Clinical trial NCT02059291
Conditions: Hereditary Periodic Fevers
Keywords: Canakinumab, interleukin-1, Hereditary Periodic Fevers, auto-inflammatory diseases
Sponsor: Novartis Pharmaceuticals
Start date: 2014-06-27; Completion date: 2017-07-04
Enrollment: 203 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is to determine whether canakinumab is able to induce and maintain a clinically meaningful reduction of disease activity in participants with Hereditary Periodic Fevers (HPF) compared to placebo.

Detailed description:
This study consists of 3 randomized cohorts (one per condition of colchicine resistant/intolerant Familial Mediterranean Fever (crFMF), Hyper Immunoglobulin D Syndrome (also known as mevalonate kinase deficiency (HIDS/MKD), and Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), and 4 study epochs:

1. Epoch 1: a screening epoch to assess participant's eligibility;
2. Epoch 2: a randomized treatment epoch of 16 weeks where participants are randomized to canakinumab 150 mg every 4 weeks (q4w) or to placebo to obtain efficacy and safety data in a double-blind placebo controlled parallel-arm setting. This epoch contained 2 possible escape options :

   1. early blinded escape option for non responders from Day 8 to Day 28 with here an add-on dose of 150mg canakinumab followed by blinded uptitration at the next scheduled visit (Day 29)
   2. late unblinded escape option for non responders from Day 29 to Day 112; with open-label uptitration
3. Epoch 3: a randomized withdrawal epoch of 24 weeks where canakinumab responders from the randomized treatment epoch were re-randomized to canakinumab 150mg q8w or placebo to assess the potential for canakinumab to maintain clinical efficacy at a reduced dosing frequency;
4. Epoch 4: an open-label treatment epoch of 72 weeks to collect long-term

Arms: arm 1: During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing \<= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing \<= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration. arm 2: During epoch 2, participants received matching placebo to canakinumab 150 mg Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing \<= 40kg) between day 8 and day 28, and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab.

150mg, participants were uptitrated to open-label canakinumab 300 mg. arm 3: During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing \<= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing \<= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration. arm 4: During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing \<= 40kg) between day 8 and day 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg. arm 5: During Epoch 2, participants received canakinumab 150mg (or 2mg/kg for participants weighing \<= 40kg) q4w for 16 weeks. If participants were eligible for blinded escape, they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing \<= 40kg) between day 8 and day 28, and then received blinded uptitration to canakinumab 300 mg q4w from day 29 through day 112. If patients on the highest allowed canakinumab dose of 300 mg (or 4 mg/kg for patients weighing ≤ 40 kg) q4w and re-flared (PGA ≥ 2 and CRP ≥ 30 mg/L) were not eligible for further up-titration arm 6: During epoch 2, participants received matching placebo to canakinumab 150 mg qw4. Participants who required blinded escape,they received a single add-on dose of canakinumab (150 mg or 2mg/kg for participants weighing \<= 40kg) between Day 8 and 28 and then received blinded one dose of placebo and one dose of canakinumab q4w from day 29 through day 112. If flare or re-flare still occurred after receipt of canakinumab 150mg, participants were uptitrated to open-label canakinumab 300 mg.
Interventions: intervention 1: Canakinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Canakinumab solution for subcutaneous injection in vial which contained 150mg/mL canakinumab in 1 mL solution. intervention 2: Matching placebo to canakinumab solution for subcutaneous injection

Protocol documents:
Prot_000.pdf: 
Global Clinical Development – General Medicine 
ACZ885 / Canakinumab 
Clinical Trial Protocol CACZ885N2301 / NCT02059291 
A randomized, double-blind, placebo controlled study of 
canakinumab in patients with Hereditary Periodic Fevers 
(TRAPS, HIDS, or crFMF), with subsequent randomized 
withdrawal/ dosing frequency reduction and open-label 
long term treatment epochs 
Authors: 
 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2013‐004291‐35 
Version number: 
v02 – Clean (Protocol amendment 2) 
Development phase: 
III 
Release date: 
22-Oct-2014
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0, November, 2013 


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Table of contents 
Table of contents ............................................................................................................. 2 
List of tables ................................................................................................................... 5 
List of figures .................................................................................................................. 6 
List of abbreviations ........................................................................................................ 7 
Glossary of terms ............................................................................................................ 9 
Protocol summary ......................................................................................................... 13 
1 
Introduction .................................................................................................................. 17 
1.1 
Background ....................................................................................................... 17 
1.2 
Purpose .............................................................................................................. 18 
2 
Study objectives ............................................................................................................ 19 
2.1 
Primary objective(s) ........................................................................................... 19 
2.2 
Secondary objectives ......................................................................................... 19 
2.3 
Exploratory objectives ....................................................................................... 19 
3 
Investigational plan ....................................................................................................... 20 
3.1 
Study design ...................................................................................................... 20 
3.1.1 
Screening epoch (Epoch 1) ................................................................ 24 
3.1.2 
Randomized treatment epoch (Epoch 2) ............................................. 24 
3.1.3 
Randomized withdrawal epoch (Epoch 3) .......................................... 27 
3.1.4 
Open-label treatment epoch (Epoch 4) ............................................... 28 
3.2 
Rationale of study design ................................................................................... 29 
3.3 
Rationale of dose/ regimen, route of administration and duration of treatment.... 29 
3.4 
Rationale for choice of comparator .................................................................... 30 
3.5 
Purpose and timing of interim analyses/design adaptations ................................ 30 
3.6 
Risks and benefits .............................................................................................. 31 
4 
Population ..................................................................................................................... 31 
4.1 
Inclusion criteria ................................................................................................ 32 
4.1.1 
Criteria applicable for all cohorts ....................................................... 32 
4.1.2 
Criteria applicable for patients with TRAPS (cohort 1) ...................... 32 
4.1.3 
Criteria applicable for patients with HIDS (cohort 2) ......................... 32 
4.1.4 
Criteria applicable for patients with crFMF (cohort 3) ........................ 33 
4.2 
Exclusion criteria ............................................................................................... 34 
5 
Treatment ...................................................................................................................... 37 
5.1 
Protocol requested treatment .............................................................................. 37 
5.1.1 
Investigational treatment .................................................................... 37 


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5.1.2 
Additional study treatment ................................................................. 37 
5.2 
Treatment arms .................................................................................................. 37 
5.3 
Treatment assignment, randomization ................................................................ 38 
5.4 
Treatment blinding............................................................................................. 39 
5.5 
Treating the patient ............................................................................................ 39 
5.5.1 
Patient numbering .............................................................................. 39 
5.5.2 
Dispensing the investigational treatment ............................................ 40 
5.5.3 
Handling of study treatment ............................................................... 40 
5.5.4 
Instructions for prescribing and taking investigational treatment ........ 41 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 41 
5.5.6 
Rescue medication ............................................................................. 41 
5.5.7 
Concomitant treatment ....................................................................... 42 
5.5.8 
Prohibited Treatment ......................................................................... 42 
5.5.9 
Discontinuation of study treatment ..................................................... 42 
5.5.10 
Withdrawal of consent ....................................................................... 43 
5.5.11 
Loss to follow-up ............................................................................... 43 
5.5.12 
Emergency breaking of assigned treatment code ................................ 44 
5.5.13 
Study completion and post-study treatment ........................................ 44 
5.5.14 
Early study termination ...................................................................... 44 
6 
Visit schedule and assessments...................................................................................... 45 
6.1 
Information to be collected on screening failures ............................................... 54 
6.2 
Patient demographics/ other baseline characteristics........................................... 54 
6.2.1 
Determination of tuberculosis status ................................................... 54 
6.2.2 
Hepatitis screen, HIV screen .............................................................. 55 
6.3 
Treatment exposure and compliance .................................................................. 56 
6.4 
Efficacy ............................................................................................................. 56 
6.4.1 
Physician’s global assessment of Disease activity (PGA) ................... 56 
6.4.2 
Physician’s severity assessment of key disease-specific signs and 
symptoms .......................................................................................... 56 
6.4.3 
Inflammatory markers ........................................................................ 57 
6.4.4 
Resolution of the index flare .............................................................. 57 
6.4.5 
New disease flare ............................................................................... 57 
6.4.6 
Auto-inflammatory Disease Activity Index (AIDAI) .......................... 57 
6.4.7 
Patient/ Parent’s global assessment of disease activity (PPGA) .......... 58 
6.4.8 
Health-related Quality of Life ............................................................ 58 
6.4.9 
Appropriateness of efficacy assessments ............................................ 60 


