An Extension Study of CACZ885N2301 (NCT02059291), Multi-center, Open Label Study of Canakinumab in Japanese Patients With Periodic Fever Syndromes (Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), Hyper Immunoglobulin D Syndrome ((Also Known as Mevalonate Kinase Deficiency) (HIDS/MKD), or Colchicine Resistant/Intolerant Familial Mediterranean Fever (crFMF))
Phase: PHASE3
Conditions: Periodic Fevers Syndrome
Sponsor: Novartis Pharmaceuticals

 
 
 
Global Clinical Development - General Medicine 
ACZ885 / Canakinumab 
Clinical Trial Protocol CACZ885N2301E2 
An extension study of CACZ885N2301, multi-center, open 
label study of canakinumab in Japanese patients with 
Periodic Fever Syndromes (TRAPS, HIDS, or crFMF) 
Authors: 
 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
NA 
Version number: 
00 (Original Protocol) 
Clinical trial phase: 
III 
Release date: 
03-Jun-2016 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
 
Clinical Trial Protocol Template Version 3.1 (February 2016) 

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Protocol No. CACZ885N2301E2 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Protocol summary ................................................................................................................ 9 
1 
Introduction ....................................................................................................................... 11 
1.1 
Background ............................................................................................................ 11 
1.2 
Purpose .................................................................................................................. 12 
2 
Study objectives and endpoints ......................................................................................... 13 
2.1 
Primary objective ................................................................................................... 13 
2.2 
Secondary objective(s) ........................................................................................... 13 
2.3 
Exploratory objectives ........................................................................................... 13 
3 
Investigational plan ........................................................................................................... 13 
3.1 
Study design........................................................................................................... 13 
3.1.1 
Screening epoch (Epoch 1) ................................................................... 13 
3.1.2 
Extension-treatment epoch (Epoch 2) ................................................... 13 
3.2 
Rationale for study design ..................................................................................... 14 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 15 
3.4 
Rationale for choice of comparator ....................................................................... 15 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 15 
3.6 
Risks and benefits .................................................................................................. 15 
4 
Population .......................................................................................................................... 16 
4.1 
Inclusion criteria .................................................................................................... 16 
4.2 
Exclusion criteria ................................................................................................... 16 
5 
Treatment ........................................................................................................................... 18 
5.1 
Study treatment ...................................................................................................... 18 
5.1.1 
Investigational and control drugs .......................................................... 18 
5.1.2 
Additional treatment .............................................................................. 18 
5.2 
Treatment arms ...................................................................................................... 18 
5.3 
Treatment assignment and randomization ............................................................. 18 
5.4 
Treatment blinding ................................................................................................. 18 
5.5 
Treating the patient ................................................................................................ 18 
5.5.1 
Patient numbering ................................................................................. 18 
5.5.2 
Dispensing the study drug ..................................................................... 18 
5.5.3 
Handling of study and additional treatment .......................................... 18 

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5.5.4 
Instructions for prescribing and taking study treatment ........................ 19 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 19 
5.5.6 
Rescue medication ................................................................................ 19 
5.5.7 
Concomitant medication ....................................................................... 20 
5.5.8 
Prohibited medication ........................................................................... 20 
5.5.9 
Emergency breaking of assigned treatment code .................................. 20 
5.6 
Study completion and discontinuation ................................................................... 20 
5.6.1 
Study completion and post-study treatment .......................................... 20 
5.6.2 
Discontinuation of study treatment ....................................................... 21 
5.6.3 
Withdrawal of informed consent ........................................................... 21 
5.6.4 
Loss to follow-up .................................................................................. 22 
5.6.5 
Early study termination by the sponsor ................................................. 22 
6 
Visit schedule and assessments ......................................................................................... 22 
6.1 
Information to be collected on screening failures .................................................. 25 
6.2 
Patient demographics/other baseline characteristics ............................................. 25 
6.3 
Treatment exposure and compliance ..................................................................... 25 
6.4 
Efficacy .................................................................................................................. 25 
6.4.1 
Appropriateness of efficacy assessments .............................................. 25 
6.5 
Safety ..................................................................................................................... 25 
6.5.1 
Physical examination ............................................................................ 25 
6.5.2 
Laboratory evaluations .......................................................................... 26 
6.5.3 
Pregnancy and assessments of fertility ................................................. 26 
6.5.4 
Appropriateness of safety measurements .............................................. 27 
6.6 
Other assessments .................................................................................................. 27 
7 
Safety monitoring .............................................................................................................. 27 
7.1 
Adverse events ....................................................................................................... 27 
7.2 
Serious adverse events ........................................................................................... 29 
7.2.1 
Definition of SAE ................................................................................. 29 
7.2.2 
SAE reporting........................................................................................ 30 
7.3 
Liver safety monitoring ......................................................................................... 30 
7.4 
Renal safety monitoring ......................................................................................... 31 
7.5 
Reporting of study treatment errors including misuse/abuse ................................ 31 
7.6 
Pregnancy reporting ............................................................................................... 32 
8 
Data review and database management ............................................................................. 32 
8.1 
Site monitoring ...................................................................................................... 32 
8.2 
Data collection ....................................................................................................... 33 
8.3 
Database management and quality control ............................................................ 33 

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8.4 
Data Monitoring Committee .................................................................................. 33 
8.5 
Adjudication Committee ........................................................................................ 34 
8.5.1 
Infection Adjudication Committee ........................................................ 34 
8.5.2 
Malignancy Adjudication Committee ................................................... 34 
9 
Data analysis ...................................................................................................................... 34 
9.1 
Analysis sets .......................................................................................................... 34 
9.2 
Patient demographics and other baseline characteristics ....................................... 34 
9.3 
Treatments ............................................................................................................. 34 
9.4 
Analysis of the primary variable(s) ....................................................................... 34 
9.4.1 
Variable(s) ............................................................................................. 34 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 34 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 35 
9.4.4 
Sensitivity analyses ............................................................................... 35 
9.5 
Analysis of secondary variables ............................................................................ 35 
9.5.1 
Efficacy variables .................................................................................. 35 
9.5.2 
Safety variables ..................................................................................... 35 
9.5.3 
Resource utilization ............................................................................... 35 
9.5.4 
Pharmacokinetics .................................................................................. 35 
9.5.5 
DNA ...................................................................................................... 35 
9.5.6 
Biomarkers ............................................................................................ 35 
9.5.7 
PK/PD ................................................................................................... 35 
9.6 
Analysis of exploratory variables .......................................................................... 36 
9.7 
Interim analyses ..................................................................................................... 36 
9.8 
Sample size calculation .......................................................................................... 36 
10 Ethical considerations ........................................................................................................ 36 
10.1 
Regulatory and ethical compliance ........................................................................ 36 
10.2 
Informed consent procedures ................................................................................. 36 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 37 
10.4 
Publication of study protocol and results............................................................... 37 
10.5 
Quality Control and Quality Assurance ................................................................. 37 
11 Protocol adherence ............................................................................................................ 37 
11.1 
Protocol amendments ............................................................................................. 38 
12 References ......................................................................................................................... 39 
13 Appendix 1: Clinically notable laboratory values ............................................................. 41 
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ..................................................................................................................... 44 
15 Appendix 3: Specific Renal Alert Criteria and Actions .................................................... 46 

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List of tables 
Table 5-1 
Prohibited treatment .............................................................................. 20 
Table 6-1 
Assessment schedule ............................................................................. 23 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 32 
Table 14-1 
Liver Event and Laboratory Trigger Definitions .................................. 44 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 44 
Table 15-1 
Specific Renal Alert Criteria and Actions ............................................. 46 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 14 
 

