 
Randomization Plan B study drug will consist of one injection of canakinumab 150 mg/1 ml, 
or the matching placebo and one injection of canakinumab 50 mg/0.5 ml, or the matching 
placebo. While investigators will be able to deduce from the size of the pre-filled syringes 
whether a patient is in Randomization Plan A or B, the chance that the patient is on active 
treatment is the same in either case (2:1). I.e. they are fully blinded with respect to active 
treatment or placebo, but can rule out one of the three possible active doses in case the patient 
was to be on active treatment.
As a result, the pre-specified primary analysis described in detail in section 6.3 comprises 
both 
1. a randomized contrast between groups that are completely double-blind versus each other 
(canakinumab 150 mg versus placebo) and veiled versus the other groups and
2. two randomized contrasts between groups that are veiled (canakinumab 300 mg versus 
placebo and 50 mg versus placebo). 
The term veiled is used in the sense of Senn (Senn 1995), who defines a veiled trial as a trial 
in which a patient's treatment group is not known, but the possibilities can be narrowed down 
to a subset of all existing treatment groups in the trial - in CANTOS every patient can clearly 
only be in 3 out of the 4 trial arms, either a patient can be on canakinumab 300 mg, 150 mg, 
or placebo or the patient can be on canakinumab 150 mg, 50 mg or placebo.
As far as combining data from trial part 1 and trial part 2 is concerned, the pre -specified 
analysis preserves the double-blind nature of the contrast in the same way that a patient-level 
(network) meta-analysis would. This is done by not making any direct comparisons between 
patients in trial part 2 and those in trial part 1 - i.e. no naïve pooling of patients across trial 
part, which would have been inappropriate, because patients were not concurrently recruited 
for the two trial parts and assignment to trial part was not at random. Instead, for example the 
50 mg dose in trial part 2 can only be compared to the placebo group in trial part 1 indirectly 
using a double contrast by combining the 50 mg versus 300 mg and 50 mg versus 150 mg 
contrasts in trial part 2 with the 300 mg versus placebo and 150 mg versus placebo contrasts 
in trial part 1. As discussed by Senn, estimates obtained in this way have a substantially 
higher variance than the direct single (potentially biased) contrast (Senn 2008). Comparisons 
between treatments randomized to Part II on the other hand pool all concomitantly 
randomized arms because the potential bias is considered to be too small to justify the loss in 
efficiency incurred by such an approach. Furthermore, it was decided that any hypothetical 
bias could be handled for several reasons. Firstly, because patients are randomly assigned to 
the two randomization plans, one can expect patients in randomization plan A and B to be 
comparable at baseline. Secondly, any possible bias is expected to be small, if it exists. While 
investigators and patients can potentially identify whether patients are either on 300 mg, 150 
mg, or placebo (trial part 1 or randomization plan A in trial part 2) or alternatively on 150 mg, 
50 mg, or placebo (randomization plan B in trial part 2), the odds of a patient being on active 
treatment are the same in either case (2:1). In either case the number of potential treatment 
groups is only narrowed down to a limited extent, namely from 4 to 3. Taken together, this 
makes it unlikely that any influence of this knowledge on investigators and patients would 
have any substantial impact with respect to e.g. patient management, follow-up or endpoint 


Novartis
Confidential
Page 29
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
reporting. Thirdly, whether this is the case can be confirmed at the end of the trial due to the 
presence of both a placebo arm and a 150 mg arm in both randomization plans. For this 
purpose the placebo groups in randomization plans A and B will be compared against each 
other for the primary MACE endpoint, the 150 mg groups in randomization plan A and B will 
be compared and the 150 mg versus placebo contrasts will be compared between 
randomization plan A and B.
3
Patient disposition, background and demographic 
characteristics
3.1
Patient disposition
The number of patients screened, randomized and included in the full analysis set (FAS), the 
per protocol set 1 (PPS1), and the safety set will be presented by treatment group and overall 
for the screened set, as well as by trial part. For the screened set the reasons for screen failures 
will be tabulated. The number and percentage of patients in the randomized set who 
completed the study, who discontinued the study (lost to follow-up, patient/guardian decision, 
technical problems, death), the reason for discontinuation of study medication, and vital status 
(known vs unknown for lost to follow-up and patient/guardian decision) will be presented for 
each treatment group and all patients, as well as by trial part. Some patients may have 
multiple visits where drug is not administered prior to permanent discontinuation. Each visit 
may have a different reason for not administering drug. For these cases, the following 
hierarchy will be used to assign the most conservative reason for permanent discontinuation 
of study medication:

If a patient has at least one AE with an outcome/ action reported as permanent treatment 
discontinuation, then AE will be the reason

If the scenario in bullet 1 did not occur and there is at least one reason on the Dosage
Administration Record CRF that states the reason for not administering study medication 
is “ADVERSE EVENT”, then AE will be the reason

If the scenarios in bullets 1 and 2 did not occur, the reason associated with the last visit the 
patient actually came into the clinic will be used as the reason for permanent 
discontinuation of study medication if the patient did not receive study medication at that 
last in-clinic visit. If the patient did receive study drug at the last in-clinic visit, the reason 
for not administering study drug associated with the first visit that the patient did not come 
into the clinic will be used as the reason for permanent discontinuation of study 
medication.
The frequency (%) of patients with protocol deviations as well as the criteria leading to 
exclusions from analysis sets will be presented in separate tables for the randomized set. 
Finally, the number of enrolled and randomized patients by region (see section 2.2) 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.
When the exact date of birth cannot be collected for data privacy reasons, the year of birth is 
collected instead and the patient’s age is imputed by the Oracle Clinical Remote Data Capture 
system (OC/RDC) on that basis. For that purpose OC/RDC assumes the patient’s birthday to 


Novartis
Confidential
Page 30
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
have been on 1 July of the year and calculates the patient’s age as the number of days between 
that day and the date of the start of screening divided by 365.25.
3.2
Background and demographic characteristics
The common background and demographic variables will be summarized by treatment and 
the total of all patients 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).
Summary of baseline demographic characteristics will include:

Age [years]; age categories <65, ≥65 to <75, ≥75 years

Sex (male/female)

Race (Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, Other) and 
Ethnicity (Hispanic, East Asian, Southeast Asian, South Asian, West Asian, Russian, 
Mixed ethnicity, Not reported, Unknown, Other)

Height [cm]

Weight [kg]

Body mass index [kg/m2] calculated as weight [kg]/ height2 [m2]; BMI categories of  <25,  
≥25 to <30,  ≥30 to <35, ≥35 kg/m2

Waist circumference [cm]
Summary of baseline risk characteristics will include:

Sitting pulse [bpm]

Mean sitting SBP [mmHg]; additionally tertiles and categorization of < 130 vs. ≥ 130 
mmHg 

Mean sitting DBP [mmHg]; additionally tertiles and categorization of < 80 vs. ≥ 80 
mmHg 

Controlled baseline blood pressure (msSBP < 130 mmHg and msDBP < 80 mmHg)

Smoking history (Never/Current/Former)

Alcohol history (amount consumed on average per day <1, 1 to 2, >2 to 3, >3 to 4, >4 to 
5, >5 or more)

Cardiovascular risk factors and other co-morbidities (as per protocol solicited events CRF, 
unless otherwise specified):
Glycemic status (T2DM, T1DM, pre-diabetes, normoglycemic; MedDRA terms to 
identify T1DM will be pre-specified)
Complications of diabetes 

Family history of diabetes

Diabetic retinopathy (Diabetic proliferative retinopathy/Diabetic non-
proliferative retinopathy)

Diabetic nephropathy

Diabetic neuropathy

Diabetic foot ulcers


Novartis
Confidential
Page 31
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Hypertension
Dyslipidemia/Hyperlipidemia
Prior TIA/stroke

Prior Transient Ischemic Attack

Prior Hemorrhagic Stroke

Prior Ischemic Stroke

Prior Stroke of unknown type




Peripheral Arterial Disease
Prior repeated MI (multiple MIs identified via narrow Myocardial infarction SMQ in 
medical history)
Prior coronary revascularization

Prior PCI  (from the Prior Coronary Revascularization Procedures CRF)

For the qualifying MI    

Not for the qualifying MI

 

Prior CABG (from the Prior Coronary Revascularization Procedures CRF)

For the qualifying MI    

Not for the qualifying MI
Heart failure (identified in Medical History using narrow Cardiac Failure SMQ)

Medical history of gout (as per protocol solicited events CRF)

Medical history of macular degeneration (list of MedDRA terms to be pre-specified)

Time since index MI: summary statistics and classification into 

< 6 months post-index MI sub-classified into

<30 days,

30 days to 3 months (≤91 days)

3 months (>91 days) to 6 months (<183 days)

≥ 6 months post-index MI sub-classified into

6 months (≥183 days) to 1 year (≤365 days)

1 year (> 365 days) to 2 year (≤731 days)

2 (>731 days) to 3 years (≤1096 days)

3 (>1096 days) to 5 years (≤1826 days)

5 (>1826 days) to 7 years (≤2557 days)

7 (>2557 days) to 10 years (3653 days)


Novartis
Confidential
Page 32
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab

> 10 years (>3653 days)

Type of qualifying MI (stemi, non-stemi, unknown)

Type of diagnosis for qualifying MI (ECG, Elevated cardiac markers, Both, cardiac 
imaging)

Number of prior MIs; number of prior MIs categorization as 0, 1, 2, 3, and ≥4

hsCRP [mg/L]; tertiles, categories <3 mg/L, 3 to < 4 mg/L, ..., 9 to < 10 mg/L, ≥ 10 mg/L

HbA1c [%]; categories <5.7%, ≥5.7 – <6.5%, ≥6.5 to <7.5%, ≥ 7.5% (overall and by each 
glycemic status)

FPG [mg/dL]; categories <100 mg/dL, ≥100 to < 126 mg/dL, ≥126 to < 200 mg/dL, and 
≥200 mg/dL (overall and by each glycemic status)

Total cholesterol [mg/dL]; total cholesterol tertiles 

LDL-C  mg/dL, LDL-C tertiles, LDL-C categories <70 mg/dL vs. ≥ 70 mg/dL, LDL-C < 
100 mg/dL vs.  ≥100 mg/dL.

HDL-C mg/dL, HDL-C categories (<50 vs. ≥50 mg/dL for female; <40 vs. ≥40mg/dL for 
male)

Triglycerides mg/dL; triglycerides tertiles; triglycerides categories < 150 vs. ≥ 150 mg/dL

eGFR [mL/min/1.73m2]; categories < 30, ≥30 to <60, ≥60 to <90 and ≥90 mL/min/1.73m2

Level of exercise (rarely/never, less than once a week, once a week, 2-3 times a week, 4-6 
times a week, daily)

Family history of MI, stroke, diabetes or premature coronary artery disease (No / Yes with 
sub-categorization by age at first event)

Highest level of education (0 years, 1-4 years, 5-8 years, 9-12 years, 13-16 years, >16 
years)
For purely descriptive purposes, treatment group comparability will be examined using the 
Cochran-Mantel-Haenszel test stratified by time since index MI (< vs. ≥ 6 months) and trial
part for the categorical variables and the F-test with time since index MI (< vs. ≥ 6 months) 
and trial part as a categorical covariate for the continuous variables as appropriate. These p -
values will be provided for descriptive purposes and will not be considered to define any 
formal basis for determining factors that should be included in statistical models. Any 
concerns about imbalances between treatment groups are already addressed by the pre-
specified sensitivity analyses that assess the treatment effects adjusted for pre-specified 
potentially prognostic covariates (see Section 6.3).
 
 
3.3
Medical History
Any condition entered on the relevant medical history / current medical conditions CRF will 
be coded using the MedDRA dictionary. Frequency tables will be provided by primary system 
organ class, preferred term and treatment group.


Novartis
Confidential
Page 33
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Adverse events occurring between screening and baseline will also be reported as medical 
history, but additionally reported separately as adverse events occurring between screening 
and baseline.
4
Study medication
The duration of the double-blind treatment 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. the patient’s study completion visit during the study close-out period
4. or the analysis cut-off.
This algorithm reflects the planned treatment schedule and the long half-life of the study drug. 
Missing dates in this algorithm will be imputed in the same way as missing dates for time -to-
event analyses.
The duration of the post-treatment phase will be computed as the number of days from the day 
after the end of the double-blind treatment phase to the end of the post-treatment phase. If the 
end of the double-blind treatment phase coincides with the end of the double-blind phase, then 
the duration of the post-treatment phase will be 0 days.
The duration of the double-blind phase and double-blind treatment phase will be summarized 
for the FAS and SAF by treatment group descriptively including by duration categories. 
Overall patient-years will also be displayed and will be computed as the sum of patient days 
for all patients divided by 365.25.The duration of treatment, and of exposure will be 
summarized for the SAF by treatment group descriptively including by duration categories. 
Overall patient-years of treatment will also be displayed and will be computed as the sum of 
patient days of treatment for all patients divided by 365.25.
Duration of exposure to study treatment excluding interruptions will be computed and 
summarized as above for the SAF, but not counting periods during which the last injection 
was more than a quarter year ago. Duration of exposure will also be summarized for patients 
who are alive at the end of the study.
An interruption is defined as the period of time in which IP is deemed to be inactive. In other 
words, if the date of the last dose + 91 days, falls prior to the following dosing date, then the 
difference between these is equivalent to the interruption duration. It should be noted that a 
single interruption may span multiple scheduled administrations of IP.
5
Concomitant medication
Prior or concomitant medications will be summarized for the safety set in separate tabulations 
based on the coding dictionary used. Medications will be presented in order of descending
frequencies, 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.