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6.5 
Safety ................................................................................................................ 60 
6.5.1 
Physical examination ......................................................................... 60 
6.5.2 
Vital signs .......................................................................................... 60 
6.5.3 
Height and weight .............................................................................. 61 
6.5.4 
Laboratory evaluations ....................................................................... 61 
6.5.5 
Electrocardiogram (ECG) .................................................................. 62 
6.5.6 
Pregnancy and assessments of fertility ............................................... 62 
6.5.7 
Appropriateness of safety measurements ............................................ 63 
6.6 
Other assessments .............................................................................................. 63 
6.6.1 
Resource utilization ........................................................................... 63 
6.6.2 
Pharmacokinetics ............................................................................... 63 
6.6.3 
Pharmacodynamics ............................................................................ 64 
6.6.4 
Pharmacogenetics/pharmacogenomics ............................................... 64 
6.6.5 
Immunogenicity ................................................................................. 65 
6.6.6 
Other biomarkers ............................................................................... 66 
7 
Safety monitoring .......................................................................................................... 66 
7.1 
Adverse events................................................................................................... 66 
7.2 
Serious adverse events ....................................................................................... 67 
7.2.1 
Definition of SAE .............................................................................. 67 
7.2.2 
SAE reporting .................................................................................... 68 
7.3 
Liver safety monitoring ...................................................................................... 69 
7.4 
Renal safety monitoring ..................................................................................... 70 
7.5 
Pregnancy reporting ........................................................................................... 71 
8 
Data review and database management ......................................................................... 72 
8.1 
Site monitoring .................................................................................................. 72 
8.2 
Data collection ................................................................................................... 72 
8.3 
Database management and quality control ......................................................... 73 
8.4 
Data Monitoring Committee .............................................................................. 73 
8.5 
Adjudication Committee .................................................................................... 73 
8.5.1 
Infection Adjudication Committee ..................................................... 73 
8.5.2 
Malignancy Adjudication Committee ................................................. 74 
9 
Data analysis ................................................................................................................. 74 
9.1 
Analysis sets ...................................................................................................... 75 
9.2 
Patient demographics and other baseline characteristics ..................................... 76 
9.3 
Treatments ......................................................................................................... 76 


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9.4 
Analysis of the primary variable(s) .................................................................... 76 
9.4.1 
Variable(s) ......................................................................................... 76 
9.4.2 
Statistical model, hypothesis, and method of analysis ......................... 77 
9.4.3 
Handling of missing values/censoring/discontinuations ...................... 77 
9.4.4 
Supportive analyses ........................................................................... 77 
9.4.5 
Sensitivity analyses ............................................................................ 78 
9.5 
Analysis of secondary variables ......................................................................... 78 
9.5.1 
Secondary efficacy variables .............................................................. 78 
9.5.2 
Exploratory efficacy variables ............................................................ 80 
9.5.3 
Safety variables.................................................................................. 82 
9.5.4 
Resource utilization ........................................................................... 83 
9.5.5 
Pharmacokinetics ............................................................................... 83 
9.5.6 
Pharmacogenetics/pharmacogenomics ............................................... 83 
9.5.7 
Biomarkers ........................................................................................ 83 
9.5.8 
PK/PD ............................................................................................... 84 
9.6 
Interim analyses ................................................................................................. 84 
9.7 
Sample size calculation ...................................................................................... 84 
10 Ethical considerations ................................................................................................... 85 
10.1 
Regulatory and ethical compliance ..................................................................... 85 
10.2 
Informed consent procedures ............................................................................. 85 
10.3 
Responsibilities of the investigator and IRB/IEC ............................................... 86 
10.4 
Publication of study protocol and results ............................................................ 86 
11 Protocol adherence ........................................................................................................ 86 
11.1 
Protocol Amendments ........................................................................................ 87 
12 References .................................................................................................................... 87 
13 Appendix 1: Clinically notable laboratory values and vital signs ................................... 89 
14 Appendix 2: Liver event and Laboratory trigger definitions and follow-up 
requirements ................................................................................................................. 92 
15 Appendix 3: Blood Collection Log ................................................................................ 95 
16 Appendix 4: Level of TB risk ........................................................................................ 96 
 
List of tables 
Table 3-1 
Criteria for add-on injection or up-titration in Epoch 2 ....................... 26 
Table 5-1 
Prohibited treatment ........................................................................... 42 


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Table 6-1 
Assessment schedule: Screening epoch (Epoch 1) and randomized 
treatment epoch (Epoch 2) ................................................................. 46 
Table 6-2 
Assessment schedule: Randomized withdrawal epoch (Epoch 3) 
and open-label treatment epoch (Epoch 4) .......................................... 50 
Table 7-1 
Specific Renal Alert Criteria and Actions ........................................... 71 
Table 14-1 
Liver event and laboratory trigger definitions ..................................... 92 
Table 14-2 
Follow up requirements for liver events and laboratory triggers ......... 92 
Table 15-1 
Blood Collection Log for PK, PD and Immunogenicity Samples ........ 95 
 
List of figures 
Figure 3-1 
Overall study design .......................................................................... 22 
Figure 3-2 
Cohort detail: Screening (Epoch 1) and randomized treatment 
Epoch 2.............................................................................................. 23 
Figure 3-3 
Cohort detail: Randomized withdrawal Epoch 3 and open-label 
treatment Epoch 4 .............................................................................. 23 
 


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List of abbreviations 
AE 
Adverse Event 
AIDAI 
Auto-Inflammatory Disease Activity Index 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BCG 
Bacillus Calmette-Guérin 
b.i.d. 
Twice a day 
CAN 
Canakinumab 
CFR 
US Code of Federal Regulations  
CDS 
Core Data Sheet (for marketed drugs)  
CRF 
Case Report/Record Form (paper or electronic) 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CTC 
Common Toxicity Criteria 
CTRD  
Clinical Trial Results Database  
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
FMF 
Familial Mediterranean Fever 
GCP 
Good Clinical Practice 
GTL 
Global Trial Lead 
HIDS 
Hyper IgD Syndrome 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
i.v. 
Intravenous 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LFT 
Liver function test (raised serum transaminases and/or bilirubin levels) 
MedDRA 
Medical dictionary for regulatory activities  
OC/RDC 
Oracle Clinical/Remote Data Capture 


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o.d. 
Once a day 
p.o. 
Oral(ly) 
PGA 
Physician’s Global Assessment of Disease Activity 
PPD 
Purified Protein Derivative 
PPGA 
Patient’s/ Parent’s Global Assessment of Disease Activity 
PSW 
Premature Subject Withdrawal 
q4w 
Every 4 weeks 
q8w 
Every 8 weeks 
QFT-GIT 
QuantiFERON®-TB Gold In-Tube 
SAE 
Serious Adverse Event 
SJIA 
Systemic Juvenile Idiopathic Arthritis 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TB 
Tuberculosis 
TD 
Investigational Treatment Discontinuation 
TRAPS 
TNF-receptor Associated Periodic Syndrome 
WHO 
World Health Organization  


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Glossary of terms 
 
Add-on therapy 
Possibility for patients based on clinical condition, to receive a 
single add-on s.c. injection of canakinumab (150 mg s.c. [or 
2 mg/kg for patients ≤40 kg]) between Day 8 and Day 28 without 
unblinding the initial randomized treatment. Add-on therapy can 
be given only once from Day 8 to Day 28. 
Assessment 
A procedure used to generate data required by the study 
Cohort  
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time 
Control drug 
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the trial 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Epoch  
A portion of the study which serves a specific purpose. Typical 
Epochs are: screening/recruitment, wash-out, treatment, and 
follow-up 
Flare 
A new disease flare is defined from Day 29 inclusive as 
simultaneous occurrence of a clinical flare and a serological flare 
defined as follows: 
• PGA ≥2 (clinical flare) 
• CRP ≥30 mg/L (serological flare) 
For patients who achieved resolution of index flare at Day 15, this 
definition will be applied from Day 15. 
Index flare resolution 
Resolution of the index flare is defined as PGA <2, and CRP 
within normal range (≤10 mg/L) or reduction by at least 70% from 
baseline assessed at Day 15. 
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.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination. 
Investigational treatment generally does not include protocol-
specified concomitant background therapies when these are 
standard treatments in that indication. 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT 
system. 
Protocol 
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial. 