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List of abbreviations
AE 
Adverse Event 
Alb 
albumin 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMD 
aged-related macular degeneration 
AST 
Aspartate Aminotransferase 
CAN 
Canakinumab 
CAPS 
Cryopyrin Associated Periodic Syndrome 
CFR 
US Code of Federal Regulations 
CRF 
Case Report/Record Form (paper or electronic) 
crFMF 
colchicine resistant Familial Mediterranean Fever 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CTC 
Common Toxicity Criteria 
ECG 
Electrocardiogram 
FMF 
Familial Mediterranean Fever 
GCP 
Good Clinical Practice 
HIDS 
Hyper IgD Syndrome 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IL 
interleukin 
i.v. 
intravenous 
IRB 
Institutional Review Board 
LFT 
Liver function test 
MedDRA 
Medical dictionary for regulatory activities 
MKD 
Mevalonate Kinase Deficiency 
OC/RDC 
Oracle Clinical/Remote Data Capture 
PGA 
Physician’s Global Assessment of Disease Activity 
PSW 
premature subject withdrawal 

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q4w 
Every 4 weeks 
q8w 
Every 8 weeks 
SAE 
Serious Adverse Event 
SJIA 
systemic juvenile idiopathic arthritis 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
Total bilirubin 
TD 
Study Treatment Discontinuation 
TRAPS 
TNF-receptor Associated Periodic Syndrome 
WHO 
World Health Organization 

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Glossary of terms 
Cohort 
A specific group of patients/subjects fulfilling certain criteria 
Dosage 
Dose of the study treatment given to the patient in a time unit (e.g. 
100 mg once a day, 75 mg twice a day) 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (e.g. 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 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” or “investigational 
medicinal product.” 
Patient/subject ID 
A unique number assigned to each patient upon signing the 
informed consent  
Study drug/ treatment 
Any single drug or combination of drugs administered to the 
patient as part of the required study procedures; includes 
investigational drug (s) or background therapy 
Study Treatment 
Discontinuation (TD) 
When the subject permanently stops taking study treatment prior 
to the defined study treatment completion date  
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the drug 
being tested in the study 
Withdrawal of consent 
Withdrawal of consent from the study is defined as when a patient 
does not want to participate in the study any longer, and does not 
want any further visits or assessments, and does not want any 
further study related contact, and does not allow analysis of 
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Protocol summary 
Protocol number 
CACZ885N2301E2 
Title 
An extension study of CACZ885N2301, multi-center, open 
label study of canakinumab in Japanese patients with 
Periodic Fever Syndromes (TRAPS, HIDS, or crFMF) 
Brief title 
An extention study of safety of canakinumab in Japanese 
patients with Periodic Fever Syndromes 
Sponsor and Clinical Phase 
Novartis 
Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
This is an open label extension study to ‘A randomized, 
double-blind, placebo controlled study of canakinumab in 
patients with Periodic Fever Syndromes (TRAPS, HIDS, or 
crFMF), with subsequent randomized withdrawal/ dosing 
frequency reduction and open-label long term treatment 
epochs’ (CACZ885N2301). 
This extension study offers the opportunity for patients 
who completed Epoch 4 of the preceding CACZ885N2301 
study to continue to be treated with ACZ885 until approval 
in Japan of the drug in Periodic Fever Syndromes or until 
development of ACZ885 in Periodic Fever Syndromes is 
suspended. 
Primary Objective 
The primary objective of this study is to evaluate safety 
and tolerability of ACZ885 in this extension study. 
Secondary Objectives 
Not applicable. 
Study design 
Japanese patients are allowed to enter this extension 
study after completion of Epoch 4 (an open-label treatment 
epoch) in CACZ885N2301 study. This study consists of 
two study epochs (Screening epoch and Extension-
treatment epoch). This study will be continued until 
approval in Japan or the discontinuation of the 
development of the drug in Periodic Fever Syndromes. 
In this study, all patients will receive the same dose and 
regimen as administered at the end of study 
CACZ885N2301 consisting of 1 or 2 subcutaneous 
injections every 4 or 8 weeks. Safety will be evaluated 
every 8 weeks. 
Population 
Completed Epoch 4 of the CACZ885N2301 study in Japan 
before the approval of canakinumab in Japan. 
Inclusion criteria 
• Completed Epoch 4 of the CACZ885N2301 study in 
Japan before the approval of canakinumab in Japan. 
• Before or at Visit 1, written informed consent must be 
obtained before any assessment is performed from 
those ≥ 20 years of age. Parent or legal guardian’s 
written informed consent and child’s assent, if 
appropriate, are required before any assessment is 
performed for patients < 20 years of age. 

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Exclusion criteria 
• Any conditions or significant medical problems in which 
the investigator judges the patient should not enter this 
extension study. 
• Pregnant or nursing (lactating) women 
• Female adolescents (≤ 18 years of age) of childbearing 
potential who do not agree to abstinence or, if sexually 
active, do not agree to the use of contraception. 
• Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless 
they are using effective methods of contraception during 
dosing of study treatment. 
Investigational and reference therapy 
• Canakinumab solution for injection in vial which 
contains 150 mg canakinumab in 1 mL solution 
Efficacy assessments 
• Not applicable. 
Safety assessments 
• Physical examination 
• Laboratory evaluations 
• Pregnancy and assessments of fertility 
Other assessments 
• No additional tests will be performed. 
Data analysis 
Due to a very limited number of patients enrolled, specific 
listings will be produced for reporting purpose, and no 
statistical analysis will be performed. 
 
Primary variable is adverse events. 
Adverse events will be coded using the MedDRA 
dictionary that provides the primary system organ class 
and preferred term information. 
A listing will be presented to display individual adverse 
events reported 
Key words 
Canakinumab, interleukin-1, Periodic Fevers Syndrome, 
TRAPS, HIDS, crFMF, auto-inflammatory diseases, 
extension study 
 