Novartis
Confidential
Page 34
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Prior medications and significant non-drug therapies are defined as any medications and 
significant non-drug therapies taken prior to the start of study drug. Concomitant medications 
and significant non-drug therapies are defined as those used during the double-blind phase. 
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, classes of medications to be precisely defined in a separate Excel file that will 
be stored in the Novartis CREDI system, will be summarized separately. These will include 
classes such as the following:

Anti-ischemic agents

Beta blockers 

Cardiac glycosides

Intravenous or oral nitrates

Calcium channel blockers

Antithrombotic agents (excluding antithrombotic intravenous and subcutaneous drugs 
intended for acute setting such as abciximab, eptifibatide, or tirofiban, which are not 
expected to be used chronically and are consequently less relevant in this population –
these will be reported separately in the Clinical Study Report)

Acetylsalicylic acid (aspirin)

Non-aspirin oral anti-platelet agents

P2Y12 inhibitors (like clopidogrel, ticagrelor and prasugrel)

Direct Thrombin Inhibitors

Other antithrombotic agents (e.g. anticoagulants)

Renin-Angiotensin-Aldosterone System inhibitors

Angiotensin Converting Enzyme (ACE) inhibitors (like ramipril) 

Angiotensin II Receptor Blockers (ARBs)

Direct Renin Inhibitors

Lipid-lowering agents

Statins

Atorvastatin

Rosuvastatin

Simvastatin

Other statins and statin combinations

Non-statins (like PCSK9 inhibitors, ezetimibe, fibrates, binding resins and nicotinic 
acid)

Diuretics

Thiazide diuretics

Non-thiazide diuretics

Anti-diabetic medications

Insulin


Novartis
Confidential
Page 35
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab

Oral hypoglycemic agents

Thiazolidinediones

Metformin and other biguanides

Sulfonylureas

Alpha glucosidase inhibitors
- sulfonamides
- glymidine

DPP-4 inhibitors

Glinides

Other oral hypoglycemic agents (incl. SGLT2 inhibitors)

GLP-1 analogs

Aldosterone antagonists

Proton pump inhibitors

Treatments for macular degeneration
Additionally, the time course of the total daily dose level of concomitant statins will be 
reported at baseline and tracked over time. For each patient, the daily dose will be determined 
as follows:
1. For each patient, the daily dose will be determined by the statin use with start/stop date.
2. The daily dose by visit will be presented for the time course of the total daily dose level.
3. For each patient, the daily dose at each visit will be defined as the median of t he daily 
doses since the last visit.
4. The median of individual patient's dose at each visit will be used as the point estimate for 
the plot/summary 
5. In order to have consistent timings for the visit, the visits will be calculated based on 
protocol visit scheduling.
For this purpose doses of different statins will be equated according to Table 5-1. Median 
statin dose level, and patients on each standardized dose level will be summarized over time 
and displayed graphically, where possible. Patients will be classified according to whether 
they receive no, low dose, medium dose or high dose statins at baseline and during the study. 
This will be done separately by time since index MI (including finer categorizations than < 
versus ≥ 6 months post index-MI) and by region. If new statins become available or 
substantial new information regarding their lipid lowering effects becomes available, this 
table may have to be updated.
Table 5-1
Conversion table for statin doses
Dose intensity of statin
Low
Medium
High
Standardized statin dose1 [mg] 
(atorvastatin equivalent)
Scaling factor
2.5
5
10
20
40
80
1602


Novartis
Confidential
Page 36
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Dose intensity of statin
Low
Medium
High
Standardized statin dose1 [mg] 
(atorvastatin equivalent)
Scaling factor
2.5
5
10
20
40
80
1602
Atorvastatin (LIPITOR)
× 1
5*
10
20
40
80
160*
Lovastatin (MEVACOR)
/ 4
10
20
40
80
Pravastatin (PRAVACHOL)
/ 4
10
20
40
80
Simvastatin (ZOCOR)
/ 2
5
10
20
40
80
Fluvastatin (LESCOL)
/ 8 
20
40
80
Rosuvastatin (CRESTOR)
× 2
2.5*
5
10
20
40
80*
Pitavastatin / itavastatin (LIVALO)
× 20
1
2
4
Ezetimibe 10 mg + Simvastatin 
(VYTORIN, INEGY)
× 2 standardized 
statin dose
10/10
10/20
10/40
10/80
Any other statin + ezetimibe or 
resin binders (e.g. colesevelam, 
cholestyramine, colestipol)  
× 4 standardized 
statin dose
* off label dosing
1 All other other drugs containing a statin should be reported for the statin dose only (including the following):
Statin + fenofibrate, + clopidogrel, + acetylsalicylic acid, + amlodipine, + ramipril
2 Efficacy response curves flatten at the maximal equivalence of atorvastatin 160 mg or rosuvastatin 40 mg: further LDL 
lowering attempts with other lipid lowering drugs do not yield further LDL lowering. I.e. any calculated standardized statin 
dose > 160 mg will be considered as a standardized statin dose of 160 mg.
6
Efficacy evaluation
The primary analysis and all analyses of secondary/
 variables will be conducted 
according to the intention-to-treat principle on the Full Analysis Set (FAS). Unless otherwise 
specified all time-to-event analyses will be based on events occurring during the double-blind 
phase. Unless otherwise specified “treatment groups” will refer to the four treatment groups 
canakinumab 300 mg, 150 mg, 50 mg or placebo. Comparing these separate active doses 
individually versus placebo will be the main method of analysis, but analyses of all 
canakinumab doses pooled versus placebo, as well as the active doses versus each other will 
also be conducted and dose response will be considered as described in section 6.5.
6.1
Variables
An overview of the primary, key secondary and other secondary variables as well as their 
components is given in Table 6.1. At the end of the study all endpoints will have been 
adjudicated by the Clinical Events Committee (CEC). The investigator reported events will 
only be considered as supportive. In order to assess the robustness of results at interim 
analyses the DMC will also be informed about events that have either been confirmed by 
adjudication, or reported by the investigator and not yet adjudicated. Events that have either 
been confirmed by the CEC or reported by the investigator but not yet been adjudicated will 
primarily be used for DMC activities to account for the time lag in adjudication.
Table 6-1
Primary, key secondary and secondary variables for CANTOS
Endpoint (variable is time 
Adjudication 
Investigator 
CEC confirmed or non-


Novartis
Confidential
Page 37
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
to endpoint)
committee (CEC) 
confirmed
reported
adjudicated investigator 
reported (“unrefuted”)
Major adverse 
cardiovascular events 
(MACE)
Primary
Supportive
Primarily for DMC monitoring
CV death
Supportive
Supportive
Primarily for DMC monitoring
fatal or non-fatal 
Myocardial infarction
Supportive
Supportive
Primarily for DMC monitoring
fatal or non-fatal stroke
Supportive
Supportive
Primarily for DMC monitoring
MACE or hospitalization for 
unstable angina requiring 
revascularization
Key secondary
Supportive
Primarily for DMC monitoring
hospitalization for 
unstable angina 
requiring 
revascularization
Supportive
Supportive
Primarily for DMC monitoring
New onset of diabetes
Key secondary
Primarily for 
DMC 
monitoring 
Primarily for DMC monitoring
All-cause mortality
Secondary
Primarily for 
DMC 
monitoring 
Primarily for DMC monitoring
All-cause mortality or 
myocardial infarction or 
stroke
Secondary
Supportive
Primarily for DMC monitoring
6.1.1
Endpoint adjudication process
An external independent blinded adjudication committee will adjudicate all deaths, strokes,  
transient ischemic attacks, MIs, hospitalization for unstable angina requiring revascularization, 
new onsets of diabetes,  all hospitalizations with adjudicatable information, and any other 
events that may be deemed appropriate for adjudication as the trial progresses.
As shown in Figure 6-1 there are 3 ways in which cases will be identified and forwarded to 
the adjudication committee.
The first identification process is by the investigator filling out an endpoint eCRF page. These 
pages trigger a notification to the Endpoint Coordinating Center (
) that a potential 
endpoint has occurred. 
 then assembles an adjudication package for the clinical endpoint 
adjudication committee (CEC).
The second identification process is by the sponsor clinical team reviews of the adverse events 
reporting via the clinical trial database, and ARGUS SAE reporting system.
The third identification process is by 
 (a “third party”) pharmacovigilence reviews of the 
Novartis ARGUS SAE reporting system of the SAEs which the sponsor clinical team did not 
send for adjudication.  
This is done to ensure all hospitalizations with adjudicatable data are sent for potential MI or 
stroke adjudication. Adjudication packages for all SAEs requiring hospitalizations with 
adjudicatable material identified by these reviews that had not been previously been identified 


Novartis
Confidential
Page 38
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
by the investigator as a Study Endpoint, are also sent to the Endpoint Coordinating Center by 
Aptiv. 
Once the Endpoint Coordinating Center (
) receives an endpoint notification, an 
adjudication packet consisting of source documents from the site is created and sent to the 
adjudication committee. The adjudication committee reviews the source documents, 
determines if the endpoint did or did not occur, and then fills out the adjudication eCRF page.
Figure 6-1
Simplified overview of the adjudication process
6.1.2
Primary efficacy variable
The primary efficacy variable is the time to first occurrence of a major adverse cardiovascular 
event (MACE) confirmed by Clinical Events Committee (CEC) adjudication, which is a 
composite endpoint consisting of CEC confirmed cardiovascular death, CEC confirmed MI, 
and CEC confirmed stroke. 
The primary clinical endpoint MACE is a well-established endpoint for CV trials. An external 
Clinical Events Committee (CEC) will review and adjudicate all clinical events that constitute 
MACE and the key components of secondary endpoints on a blinded basis as described in 
section 6.1.1.
The individual components of MACE will be also analyzed as part of the primary efficacy 
analysis.

Cardiovascular death 

Myocardial infarction (fatal or non-fatal)

Stroke (fatal or non-fatal)


Novartis
Confidential
Page 39
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
The time-to-event is computed as the number of days from randomization to the onset of the 
primary endpoint event. In the case of patients dying due to a MI, the date of the MI and not 
the date of death is considered to be the date of the endpoint. 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.
Unless otherwise specified all time-to-event analyses will be based on events occurring during 
the double-blind phase (i.e. both the double-blind treatment phase and the post-treatment 
phase). This means that only events between a patient’s randomization and the first of either 
1. the patient’s entry into the wash-out period (= end of study visit for the main study),
2. or the patient’s entry into the long-term safety extension study (=end of study visit for the 
main study),
3. or for those patients proceeding to neither wash-out period nor safety extension the 
patient’s end of study visit, but only if it occurred during the close-out period,
4. or otherwise the analysis cut-off
will be counted in these analyses as shown in Figure 6-2.
Figure 6-2
Illustrative examples of events counting for the primary analysis
Note: for patients entering the washout for pre-diabetics or the long-term safety study, events would be 
appropriately reported as part of the respective reports. Events occurring after study completion in patients not 
entering either washout or long-term safety study may still be subject to SAE reporting requirements and will be 
reported accordingly as per Novartis processes, if applicable.
Reporting of type of first endpoint
The type of first endpoint will be identified as

the first primary endpoint component (CV death incl. fatal MI or fatal stroke, non-fatal MI 
and non-fatal stroke) that occurs after randomization


Novartis
Confidential
Page 40
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab

if more than one endpoint occurs on the same day, then for the purpose of reporting the 
type of the first endpoint a fatal event will be reported by preference (i.e. CV death in 
preference to a fatal-MI or fatal-stroke and these in turn in preference to a non-fatal MI or 
non-fatal stroke)

should more than one endpoint fulfill the criteria above, then all of these will be reported 
(e.g. in case of both a non-fatal MI and non-fatal stroke on the same day “non-fatal MI and 
stroke” will be reported).
Note that the above only concerns the reporting of the type of the first endpoint. In the 
majority of tables the components of the primary endpoint will be shown separately and a 
patient may contribute to the numerator for no, one, two or all three components of the 
primary endpoint.
6.1.3
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 (i.e. excluding those that are normoglycemic at baseline)
6.1.4
Other secondary efficacy variables
The following other secondary efficacy variables will be used in analyses:

Time to first event of MI, stroke, and all-cause mortality composite

Time to all-cause mortality
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, as the expected number of deaths in the 
trial  would not have ensured adequate power for this analysis.
6.2
Summarizing results across centers, countries and regions
As the target number of patients with a primary endpoint is not much larger than the number 
of centers, time-to-event analyses will be conducted on the pooled data from all centers 
without taking the center into account. However, the consistency of results by region will be 
explored.
6.3
Statistical hypothesis, model, and method of analysis
The primary analysis and all analyses of secondary/
 variables unless otherwise 
stated will use the Full Analysis Set (FAS), which reflects the intention-to-treat principle.
The familywise type I error rate for this trial will be controlled at the one -sided 2.5% level. 
One-sided testing at the 2.5% level constitutes an equivalent level of evidence as two-sided 
testing at the 5% level. Two sided p-values will also be provided.