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Premature subject withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival. 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
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), active drug run-ins or background 
therapy. 
Study/investigational 
treatment discontinuation 
Point/time when patient permanently stops taking 
study/investigational treatment  for any reason; may or may not 
also be the point/time of premature patient withdrawal. 
Subject Number  
A number assigned to each patient who enrolls into the study  
Up-titration 
If patient’s condition requires dose increase, up-titration will be 
allowed through IRT at scheduled visits from Day 29 onwards. 
Up-titration is done stepwise until the maximum dose of 
canakinumab 300 mg q4w is reached. 
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 


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Amendment 1 
Amendment rationale 
Amendment 1 is issued to address the request from the Medicines and Healthcare Products 
Regulatory Agency (MHRA) in the UK to refer to local label requirement for birth control in 
female of child bearing potential when treated with canakinumab. This non-substantial 
amendment was first implemented in the UK, 
Changes to the protocol 
Changes to the protocol are only related to section 6.5.6 Pregnancy and assessments of 
fertility to reference the use of effective contraception in accordance with locally approved 
prescribing information. 
Amendment 2 
Amendment rationale 
Amendment 2 is issued to address the request from the Paediatric Committee (PDCO) at the 
European Medicines in the framework of respective Pediatric Investigational Plans to include 
patients >28 days in this clinical trial compared to previously ≥2 years of age. Patients >28 
days but <2 years old will enter the study directly into the open-label arm of Epoch 2, but 
won’t be considered toward the total number of patients enrolled for the primary efficacy and 
safety analyses. In addition, this amendment provides more clarity on patient’s management 
for randomized and non-randomized cohorts in accordance with clinical practice. 
Changes to the protocol 
Changes to the protocol are related to the following sections: 
Glossary of terms: updated to provide missing definitions for Add-on therapy, Flare, Index 
flare resolution and Up-titration. 
Protocol summary is updated to reflect changes made to the protocol. 
Section 2.2 Secondary objectives and Section 2.3 Exploratory objectives: revised to correct 
relevant typos and update exploratory objectives to reflect request from PDCO to include 
patients >28 days but <2 years old. 
Section 3.1 Study design and sub-sequent sections are subsequently adjusted: 
• to harmonize the study entry time and treatment for the above mentioned PDCO 
requested population >28 days but <2 years old and Japanese crFMF patients with 
non-exon 10 mutations; 
• to clarify the definition of resolution of the index flare explaining that besides a 70% 
reduction, a normal CRP level (≤10 mg/L) also indicates serologic resolution; 


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• to clarify the blinded escape criteria from Day 8 to Day 14 for patients who experience 
persistent “mild”, “moderate” or “severe” disease activity (i.e., PGA ≥2 [clinical 
flare]), or CRP persistent >10 mg/L with less than 40% reduction from baseline. 
Section 4 Population and sub-sequent sections are revised to reflect the above mentioned 
PDCO request, and to align threshold for liver function tests (ALT and AST) with clinical 
notable laboratory values in mentioned in Section 13 Appendix 1. 
Section 5 Treatment and sub-sequent sections are clarifying patients’ management for 
randomized and non-randomized cohorts and treatment blinding according to revisions in 
Section 3. 
Section 6 Visit schedule and assessments and sub-sequent sections are revised to reflect 
revisions made in Section 3 (criteria for flare definitions). 
Section 9 Data analysis and sub-sequent sections are revised to align with revisions made in 
Section 3. 
Section 13 Appendix 1 Clinically notable laboratory values and Appendix 2 are revised to 
align with criteria used across ACZ885 program. 
Changes to the protocol are shown in the track changes version of the protocol using strike 
through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol are substantial and do require IRB/IEC 
approval prior to implementation. 


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Protocol summary 
Protocol number 
CACZ885N2301 
Title 
A randomized, double-blind, placebo controlled study of canakinumab in patients 
with Hereditary Periodic Fevers (TRAPS, HIDS, or crFMF), with subsequent 
randomized withdrawal/ dosing frequency reduction and open-label long term 
treatment epochs 
Brief title 
Study of efficacy and safety of canakinumab in patients with Hereditary Periodic 
Fevers  
Sponsor and 
Clinical Phase 
Novartis 
Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to determine whether canakinumab is able to induce 
and maintain a clinically meaningful reduction of disease activity after 16 weeks 
of treatment in a greater proportion of patients with TRAPS, HIDS, or crFMF 
compared to placebo. It is further to determine whether, in patients responding to 
the initial dosing regimen, canakinumab will maintain its clinical efficacy if 
administered at a prolonged dosing interval. 
Primary Objective 
The primary objective of the randomized treatment epoch and for the overall 
study is 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. 
Secondary 
Objectives 
 
• 
To evaluate the percentage of patients who achieve a Physician Global 
Assessment of Disease Activity (PGA) <2 (“minimal” or “none”) at Week 16  
• 
To evaluate the percentage of patients with the serologic remission at Week 
16 (defined as C-reactive protein [CRP] ≤10 mg/L) 
• 
To evaluate the percentage of patients with normalized Serum Amyloid A 
(SAA) level at Week 16 (defined as SAA ≤10 mg/L) 
• 
To evaluate the percentage of canakinumab responders in Epoch 2 who 
maintain a clinically meaningful response (absence of new flares) when 
switched to canakinumab every 8 weeks compared to placebo (Epoch 3) 
• 
To evaluate the long-term safety and tolerability and immunogenicity of 
canakinumab  
• 
To evaluate the pharmacokinetics/ pharmacodynamics of canakinumab 
Study design 
This study consists of 3 cohorts (one cohort per condition: TRAPS, HIDS and 
crFMF), and 4 study epochs. 
Each cohort will follow the same study design across the 4 epochs: 
1. A screening epoch to assess patients’ eligibility of up to 12 weeks duration 
(Epoch 1) 
2. A randomized treatment epoch (Epoch 2) of 16 weeks which will provide 
efficacy and safety data in a double-blind placebo-controlled parallel-arm 
setting. This randomized treatment epoch will include 2 possible escape 
options: 
• 
Blinded escape  
• 
Open-label treatment  
3. A randomized withdrawal epoch (Epoch 3) of 24 weeks 


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4. An open-label treatment epoch (Epoch 4) of 72 weeks to collect long-term 
safety data for canakinumab 
Roll-over TRAPS patients previously participating in clinical study 
CACZ885D2203 and/or the subsequent Multiple Patient Program (MPP) 
treatment plan CACZ885D2207M will be allowed to enter the study in Epoch 3. 
Japanese crFMF patients with non-exon 10 mutations and patients >28 days but 
<2 years old will enter the study in the open-label arm of Epoch 2. 
Population 
The study population will consist of male and female patients >28 days and with 
clinically and genetically confirmed Hereditary Periodic Fevers: TRAPS (cohort 
1), HIDS (cohort 2), or crFMF (cohort 3). 
Inclusion criteria 
• Patient’s written informed consent (or parent’s written informed consent in 
case of pediatric patient) at screening 
• Male and female patients at least 2 years of age at the time of the screening 
visit. Male and female patients >28 days but <2 years old at the time of the 
screening visit will be enrolled in the open label arm only. 
• Confirmed diagnosis of TRAPS, HIDS or crFMF at screening 
• Active flare of TRAPS, HIDS or crFMF as evidenced by “mild”, “moderate” or 
“severe” disease activity (PGA ≥2) at randomization 
• CRP >10mg/L (normal CRP range ≤10 mg/L) at randomization 
Exclusion criteria 
• Use of the following therapies (within varying protocol defined timeframes): 
Corticosteroids (oral prednisone) >0.2 mg/kg/day (or greater than the 
maximum of 15 mg/day for children over 60 kg), anakinra, canakinumab, 
rilonacept, tocilizumab, TNF inhibitors, abatacept, tofacitinib, rituximab, 
leflunomide, thalidomide, cyclosporine, intravenous immunoglobulin, 6-
Merceptopurine, azathioprine, cyclophosphamide, or chlorambucil, intra-
articular, peri-articular or intramuscular corticosteroid injections, any other 
investigational biologics  
• History of malignancy of any organ system (other than localized basal cell 
carcinoma of the skin or in-situ cervical cancer), treated or untreated 
• Significant medical diseases, including but not limited to the following: 
a. History of organ transplantation 
b. Elevated alanine aminotransferase (ALT) ≥3x ULN 
c. Elevated aspartate aminotransferase (AST) ≥3x ULN 
d. Increase in total bilirubin defined as per Common Terminology Criteria 
(CTC) Grade ≥2 
e. Serious hepatic disorder (Child-Pugh scores B or C) 
f. 
Chronic Kidney Disease as per NKF stages ≥4 
g. Thyroid disease 
h. Diagnosis of active peptic ulcer disease 
i. 
Coagulopathy 
j. 
Significant CNS effects including vertigo and dizziness 
• Any conditions or significant medical problems which immunocompromise the 
patient and/ or places the patient at unacceptable risk for immunomodulatory 
therapy, e.g. 
a. Absolute neutrophil count decreased as per CTC Grade ≥1 
b. Thrombocytopenia CTC Grade ≥1 
c. Any active or recurrent bacterial, fungal (with exception of 
onychomycosis) or viral infection 