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1 
Introduction 
1.1 
Background 
Periodic Fever Syndromes, also referred to as Hereditary Recurrent Fevers or Monogenic 
Autoinflammatory Disorders, is a group of rare orphan diseases classified together under a 
single term and classically consists of 4 separate conditions: Cryopyrin Associated Periodic 
Syndrome (CAPS), TNF receptor Associated Periodic Syndrome (TRAPS), Hyper IgD 
Syndrome (HIDS)/ Mevalonate Kinase Deficiency (MKD) and Familial Mediterranean Fever 
(FMF) (Drenth and van der Meer 2001, Goldbach-Mansky 2012, Stojanov and Kastner 2005, 
Touitou and Koné-Paut 2008). There are currently no approved treatments for TRAPS, 
HIDS/MKD and colchicine resistant FMF (crFMF). 
A key feature of these conditions is the recurrent episodes of systemic inflammation with high 
and disabling fever that is accompanied by characteristic signs and symptoms of target organs 
and body systems (i.e. serositis, neutrophilic rash, muco-cutaneous ulcers, arthralgia/arthritis, 
and aseptic meningitis/headaches) (Ter Haar et al 2013, Piram et al 2011). 
The grouping of these conditions is also based on their pathophysiology, since they are now 
recognized as part of the expanding group of autoinflammatory disorders, which can be 
distinguished from autoimmune disorders by the absence of autoantibodies or antigen-specific 
T cells. Instead of a pathophysiology based on an adaptive immune response involving 
antibodies and lymphocytes, the disease mechanisms in these conditions involve innate immune 
regulation of cytokines and neutrophilic inflammation (Hoffman and Simon 2009).  
Genome-wide association studies have begun to elucidate the molecular basis of complex 
autoinflammatory diseases. The discovery of disease-causing genetic variants has defined 
autoinflammation as a disorder within the innate immune system, implicating IL-1 as a key 
cytokine, and has led to a breakthrough in therapy, with IL-1 inhibitors producing rapid and 
sustained amelioration of symptoms (Aksentijevich and Kastner 2011). 
Canakinumab (ACZ885) is a high-affinity fully human monoclonal anti-human interleukin-1β 
(IL-1β) antibody of the IgG1/κ isotype. Canakinumab is designed to bind to human IL-1β 
blocking the interaction of this cytokine to its receptors, thus functionally neutralizing the 
bioactivity of this cytokine, IL-1β is recognized as one of the principal pro inflammatory 
cytokines in a variety of inflammatory conditions (Dinarello et al 2012). 
As of 30th June 2015, approximately 10,510 patients (578 of pediatric age) received ILARIS 
treatment in Novartis-sponsored investigational clinical trials in a wide spectrum of IL-1β 
driven diseases such as: CAPS, mild asthma, psoriasis, wet aged-related macular degeneration 
(AMD), gouty arthritis, type 2 diabetes mellitus, rheumatoid arthritis, and systemic juvenile 
idiopathic arthritis (SJIA). The post-marketing cumulative patient exposure since the first 
launch of the product is estimated to be approximately 6,922.7 patient-treatment-years 
(Investigator Brochure Edition 14.0). 
Canakinumab has already been shown to be effective in treating pediatric and adult patients 
with 2 inherited auto-inflammatory conditions, in studies of CAPS (Lachmann et al 2009, 
Kuemmerle-Deschner et al 2011a, Kuemmerle-Deschner et al 2011b, Koné-Paut et al 2011) 
and in more recent studies of SJIA (Ruperto et al 2012). Both of these conditions consist of a 
spectrum of inherited defects and clinical syndromes, which all respond to canakinumab. In 

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addition, canakinumab has been shown to be effective in isolated case reports and preliminary 
studies of Periodic Fever Syndromes (Gattorno et al 2012, Gul et al 2012). 
In over 70 countries, canakinumab has been approved in the indications of either CAPS and/ or 
SJIA for which inflammation and related symptoms are expected to be caused by over-
production of IL-1β. 
In CAPS, canakinumab (starting dose of 150 mg s.c. or 2 mg/kg every 8 weeks with the option 
to raise the dose up to a maximum of 600 mg or 8 mg/kg) produced a rapid and complete 
resolution of signs and symptoms in almost all patients, with an immediate and sustained 
normalization of all serological and hematological markers of inflammation. Signs and 
symptoms started to normalize within 1 day and more than 70% of the patients achieved a 
complete clinical response within 2 to 8 days, which was sustained. Response was independent 
of age, gender, and disease phenotype. 
Over the last few years there has been an increasing body of literature about the efficacy of 
targeting IL-1 in a wide spectrum of auto-inflammatory conditions. In addition to isolated case 
reports of the efficacy of canakinumab in auto-inflammatory disorders, a preliminary 
demonstration of the efficacy and safety of canakinumab for the treatment of TRAPS, 
HIDS/MKD and crFMF has been provided by the results of 4 proof of concept (PoC), open 
label studies in patients with TRAPS (20 adult and pediatric patients), HIDS (9 adult and 
pediatric patients), and colchicine resistant/intolerant FMF (one study in 9 adults and one study 
in 7 pediatric patients). 
In all 4 PoC studies, using various dosing regimens, results of the primary endpoint showed 
rates of responses ≥ 85% in each of the 3 conditions with clinically meaningful improvements 
observed across a spectrum of measures (physician and patient based) and in inflammatory 
biomarkers. In addition, no new safety signals emerged in the study population. 
These preliminary encouraging results warranted the further assessment of the benefit/risk of 
canakinumab treatment in a Phase III program in patients suffering from these 3 rare conditions. 
Results from the primary N2301 study Epoch 2 have formed the basis of global regulatory filing 
for the treatment of the studied indications with canakinumab. This extension study is planned 
to offer the opportunity to continue the treatment with ACZ885 until approval in Japan or the 
discontinuation of the development of the drug in Periodic Fever Syndromes. Eligible patients 
are those in Japan who completed Epoch 4 of CACZ885N2301 study. 
1.2 
Purpose 
This is an open label extension study to ‘A randomized, double-blind, placebo controlled study 
of canakinumab in patients with Periodic Fever Syndromes (TRAPS, HIDS, or crFMF), with 
subsequent randomized withdrawal/ dosing frequency reduction and open-label long term 
treatment epochs’ (CACZ885N2301). The primary objective of the preceding CACZ885N2301 
study was to demonstrate that subcutaneous canakinumab administered every 4 weeks is 
superior to placebo in achieving a clinically meaningful reduction of disease activity defined as 
resolution of the index flare at Day 15 and no new disease flares over 16 weeks of treatment. 
This extension study offers the opportunity for patients who completed Epoch 4 of the preceding 
CACZ885N2301 study to continue to be treated with ACZ885 until approval in Japan of the 

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drug in Periodic Fever Syndromes or until development of ACZ885 in Periodic Fever 
Syndromes is suspended. 
2 
Study objectives and endpoints 
2.1 
Primary objective 
The primary objective of this study is to evaluate safety and tolerability of ACZ885 in this 
extension study. 
2.2 
Secondary objective(s) 
Not applicable. 
2.3 
Exploratory objectives 
Not applicable. 
3 
Investigational plan 
3.1 
Study design 
Japanese patients are allowed to enter this extension study after completion of Epoch 4 (an 
open-label treatment epoch) in CACZ885N2301 study. This study consists of two study epochs 
(Screening epoch and Extension-treatment epoch). This study will be continued until approval 
in Japan or the discontinuation of the development of the drug in Periodic Fever Syndromes. 
In this study, all patients will receive the same dose and regimen as administered at the end of 
study CACZ885N2301 consisting of 1 or 2 subcutaneous injections every 4 or 8 weeks. Safety 
will be evaluated every 8 weeks. 
3.1.1 
 Screening epoch (Epoch 1) 
At Visit 1, patients will be assessed for eligibility (Section 4) for study participation after 
completion of Epoch 4 of the CACZ885N2301 study. 
Visit 1 of this extension study and Visit 399 of the CACZ885N2301 study are conducted on the 
same day. 
 
3.1.2 
Extension-treatment epoch (Epoch 2) 
Patients who meet entry criteria at Visit 1 will enter the extension-treatment epoch (epoch 2). 
Since eligible patients initiate the extension- treatment epoch on the same day of screening, 
their first two visits (Visit 1 and Visit 101) can be on the same day. 
Patients will continue the study drug based on the final dose and regimen administered at the 
end of the CACZ885N2301 study. All patients will receive 1 or 2 ACZ885 subcutaneous 
injections every 4 or 8 weeks. Stepwise up-titration up to a dosing regimen of ACZ885 300 mg 
(or 4 mg/kg for patients weighing ≤ 40 kg) every 4 weeks (q4w) will be allowed. In case of re-