Novartis
Confidential
Page 41
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
6.3.1
Primary variable
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 (< 6 months and ≥ 6 months) and trial part 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, because comparisons against 
the placebo group in trial part 1 are only indirect via the comparisons versus other doses in 
trial part 2. 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 analysis with respect to the consistency of treatment effects in the 
two parts of the trial will also be performed.
Note that no assumption of proportional hazards is necessary to test whether there is a higher 
probability of MACE in canakinumab than on placebo, because the employed stratified log-
rank tests are valid even without proportional hazards. This assumption is only necessary to 
calculate estimated hazard ratios with confidence intervals for the effect of treatment (Bland 
and Altman 2004).
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 6-4 based on 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 H 11, 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 


Novartis
Confidential
Page 42
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
analysis for the 300 mg, 150 mg and 50 mg doses versus placebo adjusting for the interim 
analysis 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 6-4, 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. 
To illustrate the link between trial objectives and the close testing procedure, it may be helpful 
to consider what the procedure might have looked like, if the Dunnett test had not been used. 
This is shown in Figure 6-3. As discussed in detail below, introducing a Dunnett test required 
modifications with several additional vertices to ensure consonance (see Figure 6-4).
Figure 6-3
Possible closed testing procedure if Dunnett test had not been 
used
All other intersection hypotheses are tested with 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 6-4 (see comment below the figure) 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 6-4 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 


Novartis
Confidential
Page 43
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
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 variables 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 endpoint for the same dose is assigned to the 
secondary CV composite endpoint (90%) than to the new onset of diabetes endpoint (10%). 
The details for the key secondary endpoints are more fully illustrated in Figure 6-5 in section 
6.3.2, which discusses the key secondary efficacy variables.
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. 
Figure 6-4
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. See 
Figure 6-5 for a version of the graph showing full details of the Bonferroni-Holm procedure for the key secondary endpoints.
Two efficacy interim analyses, at which the trial could be stopped for demonstrated efficacy, 
or one or more active arms could be stopped for futility, will be performed respectively after 


Novartis
Confidential
Page 44
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
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. Protocol amendment 8 introduced an additional early futility analysis to 
be performed at approximately 30% of the target number of 1400 patients have experienced 
CEC confirmed MACE. The analysis plan of the early futility was discussed in a separate 
document.
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 an one-sided significance level of 0.01% at the first efficacy interim analysis, 
with an one-sided significance level of 0.04% at the second efficacy interim analysis and with 
an 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%. 
No multiplicity adjustment will be made for the additional early futility analysis, because it 
will not result in rejecting a null hypothesis for efficacy superiority.
The appropriate nominal weighted Dunnett significance levels will be calculated e.g. using the 
mvtnorm R package (Genz and Bretz 2009). For the example of the global null hypothesis this 
can be done using R code (or corresponding SAS code) similar to the following
library(mvtnorm)
alpha <- 0.0245 # level at which Dunnett test is performed
rho <- 0.5 # assumed correlation of test statistics
corr <- (1-rho)*diag(3)+rho # correlation matrix
weight <- c(0.2,0.4,0.4) # weights for hypotheses in Dunnett test
alphaw <- alpha*weight
MVN <- function(alpha1, w, corr, alpha){
x<-qnorm(1-alpha1*w) 
return(1-pmvnorm(upper=x,corr=corr) - alpha)
}
opt3 <-
uniroot(MVN, lower = alpha, upper = 2*alpha, w=weight, 
corr=corr, alpha=alpha, tol=1E-12)
critwDun <- qnorm(1-opt3$root*weight)
nominal <- opt3$root*weight
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 (trial part 1, trial part 2) using treatment (canakinumab doses and 
placebo) as a factor in the model. This will be done using SAS code similar to the following 
(or equivalent code in another programming language such as R):
proc phreg data=dataset;
  class treatment(ref=”Placebo”) <time since index MI> <trial part>;


Novartis
Confidential
Page 45
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
  model time*event(0) = treatment / ties=exact risklimits;
  strata <time since MI > <trial part>;
run;
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 arms 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 may be conducted every 6 
months. Continued follow-up would likely enhance understanding of the safety of the other 
remaining 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.
Supportive, sensitivity and subgroup analyses for the primary endpoint
The components of the composite primary efficacy endpoint (CV death, fatal or non-fatal MI, 
fatal or non-fatal stroke) will also be analyzed individually in order to evaluate their 
contributions to the overall treatment effect. No adjustment for multiplicity is foreseen for this 
purpose.
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 provide the 
most precise information on the effects in subgroups.
Dose response will be evaluated using the methods discussed in section 6.5. Additionally, 
comparisons between the canakinumab doses based on the primary model will also be 
reported.
Kaplan-Meier type analyses will be presented as described in section 6.4 overall and 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. 
Additionally, log time by treatment interaction will be evaluated to identify violations in the 
proportional hazards assumption, which might indicate a time-varying treatment effect. An 
Anderson-Darling type test based on a score process (cumulative sum of the Schoenfeld 
residuals) as recommended by Kvaløy and Neef (Kvaløy and Neef 2004) will be performed. 
For each trial arm within each trial part –log(S(time))  vs. time and log(–log(S(time)) ) vs. 
log(time) will be plotted.
To ensure that any unblinding of patients during the double-blind phase had no meaningful 
impact on the overall study results, a sensitivity analysis of the primary endpoint will be 
performed by excluding data from all patients who were unblinded during the double blind 
phase of the study (i.e. all the unblinded patients will be censored at the time of unblinding).


Novartis
Confidential
Page 46
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
The primary variable and its components will also be analyzed on the PPS1. Additio nally, in 
an on-treatment analysis on the FAS, patients will be considered censored at the latest 28 days 
after the end of the double-blind treatment phase, which corresponds to up to 119 days after 
the last study drug injection based on the long elimination half-life of the drug. 91 days 
constitute a bit over 3 half-lives and 28 days add an additional half-life. In the on-treatment 
analysis patients will stay in the risk set until this point unless their censoring date occurred 
earlier and will not leave and re-enter the risk set due to treatment interruptions. Besides 
adjudicated endpoints investigator reported outcomes will also be analyzed on the FAS.
Once the results become available a covariate adjusted analysis may be considered. This 
covariate-adjusted Cox-regression model will consider the following pre-specified baseline 
covariates: linear age, sex, race, linear BMI, smoking status, region as defined in section 2.2, 
linear baseline log hsCRP, type of qualifying MI (STEMI/NSTEMI/Unknown), glycemic 
status, duration of diabetes for diabetic patients, hypertension, linear baseline systolic blood 
pressure, linear and quadratic baseline diastolic blood pressure, history of heart failure, 
dyslipidemia, linear baseline LDL-C, linear baseline HDL-C, linear baseline triglycerides, 
linear number of prior MIs, prior PCI, prior TIA/stroke, linear eGFR, no/low or medium 
dose/high dose statin use at baseline as defined in section 5, baseline aspirin therapy, baseline 
P2Y12 therapy, RAAS inhibitor use, beta blocker use, to account for other factors that might 
affect prognosis.
Furthermore, the pre-specified subgroup analyses will be conducted for the subgroups listed 
in section 2.2. Results will be presented graphically as forest plots. The objective of the 
subgroup analyses is to evaluate the consistency of treatment effects across a wide variety of 
patient groups. For this purpose the availability of data from three different doses should be 
helpful, because most subgroup effects would be affect all doses to some extent, which 
provides an additional way of identifying spurious findings that occurred by chance. 
Additional subgroup analyses will be considered and potentially pre-specified prior to 
unblinding of trial database for final analysis. It is clear that due to the number of subgroups a 
substantial number of totally spurious numerical imbalances in treatment effects between 
subgroups has to be expected – including some with an interaction p-value ≤ 0.05 and/or with 
apparently no or reversed effects. The association between changes in hsCRP and outcomes 
will also be explored.  
To assess whether pooling randomization plan A and B in trial part 2 is appropriate, the 
placebo groups in randomization plans A and B will be compared against each other, the 150 
mg groups in randomization plan A and B will be compared and the 150 mg versus placebo 
contrasts will be compared qualitatively between randomization plan A and B.
As a further sensitivity analysis in this respect, randomization plan will be used as an 
additional stratification factor in the primary model. This analysis will use SAS code similar 
to the following (where randomization plan would be a 3 level stratification factor with 1 
level for trial part 1 and two further levels for each randomization plan in trial part 2) or 
equivalent code in another programming language such as R:
proc phreg data=dataset;
  class treatment(ref=”Placebo”) <time since index MI> 
<randomization plan>;


Novartis
Confidential
Page 47
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
  model time*event(0) = treatment treatment*<randomization plan> 
/ ties=exact risklimits;
  strata <time since index MI> <randomization plan>;
  hazardratio treatment / diff=ref cl=both;
run;
A sensitivity analysis with respect to the consistency of treatment effects in the two parts of 
the trial will also be performed. This analysis will use SAS code similar to the following or 
equivalent code in another programming language such as R:
proc phreg data=dataset;
  class treatment(ref=”Placebo”) <time since index MI> <trial part>;
  model time*event(0) = treatment treatment*<trial part> 
/ ties=exact risklimits;
  strata <time since index MI> <trial part>;
  hazardratio treatment / diff=ref cl=both;
run;
Calculation of multiplicity adjusted one- and two-sided p-values
Multiplicity adjusted p-values will be calculated for each null hypothesis as the smallest 
significance level at which one can reject that null hypothesis using the testing procedure 
shown in Figure 6-4 while also taking into account the interim analyses. For this purpose the 
algorithm described by Bretz et al. (2009) will be applied to the unadjusted one-sided p-values 
and the resultant p-values (adjusted only for the multiple endpoints and doses) will be 
adjusted for the interim analyses by scaling them by a factor of 250 (=0.025/0.0001) at the 
first efficacy interim analysis, 62.5 (=0.025/0.0004) at the second efficacy interim analysis 
and 0.025/0.0245 (≈1.02) at the final analysis. Because a weighted Dunnett test will be used 
for any intersection hypothesis from the full closure that contains at least two of H11, H21 or 
H31, the algorithm of Bretz et al. (2009) needs to be extended. For this purpose the weights 
w11, w21 and w31 used as part of that algorithm would be defined as the respective Dunnett 
level divided by the overall significance level at the respective analysis. 
For example, for the global null hypothesis instead of w11=0.2, w21=0.4 and w31=0.4 as for a 
Bonferroni test based procedure – for which w11 + w21 + w31 ≤ 1 would always hold – instead 
w11 + w21 + w31 > 1 would hold in this case. For example, using the nominal Dunnett 
significance levels for 300 mg, 150 mg and 50 mg doses at the final analysis calculated usi ng 
the mvtnorm package in R as described earlier in section 6.3.1, one obtains w11 = 0.5500504% 
/ 2.45% ≈ 0.2245103, w21 = 1.1001008% / 2.45% ≈ 0.4490207 and w31 = 1.1001008% / 2.45% 
≈ 0.4490207. 
In case health authorities, journals or the data monitoring committee require two-sided p-
values, these will be provided in a manner that firstly ensures that the test decision on the 
rejection of the primary and key secondary null hypotheses remains unchanged and that 
secondly uses in principle the same testing procedure for evaluating the potential superiority 
of placebo over each dose of the test drug.