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d. HIV infection, Hepatitis B or Hepatitis C infections 
e. Presence of tuberculosis 
f. 
Requirement for administration of antibiotics against latent TB 
g. Clinical evidence or history of multiple sclerosis or other demyelinating 
diseases, or Felty’s syndrome 
• Live vaccinations within 3 months prior to the start of the trial, during the trial, 
and up to 3 months following the last dose 
Investigational 
and reference 
therapy 
• Canakinumab 
• Placebo 
Efficacy 
assessments 
• PGA 
• Physician’s severity assessment of key disease-specific signs and symptoms 
• Rescue medication use 
• Review eDiary instructions 
• Patient/Parent Global Disease Activity (PPGA) 
• Auto-Inflammatory Disease Activity Index (AIDAI) 
Safety 
assessments 
• Physical examination 
• Vital signs 
• ECG 
• Hematology, clinical chemistry, urinalysis 
• Adverse events 
• Immunogenicity 
Other 
assessments 
• Pharmacokinetics 
• Pharmacodynamics 
• SF-12® (to be completed by patients ≥18 years of age at Baseline) 
• CHQ-PF50© (to be completed by patients >5- <18 years of age at Baseline) 
• Sheehan Disability Scale version 3 
Data analysis 
Each cohort (TRAPS, HIDS, crFMF) of the study will have its own primary and 
secondary efficacy variables analyzed separately and independently of the other 
cohorts.  
If the primary objective is achieved, all secondary endpoints in the randomized 
treatment epoch (epoch 2) will be assessed in a hierarchical testing procedure to 
evaluate the superiority of canakinumab q4w over placebo. This is performed in 
order to control the overall Type I error rate (α = 0.025, one sided tests) in the 
evaluation of these secondary efficacy variables. Testing is continued as long as 
each test showed statistical significance at the 2.5% level. 
The following hypotheses will be included the hierarchical testing procedure: 
• H1: canakinumab q4w is not different to placebo with respect to responder 
rate (defined as resolution of the index flare at day 15 and no new disease 
flare over the 16 weeks) at Week 16. 
• H2: canakinumab q4w is not different to placebo with respect to the 
percentage of patients with PGA < 2 at Week 16. 
• H3: canakinumab q4w is not different to placebo with respect the percentage 
of patients with CRP ≤10 mg/L at Week 16 
• H4: canakinumab q4w is not different to placebo with respect the percentage 
of patients with SAA ≤10mg/L at Week 16. 


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If all secondary objectives in the randomized treatment epoch are achieved, 
then the secondary objective in the randomized withdrawal/ dose reduction 
epoch (Epoch 3) will be tested. 
• H5: Canakinumab q8w is not different to placebo with respect to the 
percentage of responders (absence of new flares) at Week 40. 
The canakinumab treatment group will be compared to placebo with respect to 
the proportion of responders at Week 16 using the Fisher’s exact test. The 
proportion of responders, as well as the odds ratio and risk difference with 
corresponding 97.5% confidence interval will be presented. Between-treatment 
differences for the proportion of patients with PGA <2, CRP ≤10mg/L and SAA 
≤10 mg/L at Week 16 will be analyzed using a logistic regression model with 
treatment group, and baseline PGA, CRP and SAA values as explanatory 
variables. 
The canakinumab treatment group will be compared to placebo with respect to 
the proportion of responders at Week 40 using the Fisher’s exact test. 
Key words 
Canakinumab, interleukin-1, Hereditary Periodic Fevers, TRAPS, HIDS, crFMF, 
auto-inflammatory diseases 


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1 
Introduction 
1.1 
Background 
Hereditary Periodic Fevers (HPF), 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) and Familial Mediterranean Fever (FMF) (Drenth et al, 2001; 
Goldbach-Mansky, 2012; Stojanov et al, 2005; Touitou et al, 2008). There are currently no 
approved treatments for TRAPS, HIDS 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, 2012; 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 (Hoffmann et al, 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, 2012). 
As of 30th June 2013, approximately 8’213 patients (565 of pediatric age) received ILARIS 
treatment in Novartis-sponsored investigational clinical trials in a wide spectrum of IL-1β 
driven diseases such as: Cryopyrin-associated periodic syndromes (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 2’358.4 patient-treatment-years (Investigator Brochure Edition 12.0).  
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; Kone-Paut et al, 2011) 


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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 
addition, canakinumab has been shown to be effective in isolated case reports and preliminary 
studies of HPF (Gattorno et al, 2012; Gul et al, 2012). 
In over 60 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 
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 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.  
1.2 
Purpose 
The purpose of this study is to determine whether canakinumab at a starting dose of 150 mg 
s.c. (or 2 mg/kg for patients ≤40 kg) administered every 4 weeks is able to induce and 
maintain a clinically meaningful reduction of disease activity after 16 weeks of treatment in a 
greater proportion of patients with TRAPS, HIDS, or crFMF compared to placebo. In addition, 
it will determine the efficacy and safety of a dose individualization (up-titration) up to a 
maximum of 300 mg (or 4 mg/ kg for patients ≤40 kg) every 4 weeks, in case of lack or 
incomplete response to the initial dosing regimen. 
It is further to determine whether, in patients responding to the initial dosing regimen of every 
4 weeks, canakinumab will maintain its clinical efficacy if administered at a prolonged dosing 
interval of 150 mg s.c. (or 2 mg/kg for patients ≤40 kg) every 8 weeks. 


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Data from this study are planned to support a supplemental registration of canakinumab for 
treatment of active TRAPS, HIDS or crFMF with a dosing regimen consistent with the 
exposure range approved for CAPS. 
2 
Study objectives 
2.1 
Primary objective(s) 
The primary objective of the randomized treatment epoch and of the overall study is to 
demonstrate that canakinumab treatment at a dose of 150 mg (or 2 mg/kg in patient weighing 
≤ 40 kg) s.c. 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. 
2.2 
Secondary objectives 
The secondary objectives of the study are: 
• To evaluate the percentage of patients who achieve a Physician Global Assessment of 
Disease Activity (PGA) <2 (“minimal” or “none”) at Week 16  
• To evaluate the percentage of patients with the serologic remission at Week 16 (defined as 
C-reactive protein [CRP] ≤10 mg/L) 
• To evaluate the percentage of patients with normalized Serum Amyloid A (SAA) level at 
Week 16 (defined as SAA ≤10 mg/L) 
• To evaluate the percentage of canakinumab responders in Epoch 2 who maintain a 
clinically meaningful response (absence of new flares) when switched to canakinumab 
every 8 weeks compared to placebo (Epoch 3) 
• To evaluate the long-term safety and tolerability and immunogenicity of canakinumab  
• To evaluate the pharmacokinetics/ pharmacodynamics of canakinumab 
2.3 
Exploratory objectives 
The exploratory objectives of the study are: 
• To explore the profile in CRP and SAA over time 
• To explore the PGA and Patient/ Parent’s global assessment of disease activity (PPGA) 
profiles over time 
• To explore the Physician’s Severity Assessment of Disease Signs and Symptoms over 
time 
• To explore the percentage of patients with the serologic remission defined as normalized 
SAA level in all patients who remain on randomized treatment or require blinded rescue 
over time 
• To explore the percentage of patients who require blinded escape from Days 8 to 28 
• To explore the number and duration of fever episodes by mean of patient diaries over time 