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flare [Physician’s global assessment of disease activity (PGA) ≥ 2 AND CRP ≥ 30 mg/L], 
patients will be allowed to increase the dose as follows and accordingly to the same up-titration 
scheme in study CACZ885N2301: If flare occurs at the last visit (V399) or visit between V309 
and V399 of CACZ885N2301 study, up-titration will be allowed at visit 101.  
• If patients receive ACZ885 150 mg (or 2 mg/kg for patients weighing ≤ 40 kg) every 8 
weeks (q8w), they will increase the dose to ACZ885 150 mg q4w. 
• If patients receive ACZ885 150 mg (or 2 mg/kg for patients weighing ≤ 40 kg) q4w, they 
will increase the dose to ACZ885 300 mg q4w. 
• If patients receive ACZ885 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q8w, they 
will increase the dose to ACZ885 300 mg q4w. 
If flare occurs at the last visit (V399) it will be recorded in the CACZ885N2301 study. Safety 
will be evaluated every 8 weeks in the extension- treatment epoch (epoch 2). Patients receiving 
ACZ885 q4w or up-titrated to q4w administration, will come back every 4 weeks for 
unscheduled visits in addition to the scheduled visits as indicated in Table 6-1 
For all patients, a safety follow-up visit should be conducted (e.g. by telephone) 30 days after 
study treatment discontinuation (TD)/ premature subject withdrawal (PSW), or 8 weeks after 
last injection of investigational drug, whichever is later (Table 6-1). 
Figure 3-1 
Study design 
 
All patients will receive the same dose and regimen as administered at the end of study 
CACZ885N2301. 
3.2 
Rationale for study design 
This extension study offers the opportunity to Japanese patients who completed Epoch 4 of the 
CACZ885N2301 study to be treated with ACZ885 until approval of the drug is granted in Japan 
or the development of the drug is suspended in Periodic Fever Syndromes. Therefore, an open 
CACZ885N2301E2
CACZ885N2301
Day 785 to End of study
(Visit 102, 103...)
Approval 
CAN 150 mg q8w
CAN 150 mg q4w
CAN 300 mg q8w
CAN 300 mg q4w
Epoch 1(E2)
Epoch 2 (E2)
= Up-Titration
Visit 1/101

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label design has been selected. The visit schedule follows on from the Epoch 4 of 
CACZ885N2301 study. 
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
Since this is an extension study of the CACZ885N2301 study, patients will recieve the study 
drug with a starting dose based on final dose regimen received in the CACZ885N2301 study. 
Study duration will continue until approval of the drug is granted in Japan or the development 
of the drug is suspended in Periodic Fever Syndromes. 
3.4 
Rationale for choice of comparator 
Not applicable. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
3.6 
Risks and benefits 
In TRAPS, HIDS/MKD and FMF, antipyretics, such as NSAIDs and paracetamol, often have 
some effect at reducing fever and associated symptoms, but they do not prevent or change the 
course of flare (Ter Haar et al 2013, Hoffman and Simon 2009). Regular, repeated dosing is 
often required for the duration of the episode, which raises concern for the occurrence of adverse 
effects, including gastrointestinal irritation or liver toxicity. 
For the past 30 years, maintenance-dose colchicine has been the mainstay of therapy for 
preventing attacks and substantially reducing the risk of amyloidosis in patients with FMF. 
Occasionally, compliance can be affected by the gastrointestinal adverse effects that are 
sometimes associated with increasing the colchicine dose. There are rare patients (in the range 
of 5-10%) with FMF who are considered to be colchicine resistant (incomplete response to 
adequate colchicine dosing). However, colchicine is less effective in TRAPS and HIDS/MKD. 
Corticosteroids have limited clinical efficacy in most of the recurrent febrile syndromes, with 
reports of very high doses being required to achieve any benefit. 
Thus the risks are associated with the use of high doses of antipyretics, colchicine and 
corticosteroids, which offer only symptomatic relief, without sustained benefit. 
Preliminary data from the 4 small pilot studies with canakinumab in these 3 indications both in 
adult and pediatric patients, as well as the ongoing worldwide pharmacovigilance activities have 
not identified any new safety signals specific for patients with TRAPS, HIDS/MKD, crFMF in 
patients treated with canakinumab. 
The risk to subjects in this trial will be minimized by compliance with the inclusion/ exclusion 
criteria, close clinical and laboratory monitoring, adherence to the protocol guidelines for dose 
administration/escape treatment rules and implementation of a Risk Management Plan in place 
for canakinumab. 
Canakinumab is known to be highly effective and safe in children and adults with CAPS, a 
spectrum of inherited auto-inflammatory syndromes that are similar to TRAPS, HIDS/MKD 

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and crFMF. Preliminary data from the 4 PoC open-label trials with canakinumab in these 3 
indications in both in adult and pediatric patients has shown canakinumab to be effective, and 
potentially able to treat the underlying inflammation, rather than just the disease symptoms. 
And the result from the CACZ885N2301 study Epoch 2 data, which is placebo-controlled Phase 
3 confirmatory study with canakinumab in these 3 indications, has shown the overall favorable 
benefit-risk profile. 
4 
Population 
This study population will be Japanese patients who completed Epoch 4 of the CACZ885N2301 
study. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study must fulfill all of the following criteria: 
1. Completed Epoch 4 of the CACZ885N2301 study in Japan before the approval of 
canakinumab in Japan. 
2. Before or at Visit 1, written informed consent must be obtained before any assessment is 
performed from those ≥ 20 years of age. Parent or legal guardian’s written informed 
consent and child’s assent, if appropriate, are required before any assessment is performed 
for patients < 20 years of age. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients/subjects. 
1. Any conditions or significant medical problems in which the investigator judges the 
patient should not enter this extension study. 
2. Pregnant or nursing (lactating) women 
3. Female adolescents (≤ 18 years of age) of childbearing potential who do not agree to 
abstinence or, if sexually active, do not agree to the use of contraception as defined in the 
exclusion criterion for women of child bearing potential. For further information, please 
refer to Section 6.5.3. 
4. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. Effective contraception methods include: 
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
c. Male sterilization (at least 6 m prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject 

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d. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 
e. Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception 
f. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
In case of use of oral contraception women should have been stabile on the same pill 
for a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 

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5 
Treatment 
5.1 
Study treatment 
5.1.1 
Investigational and control drugs 
Novartis will provide the following investigational treatment: 
• Canakinumab solution for injection in vial which contains 150 mg canakinumab in 1 mL 
solution 
5.1.2 
Additional treatment 
No additional treatment beyond investigational drug and control drug are included in this trial. 
5.2 
Treatment arms 
Patients will continue the study drug based on final dose regimen recieved (e.g. one of the 
following regimen) in the CACZ885N2301 study. 
• ACZ885 150 mg (or 2 mg/kg for patients weighing ≤ 40 kg) q4w 
• ACZ885 150 mg (or 2 mg/kg for patients weighing ≤ 40 kg) q8w 
• ACZ885 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w 
• ACZ885 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q8w 
5.3 
Treatment assignment and randomization 
This is an open label study. 
5.4 
Treatment blinding 
Not applicable. 
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 
Patient numbers used in the preceding CACZ885N2301 study will be used continuously for 
those patients enrolling in this extension study. 
5.5.2 
Dispensing the study drug 
Each study site will be supplied with study drug. 
5.5.3 
Handling of study and additional treatment 
5.5.3.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 

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have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis CPO Quality 
Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions and Lot bunmer for the study treatment but no 
information about the patient. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
5.5.3.2 
Handling of additional treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
The s.c. injections of investigational treatment may be administered into the patient’s arm or 
thigh. Detailed instructions on the preparation and administration of the study drugs will be 
described in the Pharmacist Manual provided in the CACZ885N2301 study. 
All patients will receive 1 or 2 s.c. injections every 4 or 8 weeks based on the final dose regimen 
received in the CACZ885N2301 study and depending upon criteria met for up-titration (Section 
3.1.2) until TD/ PSW. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Investigational treatment dose adjustments and/or interruptions other than those detailed in 
Section 3.1.2 are not permitted. 
All dose changes must be recorded on the Dosage Administration Record CRF. 
5.5.6 
Rescue medication 
Standard doses of NSAIDs and corticosteroids can be used as needed basis to treat the signs 
and symptoms of TRAPS, HIDS/MKD or crFMF during acute flares at the discretion of the 
investigator. 
Use of rescue medication must be recorded on the concomitant medications page in the CRF. 