Novartis
Confidential
Page 48
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
On this basis, the same test procedure as shown in Figure 6-3 will also be conducted in a one-
sided fashion on the 2.5% significance level to test for the superiority of placebo over each 
canakinumab dose arm. The multiplicity adjusted two-sided p-values for each canakinumab 
dose arm will then be calculated as the minimum out of 

2 × the multiplicity adjusted one-sided p-value for the superiority of that canakinumab 
dose arm over placebo, 

2 × the corresponding multiplicity adjusted one-sided p-value for the superiority of 
placebo over that canakinumab dose arm versus 

and 1.
Exploration of dose response relationship and the effects of induction dosing 
in terms of cardiovascular endpoints
The method described in section 6.5 will be applied to assess dose response on cardiovascular 
endpoints over the whole duration of the trial.
It will be explored whether the early high induction dose regimen in 300 mg canakinumab 
arm has an impact on early (within 90 days of randomization) primary and secondary clinical 
cardiovascular events when compared to the placebo arm and to the 150 mg and 50 mg 
canakinumab arms, which have no early high induction dose regimen. For this purpose the 
primary endpoint and its components will be assessed over 90 days post-randomization. 
Similarly, the primary endpoint and its components will also be assessed at 6 months and 1 
year, repeatedly.
6.3.2
Key secondary efficacy variables
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 adjudication committee confirmed 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 H 22 for 
the secondary composite CV endpoint and H23 for the new onset of diabetes endpoint. For the 
50 mg dose they 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 and PPS1with 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 as 
described in section 6.4. The multiplicity adjustment used to protect the familywise type I 


Novartis
Confidential
Page 49
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
error rate is shown in Figure 6-4 and showing the full details of testing the key secondary 
endpoints in Figure 6-5. For each dose analyses of key secondary endpoints will be conducted
even if the primary null hypothesis for the dose has not been rejected, but formally no 
rejection of the null hypotheses for the key secondary endpoints will be possible in that case.
Figure 6-5
Closed testing procedure with full details of testing of key 
secondary endpoints
This figure as compared to Figure 6-4 shows the full details of the Bonferroni-Holm procedure for the key secondary endpoints in a graphical 
form, but is otherwise identical in content.
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 pre-
diabetes at randomization will be the time from randomization to the first of repeated FPG ≥ 
126 mg/dL or the first of repeated HbA1c ≥ 6.5% or start of new anti-diabetic concomitant 
medication(s) for glucose lowering purpose. All identified cases of new onset of diabetes will 
be confirmed by the adjudication committee. 
Due to the discrete nature of the visits when new onset of type 2 diabetes c an be determined, 
events identified at the same visit time point as defined in section 2.3.6 for different patients 
will be considered as tied events and  the 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 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, 


Novartis
Confidential
Page 50
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
pp. 127 to 137). For this variable patients without new onset of diabetes will be considered 
censored at the time of their last laboratory assessment. Patients not diagnosed at a regular 
visit or at the study completion visit will be assigned to one of the scheduled visits as per the 
algorithm in section 2.3.6.
Subgroup analyses as specified in Table 2-3-1 will be conducted for the key secondary new 
onset of diabetes endpoint. These will include subgroup analyses by race, which could 
potentially influence HbA1c levels.
Given some patients may have medical conditions that elevate their HbA1c levels that are 
unrelated to diabetes (e.g. patients with hemoglobinopathies such as sickle cell disease, while 
several other conditions causing interference such as e.g. uremia, liver disease, alcoholism and 
drug (opiate) use are excluded from this protocol), a second set of new onset diabetes criteria 
will be defined. This second set of criteria will determine new onset diabetes for these patients 
based on having either (2 consecutive HbA1c >= 6.5 % and 2 consecutive FPG values >= 126 
mg/dL from the same visits as HbA1c) or (HbA1c >= 6.5 % at one visit reported and FPG >=
126 mg/dL reported at same visit and FPG>=126 confirmed at the consecutive visit) or 2 
consecutive FPG values >= 126 mg/dL.  The identification of these patients will be done in a 
blinded fashion by a medical monitor using medical history data and other baseline data. All 
patients deemed not to have any of these medical conditions will be assessed for new onset 
diabetes as described in the first set of criteria (see paragraph above). New onset of diabetes 
data will be reported overall and separately for these patients in whom diagnoses based on 
HbA1c levels is not appropriate (defined as “FPG >= 126 mg/dl at 2 occasions” or 
“Confirmed prescription and use of Diabetes Drug” based on the New Onset Diabetes 
(Adjudication) CRF page) The analysis described above will also be performed using this 
alternative new onset diabetes definition.
Supportive and sensitivity analyses for key secondary endpoints
To support the analysis for the new onset of diabetes endpoint, the criteria defining new onset 
will be presented, the diagnostic values causing diagnosis summarized and sensitivity 
analyses conducted based on each criterion alone.
The three pooled canakinumab doses will be compared to placebo on the key secondary 
endpoints. Additionally, comparisons between the canakinumab doses will also be reported 
using the pre-specified log-rank test with hazard ratios reported based on Cox regression.
Additionally, Kaplan-Meier plots will be provided separately for each of the followings: 

Time to adjudication committee confirmed new onset of type 2 diabetes among those with 
normoglycemic at randomization

Time to adjudication committee confirmed new onset of type 2 diabetes among those with 
either pre-diabetes or normoglycemic at randomization

Time to first pre-diabetes among those with normoglycemic at randomization.
The key secondary cardiovascular endpoint will also be analyzed adjusting for the same 
covariates used for the covariate adjusted analysis of the primary variable.
The key secondary endpoint new onset of diabetes will also be supported by analyses using 
data from the study’s washout period. These analyses will be defined in a separate analysis 


Novartis
Confidential
Page 51
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
plan for the washout period and will be reported in a separate study report or addendum to the 
main study report.
6.3.3
Other secondary efficacy variables
As stated in section 6.1.3 all-cause mortality is considered a very important secondary 
endpoint due to its importance as both an efficacy and safety outcome, but 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 and PPS1with 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 both overall and by trial part. 
Patients who did not die will be considered censored at the last time they were reported to be 
alive.
These secondary endpoints will also be analyzed adjusting for the same covariates used for 
the covariate adjusted analysis of the primary variable.
The three pooled canakinumab doses will be compared to placebo on the other secondary 
endpoints. Additionally, comparisons between the canakinumab doses will also be reported.


Novartis
Confidential
Page 52
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 53
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 54
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 55
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 56
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 57
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 58
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 59
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 60
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 61
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab


Novartis
Confidential
Page 62
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
6.4
Kaplan-Meier type analyses and graphs
Because this trial has two consecutively recruited trial parts with different allocation ratios 
that may differ in important predictive covariates and since one treatment group is not even 
represented in trial part 1, simply pooling data across trial parts to produce an overall Kaplan-
Meier graph would not be appropriate. For this reason an alternative approach for producing 
such a Kaplan-Meier type graph is described in section 6.4.1 below. Such graphs and within 
any trial part Kaplan-Meier plots will follow the general principles described in section 6.4.2.
Kaplan-Meier type analyses and plots will be provided (including by trial part) for the primary 
endpoint, key secondary endpoints, secondary endpoints and 
 
6.4.1
Overall Kaplan-Meier type graphs across trial parts
A Cox model stratified for treatment group (placebo, 50 mg, 150 mg or 300 mg) and time 
since index MI (< 6 months, ≥ 6 months), with trial part as a covariate will be used to obtain 
Breslow estimates (Breslow 1974) for the predicted survival curves for each combination of 
treatment group, time since index MI and trial part – including for the 50 mg group in trial 
part 1. These predicted survival curves will then be aggregated for an appropriate cohort of 
patients within each of the 4 treatment groups to obtain a single overall Kaplan-Meier type 
graph for the 4 treatment groups.
The use of a Cox model stratified for treatment group (placebo, 50 mg, 150 mg or 300 mg) –
and also time since index MI (< 6 months, ≥ 6 months) – is a suggestion by Zhang et al. 
(Zhang et al. 2007) and Terry Therneau (personal communication, 2011). As pointed out by 
Zhang et al. such a model makes no assumption of proportional hazards between treatment 
groups or time since index MI groups. Thus, it is more appropriate for obtaining a g raphical 
representation that allows an inspection of the relative effectiveness of treatment groups over 
time. Using trial part as a covariate and assuming the same proportional effect of trial part for 
the whole follow-up period for each of the 8 strata (treatment group / time since index MI) 


Novartis
Confidential
Page 63
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
allows extrapolation of what a 50 mg group in trial part 1 would have been like, as suggested 
by Terry Therneau (personal communication, 2011). To assess the assumptions involved the 
predicted survival curves from this model for the placebo, 150 mg and 300 mg groups in each 
stratum and for the 50 mg group in all trial part 2 strata will be compared graphically to those 
from a model that treats trial part as an additional stratification variable. Should the 
assumption be strongly violated with respect to trial part having a constant effect over time, it 
would be an alternative to assume a trial part effect that is only proportional over specific time 
intervals (e.g. up to 90 days, day 91 to day 183, days 184 to 1 year, 1 year to 2 years, > 2 
years). 
The overall aggregated cohort survival estimate will be obtained from the estimates for each 
treatment group / time since index MI / trial part combination using the Hakulinen method 
(Hakulinen 1982). Compared with the more simple Ederer method this is expected to more 
closely reflect what might have been obtained, if this study had been conducted with 4 
treatment arms from the start. The reason is that the follow-up time after which administrative 
censoring at trial end will occur will differ – by design – between the trial parts (Thomsen et 
al. 1992) (Therneau and Grambsch 2000, pp. 261-287).
The cohort for which the cumulative failure rate is estimated using the Hakulinen method will 
be constructed so that within each trial part the distribution of time since index MI and 
distribution of maximal potential follow-up is the same for each treatment group. To achieve 
this within each trial part
1. All the patients in all treatment groups and time since index MI strata in that trial part are 
selected.
2. Their length of follow-up Fi and time since index MI information is retained.
3. These patients are assumed to be the (identical) hypothetical recruited cohorts for each of 
the four treatment groups.
Note that the length of follow-up Fi is taken to be 

for those patients that were censored: the time from randomization to the maximum actual 
follow-up for CV events (not just for the first event) 

for patients that had a non-fatal version of the endpoint of interest (e.g. non-fatal MI in 
case of analyzing the primary MACE endpoint) the same approach as for those patients 
that were censored will be used

for patients that had a fatal version of the endpoint of interest (e.g. fatal MI in case of 
analyzing the primary MACE endpoint) the maximum potential follow-up will be used, i.e. 
the time from randomization to the maximal potential follow-up date, defined to be the 
analysis cut-off date (see Section 2.3.7).
For each patient i let Si(t) be the estimated survival curve based on that patient’s treatment 
group, time since index MI and trial part. If patients are ordered from shortest to longest 
possible follow-up time F(1), F(2), …, F(K), then the Hakulinen estimate (Hakulinen 1982) for 
the cumulative survival function S(t) is calculated recursively for any F(k) < t ≤ F(k+1) as
S(t) = S(F(k)) × [ Σi=1,…,n Si(t) × 1{ Fi>t } ] / [ Σj=1,…,n Sj(F(k)) × 1{ Fj > F(k) } ]
as described by Thomsen et al. (Thomsen et al. 1992), Nielsen (Nielsen 1997) and Therneau 
and Grambsch (Therneau and Grambsch 2000, pp. 261-287).


Novartis
Confidential
Page 64
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Note that valid confidence intervals cannot be obtained for these estimates in a 
straightforward fashion, because of the artificially inflated “apparent sample size” resulting 
from the way in which the algorithm above ensures balanced time since index MI/trial part 
across treatment groups and censoring patterns. If pointwise confidence intervals are required 
(e.g. primary and secondary endpoints) one could create e.g. B=2,000 bootstrap samples, 
repeat the whole process above (starting from fitting the Cox model) for each bootstrap 
sample and then obtain interval percentile (or BCa) Bootstrap confidence intervals as 
described by Efron and Tibshirani (Efron and Tibshirani 1993, pp. 170-176 and pp. 184-188)
e.g. for times t=1 year, 2 years, 3 years and 4 years. algorithm might be applied.
6.4.2
Kaplan-Meier graphs for each trial part and general principles
The approach for Kaplan-Meier graphs closely follows the recommendations by Pocock et al. 
(2002).
Cumulative event rate estimates (1 – estimated survivor function) in % versus time of follow-
up in years will be shown based on Kaplan-Meier estimates. Compared to showing the 
survivor function this maximizes detail without needing a break in the scale.
While “technically, any survival plot can be extended right through to the longest follow-up 
time” as Pocock et al. point out “this extension is not good statistical practice, since for any 
such plot the eye is drawn to the right (i.e. where the plot finishes), which is where there is 
least information and greatest uncertainty”. Kaplan-Meier curves will therefore only drawn up 
to the time at which the total population at risk for the event in question has decreased to 10% 
of the size of the analysis set. This matches the recommendation by Pocock et al. who wrote 
that they “[..] recommend that survival plots be halted once the proportion of patients free of 
an event, but still in follow-up, becomes unduly small. […] What constitutes “unduly small” 
is open to debate and depends on the context. It will often be reasonable to curtail the plot 
when only around 10–20% are still in follow-up." As CANTOS is a large outcome trial the 
lower end of this range (10%) will be used.
For the kind of Kaplan-Meier type graphs described in section 6.4.1 above, this will be taken 
to mean that the graph will be truncated at the length of follow-up achieved by 10% of 
patients across all trial arms and trial parts. This means that the graph for the 50 mg dose will 
be continued somewhat past the point up to which 10% of 50 mg patients were followed up.
The number of patients at risk in each group will be displayed below the x-axis at year=0, 1, 2, 
3… and each subsequent year of follow-up to provide information on the extent of follow-up. 
Pointwise 95% confidence intervals at each full year may be shown if feasible. In line with 
the recommendations by Pocock et al. this provides some measure of statistical uncertainty 
and ensures that any visual signs of treatment differences do not look more convincing than 
they really are. Results of inferential statistics (e.g. primary model-based hazard ratios, 95% 
confidence intervals and p-value for primary endpoint) will also be shown on the figure. 
Kaplan-Meier tabulations will show number at risk, number failed, cumulative number failed, 
cumulative number censored, Kaplan-Meier estimates of failure rate with pointwise 95% 
confidence intervals. Similar tabulations will be provided by time interval also including the 
estimated hazard at interval midpoint.