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• To explore the time to first new flare in responders in Epoch 2 switched to canakinumab 
every 8 weeks compared to placebo (Epoch 3) 
• To evaluate the number of flares by patient and by Epoch 
• To explore the use of rescue medication over time 
• To explore percentage of patients who are able to reduce their corticosteroid maintenance 
dose at the end of each study epoch 
• To explore the improvement in renal function and/ or proteinuria in patients with impaired 
renal function (eGFR <89 mL/min/1.73 m2) and/ or proteinuria at Baseline 
• To explore the effect of the canakinumab-induced change of disease activity levels on 
aspects of Health-related Quality of Life. The following questionnaires will be used: 
• Auto-Inflammatory Disease Activity Index (AIDAI) 
• SF-12 Health Survey (SF-12) to be completed by patients ≥18 years of age at 
Baseline 
• Child Health Questionnaire – Parent Form 50 (CHQ-PF50) to be completed by 
patients >5 - <18 years of age at Baseline 
• Sheehan Disability Scale version 3 (SDS v3) 
• To explore the relationships between disease-associated genetic mutations and drug 
response 
• To explore the safety and efficacy of canakinumab in the non-randomized group of 
Japanese crFMF patients with non-exon 10 mutations, or patients >28 days but <2 years 
old entering the study in the open-label arm of Epoch 2, and in the roll-over TRAPS 
patients previously participating in clinical study CACZ885D2203 and/or the subsequent 
Multiple Patient Program (MPP) treatment plan CACZ885D2207M entering the study 
directly in the open-label arm of Epoch 3 
3 
Investigational plan 
3.1 
Study design 
Together with CAPS, the conditions of TRAPS, HIDS and crFMF are a well characterized 
subset within the broader family of auto-inflammatory diseases. 
The rationale for an umbrella protocol enrolling patients with these 3 conditions is based upon 
their similarity with CAPS, and is additionally based on: 
• The shared clinical features, pathophysiology, and translational evidence of the efficacy of 
IL-1 inhibition 
• The availability of preliminary data on the efficacy and safety of canakinumab in the 
open-label proof of concept studies in the 3 target diseases 
• The availability of safety data in patients with a spectrum of auto-inflammatory diseases 
(e.g. CAPS and SJIA). 
• The ability to make use of the specialized, expert diagnosis/treatment centers, where 
pediatric and adult patients with these conditions are usually referred 


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This study consists of 3 cohorts (one cohort per condition: TRAPS, HIDS and crFMF), and 4 
study epochs as illustrated in Figure 3-1. The cohort details of the study design are shown in 
Figure 3-2 and Figure 3-3. In order to provide access to treatment, roll-over TRAPS patients 
previously participating in clinical study CACZ885D2203 and/or the subsequent Multiple 
Patient Program (MPP) treatment plan CACZ885D2207M will be allowed to enter the study 
in Epoch 3 and the Japanese crFMF patients with non-exon 10 mutations or patients >28 days 
but <2 years old will enter the study in the open-label arm of Epoch 2. 
Each cohort will follow the same study design across the 4 epochs: 
1. A screening epoch to assess patients’ eligibility of up to 12 weeks duration (Epoch 1) 
2. A randomized treatment epoch (Epoch 2) of 16 weeks which will provide efficacy and 
safety data in a double-blind placebo-controlled parallel-arm setting.  
This randomized treatment epoch will include 2 possible escape options: 
a. Blinded escape from Day 8 to Day 28 
b. Open-label treatment from Day 29 to Day 112 
3. A randomized withdrawal epoch (Epoch 3) of 24 weeks where Canakinumab responder 
patients will be re-randomized to canakinumab 150 mg q8w or Placebo 
4. An open-label treatment epoch (Epoch 4) of 72 weeks to collect long-term safety data for 
canakinumab 
The non-randomized patient group including Japanese crFMF patients with non-exon 10 
mutations and patients >28 days but <2 years old will follow the following study design 
across the 4 epochs: 
1. A screening epoch to assess patients’ eligibility of up to 12 weeks duration (Epoch 1) 
2. An open-label epoch of 16 weeks (Epoch 2) 
3. An open-label epoch of 24 weeks (Epoch 3) 
4. An open-label treatment epoch of 72 weeks to collect long-term safety data for 
canakinumab (Epoch 4) 
 


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Figure 3-1 
Overall study design 
 
 
 


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Figure 3-2 
Cohort detail: 
Screening (Epoch 1) and randomized treatment Epoch 2 
 
Figure 3-3 
Cohort detail: 
Randomized withdrawal Epoch 3 and open-label treatment Epoch 4 
 
Screening epoch
│<--- (Epoch 1) --->
CAN 150 q4w
Placebo
CAN 150 q4w
CAN 300 q4w
Randomized treatment epoch
│<--------------------------------------------- (Epoch 2) ------------------------------------------------>│
n = 30
n = 30
= active treatment
= placebo
Day 1
Day 85
Week 13
Day 57
Week 9
Day 29
Week 5
Day 113
Week 17
Day -84
to
Day -3
Period when patients are eligible for blinded escape: add-on CAN 150 mg q4w
(on/ after Day 29, patients are eligible for open-label escape up to CAN 300 mg q4w)
Day 15
Week 3
CAN 150 q4w
= Randomized treatment (canakinumab)
= Blinded escape
= Open-label treatment arm
Change of treatment arm, i.e.
up-titration due to re-flare
= Randomized treatment (placebo)
CAN 150 q4w
Placebo
CAN 150 q4w
CAN 300 q4w
Open-label treatment epoch
│<-------------------------- (Epoch 4) -------------------------->│
= active treatment
= placebo
Day
281
Day
169
Day
785
= Open-label treatment q8w
= Open-label treatment q4w
Day
113
CAN 150 q4w
= Randomized treatment (canakinumab)
= Blinded escape (in randomized treatment epoch)
= Open-label escape (in randomized treatment epoch)
Randomized
treatment epoch
<--------- (Epoch 2) --------->
Day
225
Randomized
withdrawal epoch
│<------------- Epoch 3 ------------>
Day
337
Day
449
Day
505
Day
561
Day
617
Day
673
Day
393
Day
729
Placebo
CAN 150 q8w
Day
141
Day
197
Day
253
CAN 300 q4w
CAN 300 q8w
CAN 150 q8w
CAN 150 q4w
= Change of treatment arm
at end of epoch
= Up-titration due to re-flare
= Randomized treatment (placebo)
Day 1


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3.1.1 
Screening epoch (Epoch 1) 
A screening epoch of up to 12 weeks will be used to assess the eligibility (flare frequency/ 
disease activity periodicity) to one of the three study cohorts, allow patients to achieve 
significant biologic washout and to taper off non-allowed medications and/ or to achieve a 
stable regime with the permitted bridging therapies.  
Patients will be asked to come fasting for screening and all subsequent visits. 
At screening, the investigator will assign a patient to the respective cohort (i.e., TRAPS, 
HIDS or crFMF), or to the non-randomized groups, and will enter the respective condition 
into the IRT (Interactive Response Technology). Patients will receive a symptom diary and 
will be instructed to complete it and contact the site upon the first signs of a disease flare. 
Patients who meet all eligibility criteria and who will show a flare during the screening epoch 
(Epoch 1) will be eligible to enter the randomized treatment epoch (Epoch 2). The date of 
onset of the flare which will result in randomization (index flare) will be entered on the eCRF. 
Patients can be re-screened only once and no study-related re-screening procedure should be 
performed prior to written re-consent by the subject. 
Mis-randomized patients are defined as cases where IRT randomization was performed by the 
site either prematurely or inappropriately prior to confirmation of the patient’s final 
randomization eligibility and no study medication was administered to the patient. Mis-
randomized patients will not be re-screened. 
3.1.2 
Randomized treatment epoch (Epoch 2) 
3.1.2.1 
Randomization 
At baseline, eligible patients will be randomized in a ratio of 1:1 within each cohort to one of 
below 2 treatment arms: 
• Canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) every 4 weeks (q4w) 
• Placebo 
Patients from the non-randomized group will enroll to the open label arm of canakinumab 
150 mg (or 2 mg/kg for patients weighing ≤40 kg) every 4 weeks (q4w). They will be eligible 
for add-on injection and up-titration as described in the following sections but always receive 
open label medication. 
All patients will receive the first subcutaneous injection at Baseline and will return to the site 
every 4 weeks to receive additional injections of investigational treatment for 16 weeks.  
The resolution of the index flare will be assessed at Day 15. Resolution of the index flare is 
defined as PGA <2 (“minimal” or “none”), and CRP within normal range (≤10 mg/L) or 
reduction by at least 70% from baseline. Patients whose index flare has resolved will not be 
up-titrated. If their index flare has not resolved by Day 15, they will be eligible for blinded 
escape (see Section 3.1.2.2). 