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5.5.7 
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient is enrolled into this extension study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF. 
Each concomitant drug must be individually assessed against all prohibited medication. If in 
doubt the investigator should contact the Novartis medical monitor before allowing a new 
medication to be started. 
5.5.8 
Prohibited medication 
Use of the treatments displayed in Table 5-1 is NOT allowed after Screening. Once 
canakinumab is approved for Periodic Fever Syndromes (TRAPS, HIDS/MKD, or crFMF), it 
can be used according to the package insert. 
Table 5-1 
Prohibited treatment 
Medication 
Action to be taken 
Anakinra 
Investigational treatment to be discontinued 2 
Rilonacept, tocilizumab, rituximab and any other 
biologics 1 (investigational or marketed) 
Investigational treatment to be discontinued 2 
Etanercept, adalimumab, infliximab, or any TNF 
inhibitor (investigational or marketed) 
Investigational treatment to be discontinued 2 
Leflunomide, thalidomide, cyclosporine, or i.v. Ig 
Investigational treatment to be discontinued 2 
Tofacitinib 
Investigational treatment to be discontinued 2 
6-Merceptopurine, azathioprine, 
cyclophosphamide, or chlorambucil 
Investigational treatment to be discontinued 2 
Any other investigational non-biological drug 
Investigational treatment to be discontinued 2 
Any live vaccination 1 
Investigational treatment to be discontinued 2 
Treatment for tuberculosis 
Investigational treatment to be discontinued 
1 It is recommended not to initiate any live vaccination or biologic treatment until 3 months after the 
last dose of investigational treatment. Killed or inactivated vaccines may be permitted according to 
the investigator’s discretion. 
2 Investigational treatments must be permanently discontinued but patient will remain in the study 
and will be followed-up for safety. 
5.5.9 
Emergency breaking of assigned treatment code 
This is an open label study. 
5.6 
Study completion and discontinuation 
5.6.1 
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit of extension- treatment epoch planned in the protocol. 

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For all patients a safety follow-up visit should be conducted (e.g. by telephone) 30 days after 
last visit 199 or TD/PSW, or 8 weeks after last injection of investigational drug, whichever is 
later. The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care does not 
require any special treatment but it is recommended not to initiate any live vaccination or 
biologic treatment until 3 months after the last dose of study treatment. 
5.6.2 
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation. 
Study treatment must be discontinued under the following circumstances:  
• Emergence of the following adverse events: 
a. Absolute QTcF > 500 msec, confirmed by repeat electrocardiogram (ECG) 
measurements 
b. Serious infections combined with neutropenia Common Toxicity Criteria (CTC) 
grades ≥ 1 (ANC < 2.0 x 109/L) 
c. CKD as per NKF stages ≥ 4: eGFR ≤ 29 mL/min/1.73 m2 
d. Confirmed diagnosis of latent or active Tuberculosis 
e. Onset of any malignancy 
• Any of the following laboratory abnormalities: 
a. Neutropenia CTC Grades ≥ 2 : ANC < 1.5 x 109/L 
b. Thrombocytopenia CTC Grade 4: Platelets < 10.0 x 109/L 
• Pregnancy 
• Use of prohibited treatment as per Table 5-1 
• Any other protocol deviation that results in a significant risk to the patient’s safety 
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after discontinuation 
of study drug, for a study treatment discontinuation visit. Treatment discontinuation visit 
assessments detailed in the “treatment discontinuation visit” in Table 6-1 should be completed 
and recorded in the eCRF. The investigator must determine the primary reason for the patient’s 
premature discontinuation of study treatment and record this information on the Dosage 
Administration eCRF. 
5.6.3 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent from the study is defined as when a patient: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 

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and 
• Does not want any further study related contacts 
and 
• Does not allow analysis of already obtained biologic material  
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table. 
5.6.4 
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or 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 cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit would have occurred. 
5.6.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely withdrawn patient. 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 the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.  
At a minimum, patients will be contacted for safety evaluations and a follow-up visit or phone 
call for Serious Adverse Event (SAE) must be performed 30 days following study TD, 
premature subject withdrawal (PSW) or 8 weeks after last injection of study drug, whichever is 
later. 
Documentation of attempts to contact the patient should be recorded in the patient record. 
 

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Table 6-1 
Assessment schedule 
Epoch 
Screening 
(Epoch 1) 
Extension- treatment 
(Epoch 2) 
 
Visit 
1# 
101# 
102, 103…. 
199 and TD  
and/or PSW6 
Safety follow-up 
Week (Relative to Baseline of core study) 
113 
113 
121, 129…. 
 
 
Day 
785 
785 
841, 897…. 
 
PSW +30 or 8 weeks 
after last injection 
Informed consent 
X 
 
 
 
 
Demography  
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Relevant medical history/ current medical conditions 
X 
 
 
 
 
Prior and concomitant medications (including vaccination status) * 
X 
X 
X 
X 
 
Surgical and medical procedures* 
X 
X 
X 
X 
 
Disease Diagnosis 
X 
 
 
 
 
Disease characteristics  
X 
 
 
 
 
Pregnancy test –urinalysis (for females of child bearing potential) * 
 
S 
 
S 
 
Physical examination*,7 
 
S 
S 
S 
 
Weight2,3,7 
 
S 
S 
 
 
PGA2,4,7 
 
S 
S 
 
 
Hematology (local Lab) * 
 
X 
X 
X 
 
Blood chemistry (local Lab) * 
 
X 
X 
X 
 
CRP (local Lab)2,5,7 
 
S 
S 
 
 
Administration of open-label treatment1 
 
X 
X 
 
 
Adverse events* 
X 
X 
X 
X 
 
Local tolerability*,7 
 
S 
S 
S 
 
Screening phase disposition form 
X 
 
 
 
 
Study phase completion form* 
 
 
 
X 
 
Follow-up visit or phone call for SAEs* 
 
 
 
 
S 

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TD = Study treatment discontinuation; PSW = Premature subject withdrawal 
X = assessment to be recorded on clinical data base 
S = assessment to be recorded on source documentation only 
*These assessments are also to be conducted for patients who discontinue 
#  Visit 1 of this extension study and Visit 399 of the CACZ885N2301 study are conducted on the same day. Visit 1 and Visit 101 can be on the same 
day 
1. Patients receiving ACZ885 q4w or up-titrated to q4w administration will come back every 4 weeks for unscheduled visits at Day 813, Day 869 and so 
forth in addition to the scheduled visits 
2. These assessments are source documentation only and will not be entered into the CRF, because they will be used only for dose adjustment or 
judgement of up-titration due to flare. Flare is defined as simultaneous occurrence of a clinical flare and a serological flare defined as follows: 
• PGA ≥ 2 (clinical flare) 
• CRP ≥ 30 mg/L (serological flare) 
3. Body weight to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes 
4. The PGA (physician’s global assessment) will be based on a 5-point scale: 
• 0 = None (no) disease associated clinical signs and symptoms 
• 1 = Minimal disease associated signs and symptoms 
• 2 = Mild disease associated signs and symptoms 
• 3 = Moderate disease associated signs and symptoms 
• 4 = Severe disease associated signs and symptoms5. CRP will be measured at the local laboratory, including any unscheduled visits. CRP value will 
be standardized to a normal range of 0-10 mg/L. 
6. After canakinumab is approved for Periodic Fever Syndromes (TRAPS, HIDS, or crFMF) in Japan, all subjects who continue study treatment at the 
timing will be expected to perform V199 evaluation approximately 8 weeks after their most recent assessment visit, and then will enter the safety follow-
up period. 
7. If V 101 of this extension study and V 399 of the CACZ885N2301 study are conducted on the same day, Physical exam, PGA, CRP, weight, local 
tolaretability will be assessed only one time. 
 