Novartis
Confidential
Page 65
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
It is recognized that just as discussed by Pocock et al. caution is needed in interpreting the 
shape of survival plots in particular due to the lack of any pre-specified hypothesis about its 
shape and the lack of statistical power to explore subtleties of treatment difference other than 
the overall comparison.
6.4.3
Calculation of number needed to treat
The number needed to treat (to benefit) will be calculated using the method of Altman and 
Andersen (Altman and Andersen 1999) for each dose for different durations of treatment as
NNT (t) = 1 / [ Splacebo(t) hazard ratio for dose versus placebo – Splacebo(t) ]
using S(t) calculated as described in section 6.4.1. It will be extrapolated as described by 
Altman and Andersen to the 5 year timepoint from the timepoint of follow-up achieved by 10% 
of patients across all trial arms and trial parts T10% under the assumption of approximately 
constant event rates and benefit as
NNT (5 years) = ( T10% / 5 years ) × NNT (T10%).
3 year and 1 year NNTs will be calculated and it is expected that this can be done without 
such an extrapolation unless the study is stopped an interim analysis. Confidence intervals 
with appropriate coverage probabilities will be calculated using Bootstrap methods.
6.5
Methodology for dose response evaluation
Dose-response estimation will be performed to support the evaluation of a number of 
endpoints as indicated in the protocol, among them the hazard ratios derived from the analysis 
of the primary endpoint. 
Dose-response estimation will be done using parametric dose-response modelling as described 
in Pinheiro et al. (2014) combined with model averaging techniques (see Bornkamp et al. 
2015). The model averaging approach will use a weighted subset of seven possible parametric 
models as the estimate of the dose response. The parametric models are a linear model, a 
quadratic model, a model linear in log dose, an emax model, a sigmoid emax model, an 
exponential model, and a beta model as implemented in the R package DoseFinding. The 
model averaged dose response and confidence intervals will be derived from a parametric 
bootstrap. In addition, comparisons between doses will also be derived with their 
corresponding confidence intervals.
The time to event endpoints analyzed using the general approach as described in Pinheiro et al. 
(2014) will use the estimated hazard ratios and covariance matrix derived from a parametric 
regression model for survival endpoints for which the treatment estimates are given a 
proportional hazards model. Estimates for the analysis of other endpoints will be derived from 
fitting models that account for measurements collected over time whenever applicable.
 
The estimation of the dose response will be based on the methods described in Pinheiro et al. 
2014 as a more general framework for the derivation of dose responses when the response is 
any form of derived statistic for the dose groups with their corresponding variance covariance 
matrix.The derived dose response will be obtained from a model that is the average of at least 
three of fitted models of dose response where the weights will used the generalized AIC 


Novartis
Confidential
Page 66
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
measure as described in Pinheiro et al 2014. The corresponding mean dose response curve and 
its confidence intervals will be derived from a parametric boostrap procedure also described 
in the same reference.
Figure 6-6
Candidate dose response patterns
7
Safety evaluation
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 risk management 
plan (RMP), 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.
Selected safety analyses will be based on looking at events and variables recorded while 
patients were still on investigational drug (i.e. data will be considered censored at the latest 
one quarter year + 28 days = 119 days after the last study injection, and up -to/including the 
EOS visit of the core phase), as supportive analyses. 
Since the study is intended to be the only pivotal trial in the regulatory submission, selected 
key safety analyses including disposition, demographics, exposure, adverse events, serious 
adverse events, key outputs for adverse events of special interest, deaths, laboratory 
abnormalities and laboratory values over time will be repeated for those groups specified in 
table 2.3-2.
Selected safety analyses will also be shown by time period (from randomization to ≤ 3 months 
post-randomization, > 3 to ≤ 6 months, > 6 to ≤ 9 months, > 9 to ≤ 12 months, > 12 months to 
the end of core study visit) to evaluate any changes in safety during more short -term and 
longer term treatment.


Novartis
Confidential
Page 67
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
7.1
Safety assessment approach accounting for multiplicity 
No adjustments for multiplicity will be made for safety assessments.     Adjustments will be 
made for multiplicity of the primary and key secondary efficacy endpoints, as described 
earlier in this document.  
7.2
Statistical models used in multiple safety contexts
Safety data will be summarized across the two trial parts and the two randomization plans in 
trial part 2, both of which might influence safety reporting as described in section 2.4.
For this purpose hazard ratios versus placebo will be estimated for binary safety outcomes 
(e.g. at least one occurrence of adverse events) using Cox regression stratified for time since 
index MI and trial part. Time to event methods have been chosen over relative risk regression 
or logistic regression to account for differential follow-up This can be implemented using 
SAS code similar to the following:
proc phreg data=dataset;
  class treatment(ref=”Placebo”) <time since index MI> 
<trial part>;
  model time*event(0) = treatment / ties=exact risklimits;
strata <time since index MI > <trial part>;
run;
Trial part by treatment interactions will be investigated. For selected events, additional 
predictive baseline covariates may be added to the model, namely age, sex, race, region and 
other event specific variables. As summary statistics patients with an event per 100 patient 
years of follow-up (defined as follow-up to first event or censoring) will be reported. 
Rates of multiple occurrences of safety events will be compared between treatment groups for 
selected safety events of special interest, where such an analysis is of interest. A Negative 
Binomial regression including terms for treatment, trial part, and log (time at risk) as offset 
variable will be used. This model was chosen, because the number of recurrent events in a 
population will follow a negative binomial distribution if there is a distribution of different 
individual Poisson event rates in the population that follows a gamma distribution (Glynn et al. 
1993) (Glynn and Buring 1996). While the population distribution may not exactly follow a 
gamma distribution, the maximum likelihood estimation of the additional dispersion 
parameter compared to the Poisson distribution from the data allows the negative binomial 
model approximate the data in this respect and to capture the extent of unexplained 
heterogeneity in the population. The logarithm of the time at risk is used as an offset (i.e. as a 
covariate with coefficient 1), because a log link function is used in order to effectively analyze 
the rate of events per time unit. The following SAS code illustrates the statistical model and 
methods intended for this analysis:
PROC GENMOD DATA=events;
CLASS treatment(ref='Placebo') <trial part & time since index MI>;
  MODEL <number of events> = treatment 
<trial part & time since index MI> / OFFSET=<log time at risk> 


Novartis
Confidential
Page 68
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
DIST=NB LINK=LOG LRCI;
RUN;
As matching summary statistics, events per 100 patient years of follow-up will be reported. 
For selected events, additional potentially predictive covariates will be added to the model, 
namely at least age, sex, race and region. When selecting repeated events it has to be ensured 
that a single adverse event case report form entry is only counted once (e.g. by ensuring only 
one record per adverse event sequence number is counted), as analysis dataset may contain 
multiple records for one CRF report to allow identification via e.g. different SMQs.
When such a model is used for specific adverse events of interest and a sufficient number of 
events to make this display useful is available, these data will also be displayed graphically as 
events per unit time of follow-up for different time intervals (e.g. first 6 months, 6 months – 1 
year, 1 year to 2 years … or smaller time intervals as appropriate) using meaningful categories 
of time to show time patterns of event occurrence and potential changes in treatment effect 
over time. Measures of uncertainty will be provided, as well as information on the extent of 
overdispersion / population heterogeneity.
Changes from baseline in continuous safety parameters will be plotted over time based on 
both trial parts using repeated measures mixed model. The following SAS code illustrates the 
statistical model and methods intended for this analysis:
proc mixed data=dataset;
  class patient visit treatment <trial part>
<time since index MI>;
  model <change from baseline> = treatment visit treatment*visit
baseline <trial part> 
<time since index MI> 
/ s ddfm=kr;
  repeated visit / subject = patient type = un;
run;
with appropriately transformed values. Comparisons of each dose to placebo at each visit will 
be conducted if feasible. Additional analyses will add potentially predictive covariates, 
namely age, sex, race, region, education, exercise level, alcohol use, smoking history, BMI 
and hypertension to the model. The following variables will be analyzed on the log-scales 
and results will be back-transformed to report geometric means and ratios of geometric means 
versus placebo:


ALT (SGPT), AST (SGOT), total bilirubin, direct bilirubin, alkaline phosphatase

Triglycerides, HDL, LDL, VLDL

hsCRP
All other safety variables will be analyzed without any transformation based on the arithmetic 
mean and differences in arithmetic means versus placebo.


Novartis
Confidential
Page 69
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Panel plots of the results of these analyses showing means/geometric means or differences in 
means/ratios of geometric means over time will be made available for the clinical study report. 
95% pointwise confidence intervals will be provided to allow judgment on the variability in 
the underlying data, but due to the obvious multiplicity issues consideration of these 
confidence intervals or p-values from the model described above cannot form the basis of any 
formal inference.
7.3
Other safety evaluation
7.3.1
Adverse Events
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 for all randomized patients (as opposed to the safety 
set). 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.
Serious adverse events occurring after informed consent will be reported for all screened 
patients, as well as separately for all randomized patients and for screen failures.
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, up-to/including the earlier date of 119 days after the last study injection or the 
EOS visit of the core phase) excluding trial endpoints 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.
Any adverse events reported by the investigator with the onset date after randomization and 
up-to/including the end of core phase visit and prior to clinical database lock will be included 
in AE analyses irrespective of how long after last study drug intake. Adverse events occurring 
after a patient’s end of core phase visit will be reported as part of the washout phase/long-
term safety extension phase. 
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.
The number and percentage of patients reporting any AE during the double-blind phase of the 
study will be summarized by primary system organ class, preferred term and treatment. The 
most common adverse events reported (reported by 2 % of patients in any group for each 
preferred term or 2 % in any group for each SMQ) table will be presented in descending 
frequency starting from the most common event.
Separate summaries will be provided for AEs suspected by the investigator to be related to 
study drug, deaths, SAEs, and AEs leading to discontinuation.


Novartis
Confidential
Page 70
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Events reported on endpoint pages
The following events reported by investigators on the trial endpoint pages will be summarized 
by treatment group for safety purposes, because they are as per the study protocol not reported 
as adverse events (further sub-categorizations may be added as needed):

All-cause death

Non-cardiovascular death

Non-cardiovascular death due to accident/trauma

Non-cardiovascular death due to respiratory failure

Non-cardiovascular death due to infection

Non-cardiovascular death due to sepsis

Non-cardiovascular death due to malignancy

Non-cardiovascular death due to suicide

Non-cardiovascular death due to renal failure

Non-cardiovascular death due to liver failure

Non-cardiovascular death due to other non-vascular reason

Cardiovascular death

Coronary Heart Disease death

Cardiovascular death due to myocardial infarction

Cardiovascular death due to congestive heart failure/cardiogenic shock

Cardiovascular death directly related to revascularization

Cardiovascular death due to arrhythmias

Cardiovascular death due to witnessed sudden death

Cardiovascular death due to unwitnessed sudden death seen within 24 
hours

Cardiovascular death (unwitnessed death)

Cardiovascular death (death due to unknown cause)

Cardiovascular death due to other vascular causes identified as Ischemic 
Heart Disease (i.e. fulfilling narrow “Ischaemic heart disease” SMQ)

Cardiovascular death due to other vascular causes not identified as Ischemic 
Heart Disease (i.e. not fulfilling narrow “Ischaemic heart disease” SMQ)

Cardiovascular death due to atherosclerotic non-coronary vascular disease


Cardiovascular death due to stroke

Cardiovascular death due to non-hemorrhagic stroke

Cardiovascular death due to intracranial hemorrhage

Stroke or TIA

Stroke

Non-hemorrhagic cerebral infarction


Novartis
Confidential
Page 71
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab

Non-hemorrhagic infarction with hemorrhagic conversion

Primary hemorrhagic intracerebral stroke

Stroke of uncertain type

Transient Ischemic Attack requiring/not requiring hospitalization

Coronary vessels with >50% stenosis

Coronary vessels >50% stenosis: Left Main

Coronary vessels >50% stenosis: LAD

Coronary vessels >50% stenosis: LCX

Coronary vessels >50% stenosis: RCA

Coronary vessels >50% stenosis: Bypass Graft

Myocardial infarction (with 12 sub-classifications as below)

Spontaneous myocardial infarction with/without new ST segment elevation 
with/without new Q waves identified

PCI-related myocardial infarction with/without new ST segment elevation 
with/without new Q waves identified

CABG-related myocardial infarction with/without new ST segment elevation 
with/without new Q waves identified

Unstable Angina (with 4 sub-classifications as below)

Unstable angina requiring/not requiring unplanned revascularization and requiring/not 
requiring hospitalization

Coronary revascularization (with 4 sub-classifications as below)

Urgent/Elective percutaneous coronary intervention without stenting/using drug 
eluding stent/bare metal stent/unknown type of stent

Urgent/Elective coronary artery bypass graft (1 bypass graft/>=2 bypass grafts)


Novartis
Confidential
Page 72
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab

Critical limb ischemia (with 16 sub-classifications as below)

Critical limb ischemia requiring hospitalization

Critical limb ischemia in left lower extremity/left upper extremity/right lower 
extremity/right upper extremity requiring revascularization/not requiring 
revascularization and requiring hospitalization

Critical limb ischemia not requiring hospitalization

Critical limb ischemia in left lower extremity/left upper extremity/right lower 
extremity/right upper extremity requiring revascularization/not requiring 
revascularization and not requiring hospitalization

Limb amputation due to vascular cause (with 10 sub-classifications as below)

Amputation of  right lower extremity/right above knee amputation/…/left upper 
extremity

New onset diabetes

New onset diabetes based on start of new diabetes medication

New onset diabetes based on laboratory criteria

New onset diabetes based on HbA1c only

New onset diabetes based on FPG only

New onset diabetes based on HbA1c  and FPG
7.3.2
Laboratory data
Laboratory values that the laboratory reports to be below or above the limit of quantification 
will be imputed as 0.5 × and 1.5 × the respective limit of quantification. Should there be a 
substantial proportion of values below the lower limit of quantification and/or above the upper 
limit of quantification for an important laboratory parameter (see Table 7-1), the summary 
statistics (mean, standard deviation) will also be calculated as the maximum likelihood 
estimates using a parametric model for data that can be right censored and left censored at the 
upper and lower limit of quantification, respectively, using the following methods

Arithmetic mean and SD are calculated using PROC LIFEREG assuming a normal 
distribution


Novartis
Confidential
Page 73
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab

Geometric mean and CV%(geometric mean) are calculated using PROC LIFEREG 
assuming a log-normal distribution and back-transformed 

Empirical median will not be calculated in the case of censoring. Empirical minimum 
will not be calculated if there are values < lower limit of quantification, similarly the 
empirical maximum if there are values > upper limit of quantification.