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Visits to assess efficacy and safety are scheduled at Day 15, Day 29 and subsequently at 4 
weeks intervals during the randomized treatment epoch. Patients might receive an up-titration 
if they have persistent disease activity or they re-flare before Day 29 (see Section 3.1.2.2) or 
after Day 29 (see Section 3.1.2.3). 
3.1.2.2 
Blinded escape (non-resolution/ early re-flare before Day 29) 
The assignment to blinded escape will be managed by the IRT. 
Patients whose index flare has not resolved by Day 15 will be eligible for blinded escape.  
If patients experience persistent “mild”, “moderate” or “severe” disease activity (i.e., PGA ≥2 
[clinical flare]), or CRP persistent >10 mg/L with less than 40% reduction from baseline from 
Day 8 to Day 14, they will also be eligible for blinded escape at an unscheduled visit. 
In case one of the conditions described above occurs, patients will receive a single add-on s.c. 
injection of canakinumab (150 mg s.c. [or 2 mg/kg for patients ≤40 kg]) from Day 8 to 
Day 28 but will not be unblinded to their randomized treatment (see Table 3-1). This will lead 
to blinded up-titration to the next dosing regimen according to the initial randomized 
treatment and will be initiated from Day 29 onward through IRT. 
• Patients randomized to canakinumab 150 mg q4w will receive 2 injections of 
canakinumab on Days 29, 57 and 85 equaling to a canakinumab 300 mg q4w regimen 
• Patients randomized to placebo will receive 1 injection of canakinumab and 1 injection of 
placebo each on Days 29, 57 and 85 equaling to a canakinumab 150 mg q4w regimen 
If the patient’s condition is not improving after add-on injection, rescue medication should be 
used from Day 15 until treatment is administered at Day 29. All patients on blinded escape 
will be followed-up for efficacy and safety. 
Non-randomized cohort 
Canakinumab naïve Japanese crFMF patients with non-exon 10 mutations or patients >28 
days but <2 years old will initiate open-label treatment receiving canakinumab 150 mg (or 2 
mg/kg for patients weighing ≤40 kg) q4w at Day 1. Index flare resolution will be assessed at 
Day 15. 
Patients experiencing persistent “mild”, “moderate” or “severe” disease activity (i.e., PGA ≥2 
[clinical flare]), or CRP persistent >10 mg/L with less than 40% reduction from baseline from 
Day 8 to Day 28 can receive a single add-on s.c. injection of canakinumab (150 mg s.c. [or 
2 mg/kg for patients ≤40 kg]). If the patient’s condition is not improving after add-on 
injection, rescue medication should be used until the patient’s next visit at Day 29 when study 
treatment will be administered.  
In case of add-on injection, up-titration to canakinumab of 300 mg (or 4 mg/ kg for patients 
weighing ≤40 kg) q4w will be initiated from Day 29 onward through IRT. Those patients will 
not be eligible for any further up-titration but may stay in the study receiving canakinumab of 
300 mg (or 4 mg/ kg for patients weighing ≤40 kg) q4w if they are considered partial 
responders by the investigator. 


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All patients in open label arm will be followed-up for efficacy and safety. 
3.1.2.3 
Open label treatment arm (re-flare on/ after Day 29) 
If on Day 29 or after Day 29, patients still have “mild”, “moderate” or “severe” disease 
activity (PGA ≥2 [clinical flare] and CRP ≥30 mg/L [serological flare]), up-titration to the 
next dosing regimen is allowed and patients will initiate open label escape at the next 
scheduled visit including Day 29 (see Table 3-1). 
The following up-titration will be initiated at the next scheduled visit based on the IRT 
information: 
• Patients randomized to placebo will receive canakinumab 150 mg q4w. If they still have 
“mild”, “moderate” or “severe” disease activity (PGA ≥2 [clinical flare] and CRP 
≥30 mg/L [serological flare]) or re-flare at the next scheduled visit, they will increase the 
dose to canakinumab 300 mg q4w 
• Patients randomized to canakinumab 150 mg q4w will increase the dose to canakinumab 
300 mg (or 4 mg/ kg for patients weighing ≤40 kg) q4w 
Table 3-1 
Criteria for add-on injection or up-titration in Epoch 2 
 
PGA criteria 
CRP criteria 
Treatment option 
IRT update 
Day 8 to 
14 
Persistent 
PGA ≥2 OR 
CRP persistent >10 
mg/L with less than 
40% reduction from 
baseline 
Add-on injection allowed 
Blinded up-titration 
effective at next 
scheduled visit (Day 
29) 
Day 15 
PGA ≥2 OR 
CRP >10 mg/L and 
no reduction by at 
least 70% from 
baseline 
No Index flare 
resolution* 
Add-on injection allowed 
(only if add-on injection 
was not received earlier) 
Blinded up-titration 
effective at next 
scheduled visit 
Day 16 to 
28 
PGA ≥2 OR 
CRP >10 mg/L and 
no reduction by at 
least 70% from 
baseline 
Add-on injection allowed 
(only if add-on injection 
was not received earlier) 
Blinded up-titration 
effective at next 
scheduled visit 
Day 29 to 
112 
PGA ≥2 AND 
CRP ≥30mg/L 
Up-titration allowed 
Open label up-titration 
effective at next 
scheduled visit 
including Day 29 visit 
* For patient with index flare resolution at Day 15, criteria defined for Day 29 will be applied 
Single Add-on injection is allowed only once in Epoch 2 
For patients who already received blinded escape prior to Day 29 and require a second up-
titration: 
• Patients randomized to placebo who received blinded escape (150 mg q4w) prior to Day 
29 will receive open-label canakinumab 300 mg q4w 
• Patients randomized to canakinumab 150 mg q4w who received blinded escape (add on 
150 mg q4w) prior to Day 29 must not further up-titrate  


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Patients who are on the highest allowed dose of canakinumab of 300 mg (or 4 mg/ kg for 
patients weighing ≤40 kg) q4w and re-flare (PGA ≥2 and CRP ≥30 mg/L) will not be eligible 
for any further up-titration but may stay in the study receiving canakinumab of 300 mg (or 
4 mg/ kg for patients weighing ≤40 kg) q4w if they are considered partial responders by the 
investigator. If these patients discontinue treatment with canakinumab, they should remain in 
the study for safety follow-up. 
All patients on the open-label treatment arm will be followed-up for safety. 
3.1.3 
Randomized withdrawal epoch (Epoch 3) 
3.1.3.1 
Re-randomization 
All patients randomized to placebo at baseline and completing the randomized treatment 
epoch (Epoch 2) without any re-flare will be considered placebo-responders. To avoid 
exposure to canakinumab which may not be justified in light of the clinical status, these 
patients will be withdrawn from the study treatment. 
Patients who initiated blinded escape or entered the open-label treatment arm in the 
randomized treatment epoch (Epoch 2), non-randomized cohort patients and roll-over TRAPS 
patients will not be re-randomized and will enter the open-label treatment arm in Epoch 3; for 
patient management details refer to Section 3.1.3.2. 
All patients randomized to canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) 
q4w at baseline and completing the randomized treatment epoch (Epoch 2) who did not 
require blinded escape or to enter the open-label treatment arm will be re-randomized in a 
ratio of 1:1 to: 
• Canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) q8w 
• Placebo 
Re-randomized patients will receive the first s.c. injection on Day 113 and will return to the 
site every 8 weeks to receive additional injections of investigational treatment for 24 weeks. 
Visits to assess efficacy and safety are scheduled at 8 weeks intervals during the randomized 
withdrawal epoch (Epoch 3). Patients might receive an up-titration if they re-flare at 
unscheduled visits (see Section 3.1.3.2). 
3.1.3.2 
Open-label treatment arm 
The following additional up-titration (open-label treatment arm) will be allowed and managed 
by the IRT: 
• Patients re-randomized to placebo who re-flare within an interval of less than 8 weeks will 
switch to open-label canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) q4w 
• Patients re-randomized to placebo who re-flare within an interval of more than 8 weeks 
will switch to open-label canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) 
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• Patients re-randomized to canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) 
q8w will revert back to canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) 
q4w in case of a re-flare 
Non responders and non-randomized cohort patients  
Non responders (patients who initiated blinded escape or entered the open-label treatment arm 
in the randomized treatment epoch (Epoch 2)) and non-randomized patients will be switched 
to a q8w dosing interval (keeping their current escape dose [150 mg or 300 mg]). Patients will 
be allowed to revert back to q4w in case of a re-flare. 
Roll-over TRAPS patients 
TRAPS patients previously participating in clinical study CACZ885D2203 and/or the 
subsequent Multiple Patient Program (MPP) treatment plan CACZ885D2207M will be 
allowed to enter the study at Day 113 (Epoch 3) in the open-label treatment arm and continue 
receiving canakinumab based on their current dosing regimen either 150 mg or 300 mg (2 
mg/kg or 4 mg/kg for patients weighing ≤40 kg) q8w. These patients need to be screened 
(Day 1 assessments to be performed) before being eligible for entering Epoch 3 at Day 113. In 
case of experiencing a flare, up-titration will be allowed as specified above in this section. 
3.1.4 
Open-label treatment epoch (Epoch 4) 
All patients who were re-randomized to placebo on Day 113 but completed the randomized 
withdrawal epoch (Epoch 3) without re-flare will enter Epoch 4. They will present for 
scheduled visits but will not receive any investigational drug. In case they re-flare, they will 
enter the open-label treatment arm receiving canakinumab 150 mg (or 2 mg/kg for patients 
weighing ≤40 kg) q8w. In case of experiencing a flare, up-titration will be allowed as 
specified in Section 3.1.3.2. 
All other patients will enter the long-term safety open-label treatment epoch of 72 weeks 
duration. They will continue on their last dosing regimen as administered during the 
randomized withdrawal epoch (Epoch 3). Visits to assess efficacy and safety are scheduled at 
8 weeks intervals during the open-label treatment epoch (Epoch 4). 
In case of re-flares (PGA ≥2 and CRP ≥30 mg/L) before the next scheduled visit, (step-wise) 
up-titration up to a dosing regimen of canakinumab 300 mg (or 4 mg/kg for patients weighing 
≤40 kg) q4w will be allowed. The same principles for up-titration as outlined in Section 
3.1.2.3 or Section 3.1.3.2 will apply. 
No down-titration will be allowed during Epoch 4. 
Visits to assess efficacy and safety are scheduled at 8 weeks intervals during the open-label 
treatment epoch (Epoch 4). Patients might receive an up-titration if they re-flare during Epoch 
4 Patients up-titrated to q4w administration will come back every 4 weeks for unscheduled 
visits at Day 309, Day 365, Day 421, Day 477, Day 533, Day 589, Day 645, Day 701 and Day 
757 in addition to the visits scheduled defined in Table 6-2. 