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6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, and 
SAE data collected. Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data. 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: year 
of birth, age, sex, race, ethnicity, relevant medical history/ current medical condition present 
before signing informed consent. Where possible, diagnoses but not symptoms will be recorded. 
Detailed information on the patient’s vaccination status (to be recorded as part of prior 
medication), disease diagnosis and disease related prior medications/ surgical and medical 
procedures before signing informed consent will also be collected. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
All baseline characteristics to be collected are also listed in Table 6-1. 
6.3 
Treatment exposure and compliance 
Compliance is expected to be 100% since study treatment will be administered subcutaneously 
by the investigator or study personnel. 
6.4 
Efficacy 
Not applicable. 
6.4.1 
Appropriateness of efficacy assessments  
This extension study is planned to offer the opportunity to continue the treatment with ACZ885 
until approval in Japan or the discontinuation of the development of the drug in Periodic Fever 
Syndromes, for the patients who completed Epoch 4 of CACZ885N2301 study. Therefore, 
efficacy assessment is out of scope. 
6.5 
Safety 
The safety assessments presented in this Section 6.5 are mandatory for all patients including 
those for whom study treatment must be permanently discontinued as detailed in Section 5.6.2. 
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. 
A short physical exam will include the examination of general appearance and vital signs. 

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A complete physical examination or a short physical exam (investigator judges which physical 
examination is appropriate) will be at all visits. Physical examination at Visit 1/101 will not be 
necessary in this study when it was conducted at Visit 399 in the preceding N2301 study. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to signing informed consent must be 
included in the Medical History part of the CRF. Significant findings made after first 
administration of investigational drug which meet the definition of an Adverse Event must be 
recorded on the Adverse Event section of the CRF. 
6.5.2 
Laboratory evaluations 
All laboratory evaluations will be conducted locally. Clinically notable laboratory findings are 
defined in Appendix 1. 
6.5.2.1 
Hematology 
The hematology panel will include: Hemoglobin, hematocrit, red blood cell count, white blood 
cell count with differential including lymphocytes, monocytes, neutrophils, eosinophils, 
basophils, and platelet count will be measured. 
Hematology samples are to be collected at visits shown in Table 6-1. 
6.5.2.2 
Clinical chemistry 
The chemistry panel will include: Albumin, alkaline phosphatase, total and differentiated 
bilirubin, calcium, chloride, fasting total cholesterol (including LDL and HDL), creatinine, 
creatinine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), α- 
amylase, γ-glutamyltransferase (GGT), fasting glucose, sodium, potassium, inorganic 
phosphorus, total protein, lactate dehydrogenase (LDH), triglycerides, magnesium, blood urea 
nitrogen (BUN), uric acid and CRP. 
Clinical chemistry samples are to be collected at visits shown Table 6-1. 
6.5.3 
Pregnancy and assessments of fertility 
6.5.3.1 
Female adult patients (>= 18 years) 
Female patients ≥ 18 years of age and of childbearing potential except those who are determined 
to be post-menopausal and not of child-bearing potential, are required to have a pregnancy test 
performed. 
A pregnancy test must be performed at the local lab as shown in Table 6-1. 
If a pregnancy test is positive, the patient must be discontinued from the trial and followed up 
according to Section 5.6.2. 
6.5.3.2 
Female adolescents (>= 12 to < 18 years) 
All menarchal girls and their parents/ caregivers should be informed about the potential risks of 
pregnancy and the need to prevent pregnancy during the study. It is important to be sensitive in 
introducing this issue, as understanding and comprehension of puberty, sexual activity, 

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pregnancy and contraception is influenced by age, as well as factors such as precocity, socio-
economic, educational and familial background. These discussions with the patient and her 
parents/ caregivers are therefore best performed by investigators familiar with the adolescent 
and her family and should be guided by requirements of the local regulatory authorities. These 
discussions should take into account the socio-economic, cultural factors and religious beliefs 
of the adolescent participant and her family. The investigator should also discuss the 
management of the pregnancy test results with the patient and her parents/ caregivers. The 
privacy of the adolescent should be considered in accordance with the local law and ethics. 
Female patients of child-bearing potential, who are or might become sexually active, must be 
informed of the need to prevent pregnancy during the study. Women should use effective 
contraception in accordance with locally approved prescribing information. For details about 
acceptable effective contraception, refer to exclusion criterion #4 in Section 4.2. The decision 
on the contraceptive method should be reviewed at least every 3 months to evaluate the 
individual need and compatibility of the method chosen. 
6.5.3.3 
Female pediatric patients (< 12 years) 
No pregnancy tests are required. Pregnancy test will be conducted if investigator judges to be 
necessary. 
6.5.4 
Appropriateness of safety measurements  
The safety assessments selected are appropriate because subjects who completed assessment of 
long-term safety in the core study of N2301 will enter in the study in order to continue receiving 
study drug until approval in Japan. 
6.6 
Other assessments 
No additional tests will be performed on patients/subjects entered into this study. 
7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events must be sought by non-directive questioning of the patient 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 findings, laboratory test 
findings, or other assessments. 

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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1. 
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
• the severity grade 
a. mild: usually transient in nature and generally not interfering with normal activities 
b. moderate: sufficiently discomforting to interfere with normal activities 
c. severe: prevents normal activities 
• its relationship to the study treatment 
• Yes 
• No 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
• whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met. 
• action taken regarding [investigational] treatment 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
a. no action taken (e.g. further observation only)  
b. [investigational] treatment dosage increased/reduced 
c. [investigational] treatment interrupted/withdrawn 
d. concomitant medication or non-drug therapy given  
e. non-drug therapy given  
f. patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition 
of SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome. 

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Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the patient. 
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria: 
• 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 (specify what this includes) 
• 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 a 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, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 

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require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
7.2.2 
SAE reporting 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
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 the study drug 
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, 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 study treatment 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 study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
7.3 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and completion 
of AE CRF pages 

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Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.  
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2. 
For the liver laboratory trigger: 
• Repeating the liver function test (LFT) within the next week to confirm elevation. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the patient if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. The event must be recorded on 
the Adverse Event section of the CRF. 
7.4 
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study: 
• Serum event: 
• confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status 
• Urine event 
• new onset (≥ 1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable) 
• new onset (≥ 1+), hematuria or glycosuria  
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 3. The event must be recorded on the Adverse Event section of the CRF. 
7.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 

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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. 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
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 
Misuse/Abuse 
Yes 
Yes, 
Yes, even if not 
associated with an SAE 
7.6 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent 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 must be recorded on the Pharmacovigilance 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 study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on an SAE form. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site 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 

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information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
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 CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be 
disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the 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 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 for archiving at the 
investigational site. 
8.3 
Database management and quality control 
Novartis staff [or Contract Research Organization (CRO) working on behalf of Novartis] 
review the data entered into the CRFs 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 that 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 using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time can 
only be made after written agreement by Novartis Development management. 
8.4 
Data Monitoring Committee 
Not required. 