Quartiles from the parametric distribution can also be calculated upon request when 
Q1, median or Q3 does not lie between the lower and upper limits of quantification.
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(Hematology, Serum chemistry and Urinalysis). Summaries will consist of descriptive tables 
stratified by treatment and time point.  
Descriptive summary statistics (mean, median, standard deviation, Min and Max) 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 and will be calculated as:
change from baseline = post baseline values – baseline value
In addition, shift tables will be provided for all parameters except for creatinine clearance in 
order to compare a patient’s baseline laboratory evaluation relative to the extreme post-
baseline value. For the shift tables, the normal laboratory ranges will be used to evaluate 
whether an extreme post-baseline value was normal, low, or high relative to whether or not 
the baseline value was normal, low, or high. These summaries will be presented by laboratory 
test and treatment group.
The frequency and percentage of patients with clinically notable laboratory results after 
baseline will be tabulated. Clinically notable laboratory results, for those parameters where 
ranges are available, are given in Table 7-1 below and are based on the FDA Division of 
Neuropharmacology guidelines. Only patients with laboratory results not notably abnormal at 
baseline from the central laboratory at baseline will be included in the tabulations. 
Table 7-1
Clinical notable criteria for selected laboratory tests
Laboratory parameter (unit)
Lower bound of clinically 
notable range
Upper bound of clinically 
notable range
Hematology
Hematocrit (%)
30
60
Hemoglobin (g/dL)
10
20
Platelet count (x 109/L)
100
600
RBC (x 1012/L)
3.3
6.8
WBC (x109/L)
3.0
15.0
Basophils (%)
-
6
Eosinophils (%)
-
10
Lymphocytes (%)
10
60
Monocytes (%)
-
20
Absolute neutrophils (x 109/L)
1
12
Chemistry


Novartis
Confidential
Page 74
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Laboratory parameter (unit)
Lower bound of clinically 
notable range
Upper bound of clinically 
notable range
Albumin (g/L)
25
60
Alkaline Phosphatase (U/L)
-
280
BUN (mmol/L)
0.7
14.3
Calcium (mmol/L)
1.87
2.89
Chloride (mmol/L)
85
119
Creatinine (mcmol/L)
18
221
LDH (U/L)
0
500
Potassium (mmol/L)
3
6
AST (U/L)
-
100
ALT (U/L)
-
110
Total Bilirubin (mcmol/L)
-
43
Total Protein (g/L)
40
95
Uric Acid (mcmol/L)
89
595
BUN/Serum Urea (mmol/L)
0.7
14.3
Sodium (mmol/L)
125
154
Patients’ worst CTC classifications as per table 7-2 at any point during the study will also be 
provided. The number of patients with eGFR declines compared to baseline of ≥ 25%, ≥ 40% 
or ≥ 50%, or by ≥ 30 ml/min/1.73 m2 at any point in the study will be summarized as well as 
those with serum creatinine increases compared to baseline of ≥ 50%, ≥ 0.5 mg/dL, ≥ 2.0 
mg/dL, ≥ 2.5 mg/dL or ≥ 3.0 mg/dL.
 
Additionally, the occurrence of nephropathy based on selected adverse event groupings as 
defined in the CRS, doubling of post-baseline serum creatinine in comparison to baseline, 
endstage renal disease (ESRD) defined as dialysis, renal transplant, or serum creatinine >530 
μmol/L (6.0 mg/dL) and time to non-cardiovascular death due to renal failure will also be 
analyzed. An overall composite will also be provided. The continuous log-transformed urine 
albumin creatinine ratio will be also analyzed as well as eGFR over time and abnormalities 
will be considered. 
Table 7-2
NIH CTC version 4.0 grades for Chronic kidney disease, which can be 
assessed in this trial
CTC terms
Grade 1
Grade 2
Grade 3
Grade 4
Chronic kidney 
disease
eGFR†  <LLN - 60 
ml/min/1.73 m2
eGFR† 59 - 30 
ml/min/1.73 m2
eGFR† 29 - 15 
ml/min/1.73 m2
eGFR† <15 ml/min/1.73 
m2; dialysis or renal 
transplant indicated*
† CrCl not assessed in this study
* in this study to be defined as report of kidney transplant or dialysis as non-drug therapy


Novartis
Confidential
Page 75
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
7.3.3
Vital signs
Descriptive summary statistics (mean, median, standard deviation, Min, Max) 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 and will be calculated as:
change from baseline = post-baseline value – baseline value
The frequency and percentage of patients with clinically notable vital signs (based on the 
worst value in changes from baseline) will be tabulated. Clinically notable vital sign results 
are provided in Table 7-3 below. Pulse pressure will be derived as systolic – diastolic blood 
pressure and reported.
Table 7-3
Clinically notable changes in vital signs
Vital Sign (unit)
Clinically notable criteria
Weight (kg)
increase > 10% from Baseline
Systolic blood pressure (mmHg)
≤90 and decrease from baseline of ≥30 or <75
≥180 and increase from baseline of ≥30 or >200
Diastolic blood pressure (mmHg)
≤50 and decrease from baseline of ≥20 or <40
≥105 and increase from baseline of ≥20 or >115
Pulse (bpm)
≤50 and decrease from baseline of >30 or <40
≥120 and increase from baseline of >25 or >130
7.3.4
Electrocardiogram (ECG)
In the CANTOS trial, baseline and yearly thereafter ECGs will be taken; ECG results will be 
centrally read for changes including QTc changes and silent MIs for clinical CAD endpoints.
The following quantitative variables will be summarized at each visit using standard summary 
statistics: ventricular rate (heart rate), RR interval, PR interval, QRS duration, QT interval, 
and corrected QT interval (QTcF/QTcB). The difference between treatment groups in 
observed values and changes from baseline with associated 95% confidence interval will be 
provided for each of these criteria.  QTc data will be analyzed for both the Fridericia (primary) 
and Bazzett’s (secondary) corrections. 
Additionally, the number and proportion of patients with

QT > 550 ms

QT > 500 ms

QTc > 500 ms 

QTc > 480 ms

QTc > 450 ms

QTc changes from baseline > 30 ms

QTc changes from baseline > 60 ms

PR > 250 s


Novartis
Confidential
Page 76
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
will be summarized .
In addition, shift tables comparing baseline ECG results (normal, abnormal, not available, 
total) with the maximum on-study result (normal, abnormal, not available, total) will be 
provided for each variable.
Newly occurring or worsening abnormalities will also be summarized by treatment group. 
Results in elderly patients (≥ 65), by gender, in patients with congestive heart failure, elevated 
baseline QT/QTc intervals (for QT/QTc analyses) and baseline HR <55 bpm will be presented.
7.4
Safety topics of interest
This section outlines the currently planned analyses based on the current safety profiling plan. 
The safety profiling plan is an evolving document outlining the clinical safety plan at any 
stage of the clinical development of a compound. Thus, due to the length of the trial the 
analyses based on potential and identified risks may have to be updated according to new 
information while the trial is ongoing.
In general, analyses for adverse events of special interest based on a list of search criteria 
stored in the Novartis Clinical REsearch Documentation and Information system (CREDI). 
For each DMC any analyses to be included in DMC reports will be communicated to the 
academic independent statistician. Number of affected subjects and percentage will be 
provided by treatment arm. Risk ratio and 95% confidence interval will be provided for each 
dose versus placebo. If unbalances occur, time to first occurrence and number of occurrences 
will be evaluated, if appropriate and not already pre-specified. Dependent on the risk medical 
history or baseline characteristics may have to be considered further beyond what is 
prespecified below.
Table 7-4 summarizes the AEs that will be included in any summaries and analyses of AEs of 
special interest.
Frequency tables will be presented for each AEs of interest as well as the associated MedDRA 
Preferred Terms. Additionally, Kaplan-Meier plot will be presented for time-to-first event for 
each AEs of interest unless otherwise specified.
Table 7-4
List of safety topics of interest
Safety topic
Infections/opportunistic infections
Neutropenia
Thrombocytopenia
Malignancies
Hepatic safety
Autoimmunity
Injection site reactions
Disorders of lipoprotein metabolism
Vertigo/dizziness
Hypoglycemia


Novartis
Confidential
Page 77
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
7.4.1
Infections / opportunistic infections
Infections as adjudicated will be summarized based on the adjudicated information including 
whether the infection was classified as opportunistic, whether the infection was typical or 
atypical based on the patient’s medical history, response to standard antibiotic therapy, 
whether it was a chronic recurrent infection/exacerbation of a previous infection and the 
presence of risk factors for infections. 
The analyses below will be conducted separately for each of the followings if feasible

Adjudication committee confirmed infections

All investigator reported AEs of infection (independent of adjudication)

All investigator reported SAEs of infection (independent of adjudication)
Additionally, all investigator reported infections will be identified using a list of search 
criteria in the CRS which will be stored in CREDI. The occurrence of such events will be 
reported by MedDRA preferred term.
These will be classified by severity, seriousness, whether intravenous antibiotics were 
required (report of use of i.v. antibiotic as a concomitant medication), whether infection 
AEs/SAEs were suspected to be related to study drug by the investigator and whether study 
drug was discontinued due to infections. Non-cardiovascular death due to infection/sepsis will 
also be analyzed. Time to first infection will also be analyzed both in a stratified Cox 
regression model, as well as using Kaplan-Meier type analyses.
Since infections are expected to be sufficiently frequent in a long-term study to allow the use 
of multiple covariates, age, sex, race, and region will be added to the Cox regression models 
stratified by time to index MI and trial part.
The following analyses will also be presented by time period (from randomization to ≤ 3 
months post-randomization, > 3 to ≤ 6 months, > 6 to ≤ 9 months, > 9 to ≤ 12 months, > 12 to 
≤ 18 months, > 18 to ≤ 24 months, > 24 to ≤ 30 months and so on in 6 month intervals for as 
long as at least 15% of the trial population are still at risk:

The number of patients at risk, the number of patients with the specified event, and %

Annualized event rate (AER) with associated 95% CI. The annualized event rate (AER) is 
calculated as the total number of patients with specific event divided by the cumulative 
exposure of time to the first specified events.
Rates of infections including repeated infections will also be presented graphically using a 
non-parametric estimator of the mean cumulative function, analogous to the Nelson-Aalen 
estimator of the cumulative hazard function (Johnston and So (2003)) 
and will be 
summarized including graphs of infections in different time periods. The following time 
intervals will be used: from randomization to ≤ 3 months post-randomization, > 3 to ≤ 6 
months, > 6 to ≤ 9 months, > 9 to ≤ 12 months, > 12 to ≤ 18 months, > 18 to ≤ 24 months, > 
24 to ≤ 30 months and so on in 6 month intervals for as long as at least 15% of the trial 
population are still at risk.
Inferential analysis of the rate of infections will use a negative binomial regression model as
described in section 7.2. It will be ascertained by the use of time-dependent period variables 
whether any potential treatment differences become larger over time, as well as testing for the 


Novartis
Confidential
Page 78
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
interaction of log(time) and treatment. This will be done using a negative binomial model 
with SAS code similar to the following or equivalent code in another programming language 
such as R:
PROC GENMOD DATA=events;
CLASS treatment(ref='Placebo') <trial part & time since index MI>
<time period> sex race region;
  MODEL <number of events> = 
treatment <time period> treatment*<time period>
<trial part & time since index MI> 
age sex race region / DIST=NB LINK=LOG LRCI
OFFSET=<log time at risk in time period> ;
  REPEATED SUBJECT=patient / TYPE=UNSTR WITHINSUBJECT=<time period>;
RUN;
Time to first infection will be analyzed by each of eight subgroups that might be at higher risk 
(e.g. elderly patients, diabetic status, patients with low baseline neutrophil counts, current 
smokers history, obese patients, region, asthma patients, and COPD patients), see definitions 
in Table 7-5.  This will be done in separate stratified cox models for each subgroup, with 
treatment, subgroup, and treatment*subgroup as covariates. 
Table 7-5
Higher Risk Subgroups
Elderly 
>=65 years (yes/no)
Diabetics
based on diabetics definition in Table 2.3-1 (yes/no)
Low baseline neutrophils
CTC >=3 at baseline (yes/no)
Current smokers
Current smokers (yes/no)
Obese patients
BMI >=35kg/m2 at baseline (yes/no)
Regions 
The same as above in Table 2.3-1
Asthma patients
PT=”Asthma” in MH (yes/no)
COPD patients
PT=”COPD” in MH (yes/no)
It will be explored whether any potential risk of infections changes based on whether patients 
have reported a vaccination within 3 months from/including baseline (yes/no), by modelling 
the time to first infection including treatment, subgroup (vaccination within 3 months, yes/no), 
and treatment*subgroup.  This analysis will also be done for the 6 month time frame (yes/no -
live vaccination within 6 months from/including baseline).It should be noted that live 
vaccinations within 3 months were not permitted in this study. 
Separate summaries of infections and tuberculosis related adverse events (defined by HLTs 
"Tuberculous infections" and "Mycobacteria identification and serology") will be produced 
for the patients who had tuberculosis, latent or suspected tuberculosis at the start of the study 
and received randomized study medication. A patients' listing will be provided.