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3.2 
Rationale of study design 
This study design is customized to this orphan disease area, while the development programs 
conducted so far in similar conditions (i.e., CAPS, SJIA) have been based mostly on open-
label single arm studies and studies with an open-label run-in followed by a randomized 
withdrawal/ dosing frequency reduction. 
One pertinent recent precedence for a placebo controlled randomized parallel group study in 
auto-inflammatory diseases is represented by the tocilizumab registration trial in SJIA (De 
Benedetti et al., 2012). 
This study design with its escape options during the randomized treatment epoch (Epoch 2) 
might provide limited placebo controlled safety data whereas the randomized withdrawal/ 
dose reduction epoch (Epoch 3) will assess the potential of maintaining clinical efficacy at a 
reduced dosing frequency. The open-label treatment epoch (Epoch 4) will provide long-term 
safety data. 
However, safety data will be evaluated open-label within individual cohorts as well as at 
pooled level. 
3.3 
Rationale of dose/ regimen, route of administration and duration 
of treatment 
The initial dosing regimen defined for this protocol (150 mg s.c. or 2 mg/ kg s.c.) is based on 
the evidence from the clinical program in approved indications such as CAPS and the 
completed or ongoing trials in TRAPS, HIDS, and crFMF in light of the shared IL-1 beta-
driven pathophysiology of the disease. 
Because of the rarity of these three conditions no formal dose finding study was conducted 
and the dosing regimens tested in the open-label studies were derived from the investigators’ 
translational experience with other IL-1 inhibitors used off-label and for which usually higher 
doses compared to those used in CAPS were needed to achieve control of disease activity in 
HPF. 
A dosing schedule of 150 mg s.c. every 4 weeks (or 2 mg/kg s.c every 4 weeks for patients 
≤40 kg) has been demonstrated to be highly effective in three (of the four) open-label PoC 
trials, specifically those in TRAPS and crFMF patients. A higher dose (300 mg or 4 mg/kg) 
with a longer interval (every 6 weeks) was tested in HIDS patients and was very effective. 
In this study, an initial dose regimen of 150 mg s.c. (or 2 mg/kg s.c for patients ≤40kg) q4w is 
used to harmonize exposure between these three conditions while allowing for up-titration to 
a maximal dose of canakinumab 300 mg (or 4 mg/kg for patients weighing ≤40 kg) q4w to 
optimize the regimen and thus achieve efficacy in difficult cases. 
In order to evaluate if clinical efficacy can be maintained at a lower dosing frequency, 
canakinumab 150 mg s.c. (or 2 mg/kg s.c for patients ≤40 kg) at a reduced frequency (q8w) 
will be evaluated during the randomized withdrawal epoch (Epoch 3). 


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The dose regimens to be used in the open-label treatment arm (across Epochs 2 – 4) are 
considered to constitute the lowest clinically efficacious doses to maintain clinical efficacy in 
individual patients. 
Of note, the safety profile of canakinumab in CAPS patients has not been observed to change 
with up-titration to 300 mg (or 4 mg/kg s.c. for patients ≤40 kg) every 8 weeks. The safety of 
canakinumab is supported by clinical and post-marketing safety data from CAPS using doses 
up to 600 mg (or 8 mg/kg) every 8 weeks and from SJIA clinical trials which utilized higher 
starting doses of 4 mg/kg every 4 weeks. Safety data from all four of the open label PoC trials 
in TRAPS, HIDS and crFMF are consistent with the known safety profile of canakinumab. 
The protocol will include patients as young as 2 years old in the randomized population 
and >28 days but <2 years old in the non-randomized group, while the current trials had a 
minimum age of 4 years. The CAPS experience suggests that patients less than 4 years old 
(<15 kg of weight) often require higher starting doses (4 mg/kg q8w), likely related to their 
relatively higher levels of IL-1β and higher relative prevalence of the more severe phenotype. 
This protocol will use the same 2 mg/kg s.c. dose in pediatric patients <4 years of age (or 
<15 kg of body weight), with the possibility of up-titration based on early assessment of 
clinical response. In CAPS patients up-titration in patients weighing ≤40 kg, is associated 
with transient, non-serious infections common in children (e.g., ear infections, gastroenteritis). 
The same patients did not experience increasing serious infections or hematology 
abnormalities with dose escalations. 
In summary, an initial dose of 150 mg s.c. (or 2 mg/kg s.c. for patients ≤40 kg) q4w is 
expected to provide positive benefit /risk to TRAPS, HIDS or crFMF patients participating in 
this trial by providing exposure to canakinumab which has shown evidence of efficacy in 
prior open label trials and which is often necessary in pediatric patients or in more severe 
clinical phenotypes. The resulting range of exposure is regarded as safe, as previously 
demonstrated in CAPS patients and as observed in the safety profile of patients participating 
in the preliminary studies. 
3.4 
Rationale for choice of comparator 
Currently there are no approved treatment options for the target patient population. Therefore 
there are no ethical concerns with using a placebo comparator, which will provide a good 
estimate of the size of the treatment effect. Thus the use of a placebo comparator with an early 
escape option is appropriate. 
3.5 
Purpose and timing of interim analyses/design adaptations 
If enrollment into the study is completed as scheduled, no interim analysis of the randomized 
treatment epoch (Epoch 2) is planned (see Section 9.6 for details about scenarios which may 
trigger an interim analysis). 
Interim analyses at the end of Epoch 2 and Epoch 3 to support regulatory filing will be 
performed as detailed in Section 9.6. 


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3.6 
Risks and benefits 
In TRAPS, HIDS 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, 2012; Hoffman, 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.  
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, 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 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. 
4 
Population 
The study population will consist of male and female patients >28 days and confirmed 
TRAPS (cohort 1), HIDS (cohort 2), or crFMF (cohort 3). 
It is aimed to randomize a total of 180 patients (60 per cohort, 30 per treatment arm) in 
approximately >20 centers worldwide. Since a 20% screening failure rate is expected, it is 
estimated that approximately 225 patients have to be screened. 
The following patient populations will be screened at Day 1 and directly entered into the 
open-label treatment arm of the randomized withdrawal epoch (Epoch 3) at Day 113: 