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8.5 
Adjudication Committee 
8.5.1 
Infection Adjudication Committee 
Not applicable. 
8.5.2 
Malignancy Adjudication Committee 
Not applicable. 
9 
Data analysis 
Due to a very limited number of patients enrolled, specific listings will be produced for 
reporting purpose, and no statistical analysis will be performed. 
9.1 
Analysis sets 
The following analysis sets will be used for the data analysis. 
The Safety Set will consist of all patients receiving at least a single dose of study medication 
in the extension study. 
9.2 
Patient demographics and other baseline characteristics 
Demographic and baseline characteristics will be listed. 
Any significant prior or active medical condition at the time of signing informed consent will 
be also listed. 
9.3 
Treatments 
The exposure to investigational treatment (number of doses) and duration of exposure (days) 
during this study will be listed for the Safety Set. 
Rescue medication will be also listed. 
9.4 
Analysis of the primary variable(s) 
Analysis of the primary variable will be performed on the Safety set. 
9.4.1 
Variable(s) 
Primary variable is adverse events. 
Adverse events will be coded using the MedDRA dictionary that provides the primary system 
organ class and preferred term information. 
A listing will be presented to display individual adverse events reported. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
Not applicable. 

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9.4.3 
Handling of missing values/censoring/discontinuations 
Not applicable. 
9.4.4 
Sensitivity analyses 
Not applicable. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
Not applicable. 
9.5.2 
Safety variables 
All safety evaluations will be performed on the Safety set. 
9.5.2.1 
Adverse events 
Adverse event is primary variable. 
9.5.2.2 
Weight 
Not applicable. 
9.5.2.3 
Vital signs 
Not applicable. 
9.5.2.4 
Laboratory evaluations 
Laboratory evaluations will be listed by patient. 
9.5.3 
Resource utilization 
Not applicable. 
9.5.4 
Pharmacokinetics 
Not applicable. 
9.5.5 
DNA 
Not applicable. 
9.5.6 
Biomarkers 
Not applicable. 
9.5.7 
PK/PD 
Not applicable. 

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9.6 
Analysis of exploratory variables 
Not applicable. 
9.7 
Interim analyses 
Not applicable. 
9.8 
Sample size calculation 
Patients who completed Epoch 4 of the preceding CACZ885N2301 study in Japan will be 
eligible for entry into this extension study. Therefore the maximum number of patients is 10. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
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(s) of the patient. 
In cases where the patient’s representative gives consent, the patient must 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. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study. 

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10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment procedures 
(e.g., advertisements) and any other written information to be provided to patients. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
10.4 
Publication of study protocol and results 
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 trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 
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 (CQA), 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 SOPs, and are performed according to written Novartis processes. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 

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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 prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients/subjects may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. 

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12 
References 
References are available upon request 
Aksentijevich I and Kastner DL (2011) Genetics of monogenic autoinflammatory diseases: 
past successes, future challenges. Nat Rev Rheumatol; 7(8):469-78. 
Dinarello CA, Simon A, van der Meer JW (2012) Treating inflammation by blocking 
interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov; 11(8):633-52. 
Drenth JP and van der Meer JW (2001) Hereditary periodic fever. N Engl J Med; 
345(24):1748-57. 
Gattorno M, Obici L, Meini A, et al (2012) Efficacy and Safety of Canakinumab in Patients 
with TNF Receptor Associated Periodic Syndrome. Arthritis Rheum; 64(10) S322 abstract 
749. 
Goldbach-Mansky R (2012) Immunology in clinic review series; focus on autoinflammatory 
diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and 
an emerging role for cytokines beyond IL-1. Clin Exp Immunol; 167(3):391-404. 
Gul A, Ozdogan H, Erer B, et al (2012) Efficacy and Safety of Canakinumab in Adults with 
Colchicine Resistant Familial Mediterranean Fever. Arthritis Rheum; 64(10) S322 abstract 
750. 
Hoffman HM and Simon A (2009) Recurrent febrile syndromes: what a rheumatologist needs 
to know. Nat Rev Rheumatol; 5(5):249-56. 
Koné-Paut I, Lachmann HJ, Kuemmerle-Deschner JB, et al (2011) Sustained remission of 
symptoms and improved health-related quality of life in patients with cryopyrin-associated 
periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled 
randomized withdrawal study. Arthritis Res Ther; 13(6):R202. 
Kuemmerle-Deschner JB, Hachulla E, Cartwright R, et al (2011a) Two-year results from an 
open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in 
patients with cryopyrin-associated periodic syndrome across different severity phenotypes. 
Ann Rheum Dis; 70(12):2095-102. 
Kuemmerle-Deschner JB, Ramos E, Blank N, et al (2011b) Canakinumab (ACZ885, a fully 
human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with 
cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther; 13(1):R34. 
Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al (2009) Use of canakinumab in the 
cryopyrin-associated periodic syndrome. N Engl J Med; 360(23):2416-25. 
Piram M, Frenkel J, Gattorno M, et al (2011) A preliminary score for the assessment of 
disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory 
Diseases Activity Index) Consensus Conference. Ann Rheum Dis; 70(2):309-14. 
Ruperto N, Quartier P, Wulffraat N, et al (2012) A phase II, multicenter, open-label study 
evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile 
idiopathic arthritis with active systemic features. Arthritis Rheum; 64(2):557-67. 
Schwartz GJ, Munoz A, Schneider MF, et al (2009) New Equations to Estimate GFR in 
Children with CKD. J Am Soc Nephrol; 20(3):629-37. 

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Stojanov S and Kastner DL (2005) Familial autoinflammatory diseases: genetics, 
pathogenesis and treatment. Curr Opin Rheumatol; 17(5):586-99. 
Ter Haar N, Lachmann H, Ozen S, et al (2013) Treatment of autoinflammatory diseases: 
results from the Eurofever Registry and a literature review. Ann Rheum Dis; 72(5):678-85. 
Touitou I and Koné-Paut I (2008) Autoinflammatory diseases. Best Pract Res Clin 
Rheumatol; 22(5):811-29. 

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13 
Appendix 1: Clinically notable laboratory values 
Notable laboratory abnormalities in adult patients (≥ 18 years of age) 
Post-baseline values will be flagged as notable abnormalities as follows: 
Biochemistry 
1. ALT (SGPT): > 3 x, 5 x, 10 x, and 20 x Upper Limit of Normal (ULN) 1 
2. AST (SGOT): > 3 x, 5 x, 10 x, and 20 x ULN 1 
3. Elevation of AST and/ or ALT (> 3 x ULN) accompanied by elevated bilirubin 
(> 1.5 x ULN, > 2 x ULN) 1 
4. Any elevations of bilirubin; elevated total bilirubin (TBL) to > 2 x ULN 1 
5. Any elevations of ALP > 1.5 x ULN 1 
6. Gamma-Glutamyltransferase (GGT): > 3 x ULN 
7. Creatinine (serum): ≥ 3 x ULN 
8. Creatinine clearance (CrCl) (Cockroft-Gault formula) 2: ≥ 25% decrease from baseline 
9. Triglycerides: > 5 x ULN 
Hematology 
1. Hemoglobin: ≥ 20 g/L decrease from baseline or < 100 g/L 
2. Platelet count 3 
a. CTC Grade 1: < Lower Limit of Normal (LLN) – 75 x 109/L 
b. CTC Grade 2: < 75 – 50 x 109/L 
c. CTC Grade 3: < 50 – 25 x 109/L 
d. CTC Grade 4: < 25 x 109/L 
3. White blood cell count 3 
a. CTC Grade 1: < LLN – 3 x 109/L 
b. CTC Grade 2: < 3 – 2 x 109/L 
c. CTC Grade 3: < 2 – 1 x 109/L 
d. CTC Grade 4: < 1 x 109/L 
4. Absolute neutrophils 3 
a. CTC Grade 1: < LLN – 1.5 x 109/L 
b. CTC Grade 2: < 1.5 – 1 x 109/L 
c. CTC Grade 3: < 1 – 0.5 x 109/L 
d. CTC Grade 4: < 0.5 x 10E9/L 
5. Absolute lymphocytes: < LLN 
6. Absolute eosinophils: ≥ 2.5 x, ≥ 3 x ULN 
Urinalysis 
a. Protein urine dipstick: ≥ ++ 