Novartis
Confidential
Page 79
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Duration of infections
To investigate whether the duration of infections is affected by canakinumab, duration will be 
summarized for each of the endpoints below:

Mean of the durations in days for each patient

Maximum of the durations in days for each patient

Proportion of total durations of infections over total duration of follow-up for each patient 
7.4.2
Hepatic safety data
Presentation of hepatic safety data will follow the internal Novartis standards for hepatic 
safety analyses. The risk of liver toxicities will be quantified and described in terms of onset, 
dose, duration and severity.
Hepatic effects (LFT abnormality) will be identified with selected adverse events (as defined 
in the CRS),  and the laboratory parameters mainly AST (aspartate aminotransferase; also 
known as SGOT), ALT (alanine aminotransferase; also known as SGPT), ALP (alkaline 
phosphatase) and TBL (total bilirubin; conjugated (direct) (DBL) and unconjugated (indirect) 
bilirubin). 
All analyses (whether e.g. Cox regression, analysis of covariance or ordinal regression) will 
take into account baseline log ALT, log AST, log TBL, log direct bilirubin values (only if 
available in all patients), alcohol use, age, sex, race and region as long as the number of 
events allows it.
All analyses, when possible, will be performed with baseline glycemic status as a subgroup 
and including a treatment by baseline subgroup interaction and repeated with abnormal LFTs 
at baseline as a subgroup including a treatment by baseline subgroup interaction.
Criterion-based “event” tables
Threshold values of interest for liver function tests are given below.
Table 7-6
Hepatic events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN; >10xULN
AST
>3xULN; >5xULN; >8xULN; >10xULN
ALT or AST
>3xULN; >5xULN; >8xULN; >10xULN
TBL
>1.5xULN; >2xULN
DBL
>1.5xULN; >2xULN
TBL and DBL
TBL>1.5xULN+(DBL>ULN,>1.5xULN or >2xULN)
TBL>2x ULN+(DBL>ULN, >1.5xULN or >2xULN)
ALP
>2xULN; >3xULN
(ALT or AST) & (TBL or DBL)
ALT or AST >3xULN & TBL or DBL >2xULN
ALT or AST >5xULN & TBL or DBL >2xULN
ALT or AST >10xULN & TBL or DBL >2xULN


Novartis
Confidential
Page 80
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Parameter
Criterion
ALP & (TBL or DBL)
ALP >3xULN & TBL or DBL >2xULN
(ALT or AST) & (TBL or DBL) & ALP
AT >3xULN & TBL or DBL > 2xULN & ALP < 
2xULN (potential Hy’s Law case)
Note: elevated ALP may suggest obstruction as a 
consequence of gall bladder or bile duct disease; 
ALP may also be increased in malignancy. FDA 
therefore terms Hy’s Law cases as indicators of 
pure hepatocellular injury. This does not mean 
that cases of AT >3xULN & TBL >2xULN & ALP ≥ 
2xULN may not result in severe drug-induced 
liver injury (DILI).
AST = Aspartate aminotransferase; also known as SGOT, ALT = Alanine aminotransferase; also known as SGPT, 
ALP = Alkaline phosphatase, TBL = Total bilirubin, DBL = conjugated (direct) bilirubin
The laboratory results meeting specified criteria standard table will be used to provide the 
number and percentage of patients having AST, ALT > 3, 5, 8, 10 x ULN or TBL >1.5, 2 x 
ULN or ALP > 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, ALT >3xULN & 
TBL >2xULN & ALP <2xULN at the same lab measurement. 
Shift-tables
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, direct bilirubin and ALP. These summaries will be presented by laboratory 
test and treatment group.
Standard laboratory change from baseline tables
The lab standard tables will be produced on all the laboratory parameters including changes 
from baseline in liver parameters. Continuous liver function test values will be plotted over 
time and analyses of covariance adjusting for covariates will also be performed.
Adverse event tables
Selected groupings (e.g., SMQ, HLGT, HLT) of adverse events, as defined in the CRS will be 
presented including the respective preferred term frequencies.
Notable events may be defined as liver-related death (Non-cardiovascular death due to liver 
failure); liver transplantation (from the SAEs and AEs); liver-related study drug 
discontinuation (from the AEs); any of the 3 events. 
The relative risk of the selected groupings (e.g., SMQ, HLT, HLGT) on each of the active 
treatment dosages relative to control will be calculated with 95% confidence intervals. 
The number and percentage of patients with selected groupings of adverse events will be 
presented. 


Novartis
Confidential
Page 81
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
Graphical displays
For all patients with liver values (AST, ALT, ALP, TBL) matching the thresholds of 5xULN 
and Hy’s Law (Table 7-6), single patient LFT profile graphs will be generated showing all 
AST, ALT, ALP, TBL lab values reported for this study and the time of study treatment for 
these patients. An evaluation of Drug Induced Serious Hepatotoxicity (eDISH) plot will also 
be created.  
7.4.3
Malignancy
Occurrence of malignancies as adjudicated by the blinded adjudication committee will be 
summarized based on whether they are

Primary type (by MedDRA high level group term/high level term including secondary 
paths and preferred terms)

Newly detected or represent an existing malignancy

Whether the patient’s history includes this malignancy

Evidence of metastases and their stage

Whether the presentation was considered typical or atypical

Whether and which risk factors there were

Whether the malignancy was considered unusual and was the response to therapy as 
expected.  
Malignancies from adverse event reports will be identified using the list of search criteria in 
the CRS. They will be reported as part of the safety analyses described in section 7.3.1. 
Preferred terms will be reported to allow assessment of the occurrence of malignancies by site. 
The analyses discussed below will be performed separately based on the CEC confirmed 
malignancies,  the investigator reported AEs of malignancies, and the investigator reported 
SAEs of malignancies, if feasible. Time-to-event analyses will be conducted and Kaplan-
Meier type plots will be presented. This will also be done for non-cardiovascular deaths due to 
malignancy.
To assess whether there is an imbalance when follow-up becomes longer, time-to-first event 
will be explored looking at <= 2 years of follow-up versus >2 years of follow-up, separately. 
This will be explored in a Cox regression model including treatment, follow-up (<= 2 years 
or > 2 years) and the interaction term as covariates.
Following analyses will also be presented by time period (from randomization to ≤ 3 months 
post-randomization, > 3 to ≤ 6 months, > 6 to ≤ 9 months, > 9 to ≤ 12 months, > 12 to ≤ 18 
months, > 18 to ≤ 24 months, > 24 to ≤ 30 months and so on in 6 month intervals for as long 
as at least 15% of the trial population are still at risk.

The number of patients at risk, the number of patients with the specified event, and %

Annualized event rate (AER) with associated 95% CI. The annualized event rate (AER) is 
calculated as the total number of patients with specific event divided by the cumulative 
exposure of time to the first specified events.


Novartis
Confidential
Page 82
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
7.4.4
Thrombocytopenia
Effects with respect to thrombocytopenia will be assessed by the laboratory analyses 
described in section 7.3.2, additionally criteria for decreased platelet counts per CTC grades 
as shown in table 7-7 will be reported and baseline platelet counts will be taken into account 
in this analysis.  Shifts versus baseline will also be shown per CTC grade.
Table 7-7
NIH CTC version 4.0 grades for platelets
CTC terms
Grade 1
Grade 2
Grade 3
Grade 4
Platelet count 
decreased
<LLN-75,000/mm3; 
<LLN-75.0 x 109/L
<75,000-
50,000/mm3; <75.0 -
50.0 x 109/L
<50,000 - 25,000/ 
mm3; <50.0 - 25.0 x 
109/L
<25,000/mm3; <25.0 
x 109/L
The occurrence of the groupings of adverse events will be analyzed using Cox regression as 
described in section 7.2 also adding the baseline platelet count to the model and looking for an 
interaction with treatment.  
The baseline use of antithrombotic medications will be evaluated as a subgroup and treatment 
by subgroup interactions will be evaluated for both the occurrence thrombocytopenia (AE of 
special interest) and bleeding events (Haemorrhages SMQ), using Cox regression.
Time to the 1st-occurrence of CTC grades ≥3, and time to the 1st-occurrence of bleeding 
events will be plotted over time using Kaplan-Meier type graphs. A negative binomial 
regression, as described in section 7.2, will be used to analyze the occurrence of the bleeding 
events over time. A repeated measures analysis will be performed on the continuous platelet 
counts change from baseline with the following factors/covariates: treatment, time, time by 
treatment interaction, time since index MI, randomization plan, and baseline platelet count. 
Platelet counts change from baseline will also be plotted over time.
7.4.5
Neutropenia
Drug effects on neutrophils will be assessed by the laboratory analyses described in section 
7.3.2, additionally decreased neutrophil counts (occurrence of neutropenia) per CTC grades as 
shown in table 7-8 will be reported and baseline neutrophil / white blood cell counts will be 
taken into account in this analysis. Shifts versus baseline will also be shown per CTC grade. 
Whether baseline neutropenia or early drops in neutrophil counts (or neutropenia) are 
indicative of infections (defined using adjudicated events of infection, investigator reported 
infections, and AEs of special interest) will be explored in two separate Cox regression 
models; one including treatment, baseline neutropenia  and the interaction term as covariates, 
and the second model including treatment, early drops in neutrophil counts (or neutropenia)  
and the interaction term as a covariate.  There are two definitions for the early drop in 
neutrophil counts (or neutropenia) subgroup, one using an ordinal variable and one using 
percentage change from baseline, and these are both computed at visits 3 and 4, see Table 2.3-
3. There will therefore be four models for this endpoint and these will be displayed in the 
same table.
Table 7-8
NIH CTC version 4.0 grades for neutrophils
CTC terms
Grade 1
Grade 2
Grade 3
Grade 4
Neutrophil count 
<LLN - 1500/mm3; 
<1500 - 1000/mm3; 
<1000 - 500/mm3; 
<500/mm3; <0.5 x 


Novartis
Confidential
Page 83
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
CTC terms
Grade 1
Grade 2
Grade 3
Grade 4
decreased
<LLN - 1.5 x 109/L
<1.5 - 1.0 x 109/L
<1.0 - 0.5 x 109/L
109/L
Whether neutrophil differences change over time will be assessed graphically, as well as using
a repeated measures analysis of the continuous neutrophil count change from baseline with 
the covariates: treatment, time, time by treatment interaction, time since index MI, 
randomization plan, and baseline neutrophil count. Whether the occurrence of abnormalities 
(especially CTC grade ≥ 3) depends on the potential risk factor baseline neutrophil counts will 
be investigated using a cox regression model with time to first occurrence of abnormalities 
(CTC grade ≥ 3) with treatment, baseline neutrophil counts and treatment by baseline 
neutrophil counts interaction.
The number of patients that discontinued treatment and then returned to normal values or did 
not return to normal values, as well as those that did not discontinue and then returned to 
normal values or did not return to normal values will be summarized. The usage of 
concomitant medications given to normalize white blood cells counts/neutrophil counts will 
be summarized.
7.4.7
Disorders of lipoprotein metabolism
Drug effects on lipids will be assessed by the laboratory analyses described in section 7.3.2. 
Additional subgroups based on the use of lipid-lowering medications (including classes of 
these such as statins and fibrates) at baseline will be investigated. CV outcomes are the 
primary endpoint of this study and sub-group analyses for CV outcomes by baseline lipid 
values are planned (see section 2.2). Additionally, the dose of statins used will be tracked as 
described in section 5. The incidence of adverse events such as myopathy that could result 
from different statin usage patterns may be explored based on the findings. The number of 
patients with persistently elevated triglycerides (>50% of visits with TG > 500 mg/dL), as 
well as the occurrence of adverse events such as pancreatitis (acute pancreatitis SMQ) that 
could result from persistent elevations will be summarized.


Novartis
Confidential
Page 84
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
7.4.8
Hypoglycemia
As per the draft FDA requirements for the evaluation of prevention of diabetes, rates of 
hypoglycemia will be compared statistically between groups. Hypoglycemic events will be 
identified using the the  SMQ Hypoglycaemia. Comparisons between treatment groups will be 
both done as time to first event analyses (including reporting the number of affected patients), 
as well as analyzing count data (number of patients with a certain number of hypoglycemic 
episodes – i.e. none, 1 episode, 2 episodes etc.) using negative binomial regression as 
described in section 7.2. Baseline glucose and HbA1c values will be used as covariates in 
analyses.
Such reporting will be done for all hypoglycemic events as well as for events classified as 
severe by the investigator and events classified by the investigator as SAEs. 
7.4.9
Autoimmunity 
Autoimmunity reactions will be described including severity and seriousness, as well as 
occurrence at ANA antibodies by the end of the study.
7.4.10
Injection site reactions
Events of injection site reactions including including SAEs and those reactions leading to 
drug discontinuation will be summarized by treatment group and presenting both the 
frequency and the severity of the events.
7.4.11
Vertigo/dizziness
Events of vertigo and dizziness will be summarized by treatment group and presenting both 
the frequency and the severity of the events.
7.4.12
Other safety topics
The following safety topics will be identified using a list of search criteria in the CRS unless 
specified otherwise. 

Routine risk of QT prolongation will be evaluated as described in section 7.3.4.

Increased uric acid levels will be assessed by the laboratory analyses described in section 
7.3.2.

Long term effects on on kidney function will be assessed by the laboratory analyses 
described in section 7.3.2.

Interactions with vaccines will be assessed separately by drug interactions.
8
Interim analyses
Interim analyses of efficacy, futility and safety will be carried out during the study. Two 
interim analyses of efficacy will be performed when about 50% of the target num ber 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 


Novartis
Confidential
Page 85
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
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. 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.
Protocol amendment 8 introduced an additional early futility analysis to be performed at 
approximately 30% of the target number of 1400 patients have experienced CEC confirmed 
MACE. The analysis plan of the early futility was discussed in a separate document. No 
multiplicity adjustment will be made for the additional early futility analysis, because it will 
not result in rejecting a null hypothesis for efficacy superiority.
Interim analysis will be performed by an independent academic statistical data analysis center 
at 
 external to Novartis, who will not 
be involved in the trial conduct. The results will be reviewed by the Data Monitoring 
Committee (DMC).
Investigators, Novartis employees and others who are involved in the conduct of the trial and 
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. 
DMC
In CACZ885M2301, a DMC will monitor the trial’s progress, safety and efficacy on a regular 
basis or per the request of the DMC. Details regarding the reasons for the DMC and the 
grounds for stopping/continuing trials, as well as the DMC procedures are provided in the
DMC charter.
9
Sample size and power considerations
Sample size and power considerations are addressed in section 9.6 and 9.7 of the clinical trial 
protocol.
Appendix 1: Post-stroke functional assessment sub-study
Full details of the planned analyses for the Stroke Functional Assessment Sub-study, will be 
specified separately, prior to completion of the first Interim analysis.
In line with the primary objective of the post-stroke functional assessment sub-study to 
evaluate whether canakinumab arms facilitate functional recovery from stroke, the primary 
endpoint for this sub-study is the modified Rankin scale assessment 90 days post-stroke. 


Novartis
Confidential
Page 86
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
 
Note that while patients were initially randomly assigned to treatments, the subset of patients 
experiencing a stroke may represent a biased subset. The impact of the occurrence of fatal 
strokes in the main study on the results of the sub-study also needs to be considered.
Besides basic summary statistics the main study report will report an intention-to-treat 
analysis that will rank patients from best to worse as

alive at trial end and no stroke,

alive at trial end and stroke with best Rankin scale 

alive at trial end and stroke with worst Rankin scale 

dead at trial end
Ranking within these categories will be done with earlier stroke/death being worse than a 
stroke/death occurring later.
10
References
1. Allison PD (1995) Survival analysis using the SAS® System: A Practical Approach, Cary, 
NC: SAS Institute Inc.
2. Benjamini Y, Hochberg Y (1995) Controlling the False Discovery Rate: A Practical and 
Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society, B, 57, 
289–300.
3. Bhattaram VA, Siddiqui O, Kapcala LP, Gobburu JVS (2009) Endpoints and Analyses to 
Discern Disease-Modifying Drug Effects in Early Parkinson’s Disease. The AAPS Journal 
2009; Vol. 11, No. 3:456-464.
4. Bland JM, Altman DG (2004) Statistics Notes – The logrank test. BMJ 2004;328:1073.
5. Brannath W, Bretz F (2010)  Shortcuts for locally consonant closed test procedures. J 
American Statistical Association ; 105(490),: 660-9.
6. Breslow NE (1974) Covariance analysis of censored survival data. Biometrics, 30:89-99.
7. 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.
8. Brown H, Prescott R (2006) Applied mixed models in medicine. 2nd ed. 2006: John 
Wiley and Sons, Ltd, Chichester.
9. Buchanan TA (2007) (How) Can We Prevent Type 2 Diabetes? Diabetes 56:1502-1507.
10. Cox DR (1972) Regression models and life-tables (with discussion). J. R. Statist. Soc, B; 
34:187-220.
11. Cox DR (1977) The role of significance tests. Scand J Statist 4: 49-70.
12. Cox and Snell (1989) The analysis of binary data. 2nd ed. 1989: Chapman and Hall, 
London.
13. Crowe BJ, Xia HA, Berlin JA, Watson DJ, Shi H, Lin SL, Kuebler J, Schriver RC, 
Santanello NC, Rochester G, Porter JB, Oster M, Mehrotra DV, Li Z, King EC, Harpur ES, 
Hall DB (2009) Recommendations for safety planning, data collection, evaluation and 


Novartis
Confidential
Page 87
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
reporting during drug, biologic and vaccine development: a report of the safety planning, 
evaluation, and reporting team. Clin Trials. 6(5):430-40.
14. Diabetes Prevention Program Research Group (2002) Reduction in the incidence of type 2 
diabetes with lifestyle intervention or metformin. NEJM; 346:393-403.
15. Dunnett CW (1955) A multiple comparison procedure for comparing several treatments 
with a control. J American Statistical Association; 50:1096-1121.
16. Efron B, Tibshirani RJ (1993) An Introduction to the Bootstrap. Chapman & Hall/CRC.
17. Ezetimibe Report on Deliberation results; March 6, 2007 PMDA Date of application 
October 31, 2003
18. EuroQoL Group (2009) EQ-5D User guide. Basic information on how to use EQ-5D, 
version 2.0, March 2009.
19. Fairclough D (2002) Design and analysis of quality of life studies in clinical trials. 
Chapman and Hall, New York.
20. Gail MH, Byar DP (1986) Variance Calculations for direct adjusted survival curves with 
applications to testing for no treatment effect. Biom J 28 (1986) 5, 587-599.
21. Genz A, Bretz F (2009). Computation of multivariate normal and t probabilities. Lecture 
Notes in Statistics, Vol. 195. Springer, Heidelberg.
22. Glynn RJ and Buring JE (1996)  Ways of measuring rates of recurrent events. BMJ 1996; 
312:364-7.
23. Glynn RJ, Stukel TA, Sharp SM, Bubolz TA, Freeman JL, Fisher ES (1993) Estimating 
the Variance of Standardized Rates of Recurrent Events, with Application to 
Hospitalizations among the Elderly in New England. Am J Epidemiol 1993;137:776-86.
24. Graham JW, Olchowski AE, Gilreath TD (2007). How Many Imputations are Really 
Needed? Some Practical Clarifications of Multiple Imputation Theory. Prev Sci (2007) 
8:206–213.
25. Hakulinen (1982) Cancer survival corrected for heterogeneity in patient withdrawal. 
Biometrics, 38:933-942.
26. Holm S (1979) A simple sequentially rejective multiple test procedure. Scan J Statist 
6:65–70.
27. Holzhauer B (in press) Design and Analysis of Diabetes Prevention Trials for Glucose-
lowering Drugs. Statistics in Biopharmaceutical Research. 
DOI:10.1080/19466315.2013.861766
28. Kenward MG, Carpenter J (2007). Multiple imputation: current perspectives. Stat 
Methods Med Res 2007 16: 199.
29. Kenward MG, Molgenberghs G (1998) Likelihood based frequentist inference when data 
are missing at random. Statistical Science, Vol. 13, No. 3: 236-247.
30. Kenward MG, Roger JH (1997) Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood. Biometrics, 53, 983–997.
31. Kvaløy and Neef (2004) Tests for the Proportional Intensity Assumption Based on the 
Score Process. Lifetime Data Analysis, 10, 139–157.
32. Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F for Chronic 
Kidney Disease Epidemiology Collaboration (2007). Expressing the Modification of Diet 


Novartis
Confidential
Page 88
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
in Renal Disease Study Equation for Estimating Glomerular Filtration Rate with 
Standardized Serum Creatinine Values. Clinical Chemistry 53:4: 766–772.
33. Little RJA, Rubin DB. Statistical Analysis with Missing Data. J. Wiley & Sons, New 
York, 1987.
34. Liu G, Gould AL (2002) Comparison of alternative strategies for analysis of longitudinal 
trials with dropouts. Journal of Biopharmaceutical Statistics 2002; 12: 2, 207 - 226.
35. Lunn M, McNeil D (1995) Applying Cox Regression to Competing Risks. Biometrics 51, 
524-532.
36. Mallinckrodt CH, Kaiser CI, Watkino JG, Molenberghs G, Carroll RI. The effect of 
correlation structure on treatment contrasts estimated from incomplete clinical trial data 
with likelihood-based repeated measures compared with last observation carried forward 
ANOVA. Clinical Trials 2004; 1: 477-489, DOI: 10.1191/1740774504cn049oa.
37. Mallinckrodt CH, Watkin JG, Molenberghs G, Carroll RJ (2004). Choice of the primary 
analysis in longitudinal clinical trials. Pharmaceut. Statist. 2004; 3: 161–169, 
DOI:10.1002/pst.124.
38. Mallinckrodt CH, Kaiser CJ, Watkin JG, Detke MJ, Molenberghs G, Carroll RJ (2) Type I 
error rates from likelihood-based repeated measures analyses of incomplete longitudinal 
data. Pharmaceut. Statist. 2004; 3: 171–186, DOI:10.1002/pst.131.
39. Maruyama T., Takeda M et al Comparison of preventive effect on CV events with 
different statins. the Circle study Circ J 2011; 75 (8): 1951-9
40. Murray GD, Findlay JG (1988). Correcting for the bias caused by drop-outs in 
hypertension trials. Statistics in Medicine Volume 7, Issue 9: 941–946, DOI: 
10.1002/sim.4780070905. 
41. National Drug Monograph January 2012: www.pbm.va.gov
42. Nielsen B (1997) Expected Survival in the Cox Model. Scan J Statist 24: 275 – 287.
43. Peto R (1972) Discussion on Professor Cox’s Paper. J. R. Statist. Soc., B; 34:205-207.
44. Pocock J, Clayton TC, Altman DG (2002) Survival plots of time-to-event outcomes in 
clinical trials: good practice and pitfalls. Lancet 2002; 359; 1686-89.
45. Rubin DB (1976). Inference and missing data. Biometrika 63, 581-592.
46. Rubin BR (1996). Multiple imputation after 18+ years. JASA; 91:473-489.
47. Saku K, Patrol study comparison of Rosuvastatin, Lovastatin and Pitavastatin:, 
Circulation Journal 2011;75 (6):1493-505
48. Senn S (1995) A personal view of some controversies in allocating treatments to patients 
in clinical trials. Statistics in Medicine, Vol. 14, 2661-2674.
49. Senn S (2008) Lessons from TGN1412 and TARGET: implications for observational 
studies and meta-analysis. Pharmaceut. Statist. 2008; 7: 294–301.
50. Schafer, JL (1997). Analysis of Incomplete Multivariate Data, New York: Chapman and 
Hall.
51. Siddiqui O, Hung HMJ O'Neill R(2009) MMRM vs. LOCF: A Comprehensive 
Comparison Based on Simulation Study and 25 NDA Datasets. Journal of 
Biopharmaceutical Statistics, 19: 2, 227-246, DOI: 10.1080/10543400802609797.
52. Stewart WH, Ruberg SJ (2000) Detecting dose response with contrasts. Statist. Med. 2000; 
19:913-921.


Novartis
Confidential
Page 89
Agreements for SAP
14-Apr-2017 (10:14)
CACZ885M2301/canakinumab
53. Teramoto T. The clinical impact of pitavastatin: comparative studies with other statins on 
LDL-C and HDL-C
54. Therneau TM, Grambsch PM (2000) Modeling Survival Data – Extending the Cox Model. 
Springer. 
55. Thomsen BL, Keidin N, Altman DG (1992) Letter to the editor: A note on the calculation 
of expected survival illustrated by survival of liver transplant patients. Statistics in 
Medicine, Vol. 11, 1527-1532.
56. Zhang X, Loberiza FR, Klein JP, Zhang M-J (2007) A SAS macro for estimation of direct 
adjusted survival curves based on a stratified Cox regression model. Computer methods 
and programs in biomedicine 88 (2007) 95-101.