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Notable laboratory abnormalities in pediatric patients (< 18 years of age) 
Post-baseline values in pediatric patients (at the time of the assessment) will be flagged as 
notable abnormalities as follows: 
Biochemistry 
1. ALT (SGPT): > 3 x, 5 x, 10 x, and 20 x Upper Limit of Normal (ULN) 1 
2. AST (SGOT): > 3 x, 5 x, 10 x, and 20 x ULN 1 
3. Elevation of AST and/ or ALT (> 3 x ULN) accompanied by elevated bilirubin 
(> 1.5 x ULN, > 2 x ULN) 1 
4. Any elevations of bilirubin; elevated total bilirubin (TBL) to > 2 x ULN 1 
5. Any elevations of ALP > 1.5 x ULN 1 
6. GGT: ≥ 3 x, 5 x ULN 
7. Creatinine (serum): ≥ 1.5 x ULN 
8. Creatinine clearance (Schwartz formula 4): ≥ 25% decrease from baseline, ≥ 2 consecutive 
visits 
9. Total Cholesterol: ≥ 1.5 x ULN 
10. Triglycerides: ≥ 5.7 mmol/L 
11. Creatinine clearance (Schwartz formula 4): ≥ 25% decrease from baseline for ≥ 3 months 
in duration in combination with protein urine dipstick resulting in new protein ≥ 1+, ≥ 3 
months in duration 
Hematology 
1. Hemoglobin: ≥ 20 g/L decrease from baseline or < 85 g/L (patients < 16 years of age) or 
< 100 g/L (patients ≥ 16 years of age) 
2. Platelet count 3 
e. CTC Grade 1: < Lower Limit of Normal (LLN) – 75 x 109/L 
f. CTC Grade 2: < 75 – 50 x 109/L 
g. CTC Grade 3: < 50 – 25 x 109/L  
h. CTC Grade 4: < 25 x 109/L 
3. White blood cell count 3 
e. CTC Grade 1: < LLN – 3 x 109/L 
f. CTC Grade 2: < 3 – 2 x 109/L 
g. CTC Grade 3: < 2 – 1 x 109/L 
h. CTC Grade 4: < 1 x 109/L 
4. Absolute neutrophils 3 
e. CTC Grade 1: < LLN – 1.5 x 109/L 
f. CTC Grade 2: < 1.5 – 1 x 109/L 
g. CTC Grade 3: < 1 – 0.5 x 109/L 
h. CTC Grade 4: < 0.5 x 10E9/L 
5. Absolute lymphocytes: < LLN 
6. Absolute Eosinophils: ≥ 1.1 x ULN, ≥ 0.45 x 109/L 
Urinalysis 

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• Protein urine dipstick: ≥+ for ≥ 3 months in duration 
 
1 Adapted from FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(July 2009) 
2 Cockroft-Gault formula (Men): CrCl (mL/min) = [((140-age (years)) x weight (kg)) ∕ (serum creatinine 
(μmol/L) ∕ 88.4) (mg/dL) x 72] 
2 Cockroft-Gault formula (Women): CrCl (mL/min) = [((140-age (years)) x weight (kg)) ∕ (serum 
creatinine (μmol/L) ∕ 88.4) (mg/dL) x 72] x 0.85 
3 Common Terminology Criteria for Adverse Events, US Department of Health and Human Services 
(v4.03: 14-Jun-2010) 
4 Creatinine clearance was derived using the following formula: 
CrCl (mL/min/1.73 m2) = [0.413 x length (cm) ∕ (serum creatinine mg/dl)] (Schwartz et al 2009). 

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14 
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements 
Table 14-1 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
3 × ULN < ALT / AST ≤ 5 × ULN 
1.5 × ULN < TBL ≤ 2 × ULN 
LIVER EVENTS 
ALT or AST > 5 × ULN 
 
ALP > 2 × ULN (in the absence of known bone pathology) 
 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
ALT or AST > 3 × ULN and INR > 1.5 
 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN 
and TBL > 2 × ULN [mainly conjugated fraction] without 
notable increase in ALP to > 2 × ULN) 
 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia 
 
Any adverse event potentially indicative of a liver toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
case a 
Discontinue the study treatment 
immediately 
Hospitalize, if clinically appropriate 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolution c (frequency 
at investigator discretion) 
ALT or AST 
> 8 × ULN 
Discontinue the study treatment 
immediately 
Hospitalize if clinically appropriate 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolution c (frequency 
at investigator discretion) 
> 3 × ULN and 
INR > 1.5 
Discontinue the study treatment 
immediately 
Hospitalize, if clinically appropriate 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolution c (frequency 
at investigator discretion) 
> 5 to ≤ 8 × ULN 
Repeat LFT within 48 hours 
If elevation persists, continue follow-up 
monitoring 
If elevation persists for more than 2 
weeks, discontinue the study drug 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolution c (frequency 
at investigator discretion) 

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Criteria 
Actions required 
Follow-up monitoring 
> 3 × ULN 
accompanied by 
symptoms b 
Discontinue the study treatment 
immediately 
Hospitalize if clinically appropriate 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolution c (frequency 
at investigator discretion) 
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic) 
Repeat LFT within the next week 
If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks  
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
bone pathology) 
Repeat LFT within 48 hours 
If elevation persists, establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
TBL (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
Repeat LFT within 48 hours 
If elevation persists, discontinue the study 
drug immediately 
Hospitalize if clinically appropriate 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolution c (frequency 
at investigator discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic) 
Repeat LFT within the next week 
If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
Jaundice 
Discontinue the study treatment 
immediately 
Hospitalize the patient 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolution c (frequency 
at investigator discretion) 
Any AE potentially 
indicative of a liver 
toxicity* 
Consider study treatment interruption or 
discontinuation 
Hospitalization if clinically appropriate 
Establish causality 
Investigator discretion 
a Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b (General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after 
a maximum of 6 months, (4) liver transplantation, and (5) death. 

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15 
Appendix 3: Specific Renal Alert Criteria and Actions 
Table 15-1 
Specific Renal Alert Criteria and Actions 
Serum Event 
Serum creatinine increase 
25 - 49% compared to baseline 
Confirm 25% increase after 24-48h 
Follow up within 2-5 days 
Acute Kidney Injury: Serum creatinine increase 
≥ 50% compared to baseline 
Follow up within 24-48h if possible 
Consider study treatment interruption 
Consider patient hospitalization /specialized 
treatment 
Urine Event 
New dipstick proteinuria ≥ 1+ 
Albumin- or Protein-creatinine ratio increase 
≥ 2-fold 
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or 
≥ 3 mg/mmol; 
Protein-creatinine ratio (PCR) ≥ 150 mg/g 
or > 15 mg/mmol 
Confirm value after 24-48h 
Perform urine microscopy 
Consider study treatment interruption / or 
discontinuation 
New dipstick glycosuria ≥ 1+ not due to 
diabetes 
Blood glucose (fasting) 
Perform serum creatinine, ACR 
New dipstick hematuria ≥ 1+ not due to trauma 
Urine sediment microscopy 
Perform serum creatinine, ACR 
For all renal events: 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed  
Monitor patient regularly (frequency at investigator’s discretion) until either: 
 Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.