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• TRAPS patients previously participating in clinical study CACZ885D2203 or the 
subsequent MPP treatment plan CACZ885D2207M (at most 19 patients). 
In addition, the following patient populations will be screened and will enter into the open-
label treatment arm of the Epoch 2 at Day 1: 
• Male and female patients >28 days but <2 years old with bodyweight ≥3.75 kg 
• Approximately 5 Japanese crFMF patients with non-exon 10 mutations otherwise 
fulfilling all the mandatory inclusion and exclusion criteria. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
4.1.1 
Criteria applicable for all cohorts 
1. Patient’s written informed consent from those ≥18 years of age must be obtained before 
any assessment is performed. Parent or legal guardian’s written informed consent and 
child’s assent, if appropriate, are required before any assessment is performed for patients 
< 18 years of age.  
2. Male and female patients at least 2 years of age at the time of the screening visit. Male and 
female patients >28 days but <2 years old with bodyweight ≥3.75 kg at the time of the 
screening visit will be enrolled in the open label arm only. 
4.1.2 
Criteria applicable for patients with TRAPS (cohort 1) 
At Screening: 
3. Clinical diagnosis of TRAPS but no active flare at the time of screening 
4. Mutation of the TNFRSF1A gene 
5. Chronic or recurrent disease activity periodicity. Recurrent TRAPS patients must have 
experienced more than 6 flares/ year. 
For patients receiving therapy with biologics, this criterion applies to the last 12 months 
before they started any therapy with biologics. 
At Randomization: 
6. Active clinical TRAPS flare as evidenced by “mild”, “moderate” or “severe” disease 
activity (PGA ≥2) 
7. CRP >10 mg/L (Normal CRP range ≤10 mg/L) 
At beginning of randomized withdrawal epoch (Epoch 3) (applicable only for patients 
previously participating in CACZ885D2203 or CACZ885D2207M): 
8. Completion of clinical study CACZ885D2203 and/or 
9. Current participation in MPP treatment plan CACZ885D2207M on a stable dose regimen 
4.1.3 
Criteria applicable for patients with HIDS (cohort 2) 
At Screening: 
10. Clinical diagnosis of HIDS but no active flare at the time of screening 


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11. Genetic/enzymatic diagnosis of HIDS 
12. Prior documented history of ≥3 febrile acute HIDS flares in a 6-month period when not 
receiving prophylactic treatment (e.g. daily anakinra treatment). 
For patients receiving therapy with biologics, this criterion applies to the last 12 months 
before they started any therapy with biologics. 
At Randomization: 
13. Active clinical HIDS flare as evidenced by “mild”, “moderate” or “severe” disease 
activity” (PGA ≥2) 
14. CRP >10 mg/L (Normal CRP range ≤10 mg/L) 
4.1.4 
Criteria applicable for patients with crFMF (cohort 3) 
At Screening: 
15. Diagnosis of type 1 FMF disease according to Tel Hashomer criteria (Livneh et al, 1997) 
but no active flare at the time of screening 
16. At least one of the known MEFV gene exon 10 mutations 
17. One of the following two: 
a. Documented active disease despite colchicine therapy (from a minimum of 1.5 mg up 
to 3.0 mg/day or equivalent pediatric age/ weight adjusted dosing regimen depending 
on Local Guidelines/ standard practice). Patients on current colchicine treatment will 
continue at stable dose during the study. 
b. Documented intolerance to effective doses of colchicine (from a minimum of 1.5 mg 
up to 3.0 mg/day or equivalent pediatric age/ weight adjusted dosing regimen 
depending on Local Guidelines/ standard practice)  
18. Historical data showing a frequency of at least 1 attack/month 
For patients receiving therapy with biologics, this criterion applies to the last 12 months 
before they started any therapy with biologics. 
At Randomization: 
19. Acute crFMF flare characterized by inflammation and serositis in the opinion of the 
investigator, lasting approximately 12 to 72 hours 
20. Active clinical crFMF flare as evidenced by “mild”, “moderate” or “severe” disease 
activity” (PGA ≥2) 
21. CRP >10 mg/L (Normal CRP range ≤10 mg/L)  
Applicable exclusively for Japanese crFMF patients with non-exon 10 mutations: 
At Screening: 
22. Criteria #15, #17, #18 as outlined above  
23. At least one MEFV gene non-exon 10 mutation 
At beginning of Epoch 3: 
24. Criteria #19, #20, and #21 as outlined above 


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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. 
1. 
Use of the following therapies: 
a. Corticosteroids (prednisone equivalent > 0.2 mg/kg/day [or greater than the maximum 
of 15 mg/ day for children over 60 kg]) within 1 week prior to Baseline  
b. Anakinra within 24 hours prior to Baseline  
c. Canakinumab within 3 months prior to Baseline (not applicable for patients rolling-
over from CACZ885D2203/ CACZ885D2207M) 
d. Rilonacept within 4 weeks prior to Baseline  
e. Tocilizumab within 6 weeks prior to Baseline  
f. Etanercept within 2 weeks prior to Baseline 
g. Infliximab within 4 weeks prior to Baseline 
h. Adalimumab within 6 weeks prior to Baseline 
i. Golimumab within 6 weeks prior to Baseline 
j. Certolizumab within 6 weeks prior to Baseline 
k. Abatacept within 7 weeks prior to Baseline  
l. Tofacitinib within 24 hours prior to Baseline  
m. Rituximab within 24 weeks prior to the Baseline  
n. Leflunomide within 8 weeks prior to the Baseline 
Documentation of a completion of a full cholestyramine elimination treatment after 
most recent leflunomide use will be required. 
o. Thalidomide within 4 weeks prior to Baseline  
p. Cyclosporine within 4 weeks prior to Baseline  
q. Intravenous immunoglobulin (i.v. Ig) within 8 weeks prior to Baseline  
r. 6-Merceptopurine, azathioprine, cyclophosphamide, or chlorambucil within 12 weeks 
prior to Baseline  
s. Intra-articular, peri-articular or intramuscular corticosteroid injections within 4 weeks 
prior to Baseline  
t. Any other investigational biologics within 3 half-lives prior to the Baseline visit 
u. Any other investigational drugs, other than investigational biologic treatment, within 
30 days (or 3 months for monoclonal antibodies) or 3 half-lives prior to the Baseline 
visit, whichever is longer 
2. 
History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes or to any of the excipients. 
3. 
History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients participating in the study such as: 


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a. Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker 
b. History of familial long QT syndrome or known family history of Torsades de Pointes 
4. 
Concomitant use of agents known to prolong the QT interval unless it can be 
permanently discontinued for the duration of the study 
5. 
History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases. 
6. 
Significant medical diseases, including but not limited to the following: 
a. Any organ transplant recipient, or patient currently listed for imminent transplant (i.e. 
patients on an administrative transplant waiting list will not be excluded), or admitted 
for any transplantation. 
b. Elevated alanine aminotransferase (ALT) ≥3x ULN (if ALT at screening is >3x but 
<5x ULN, a re-test will be allowed. If ALT at re-test is <3x ULN and confirmed at 
another re-test, the patient will be eligible for participation) 
c. Elevated aspartate aminotransferase (AST) ≥3x ULN (if AST at screening is >3x but 
<5x ULN, a re-test will be allowed. If AST at re-test is <3x ULN and confirmed at 
another re-test, the patient will be eligible for participation) 
d. Increase in total bilirubin (TBL) defined as per CTC Grade ≥2: TBL >1.5x ULN 
e. Serious hepatic disorder (Child-Turcott-Pugh scores B or C) 
f. Chronic Kidney Disease as per NKF stages ≥4: eGFR ≤29 mL/min/1.73 m2 
g. Thyroid disease (unless the patient is taking a stable dose of thyroid hormone or anti-
thyroid medications [hyperthyroidism] for at least 12 weeks), which in the opinion of 
the investigator should exclude the patient from the study 
h. Diagnosis of active peptic ulcer disease as determined by endoscopy, radiography, 
angiography, or other appropriate means within 12 months prior to screening.  
i. Coagulopathy (regardless if controlled by pharmacotherapy or not) 
j. Significant CNS effects including vertigo and dizziness, or major neurologic event, 
including cerebrovascular events, within 60 days of screening  
7. 
Any conditions or significant medical problems which in the opinion of the investigator 
immunocompromises the patient and/ or places the patient at unacceptable risk for 
immunomodulatory therapy, such as: 
a. Absolute neutrophil count (ANC) decreased as per CTC Grade ≥1: Neutrophils <LLN 
– 1.5 x 109/L or below 
b. Thrombocytopenia as per CTC Grade ≥1: Platelets <LLN – 75.0 x 109/L or below 
c. Any active or recurrent bacterial, fungal (with exception of onychomycosis) or viral 
infection 
d. Presence of Human Immunodeficiency Virus (HIV) infection, Hepatitis B or Hepatitis 
C infections based on screening lab results 
e. Clinical evidence or history of multiple sclerosis or other demyelinating diseases, or 
Felty’s syndrome 


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8. 
History or evidence of tuberculosis (TB) (active or latent) infection or one of the risk 
factors TB such as but not limited or exclusive to: 
a. History of any of the following: residence in a congregate setting (e.g. jail or prison, 
homeless shelter, or chronic care facility), substance abuse (e.g. injection or non-
injection); health-care workers with unprotected exposure to patients who are at high 
risk of TB or patients with TB disease before the identification and correct airborne 
precautions of the patient, or 
b. Close contact (i.e. share the same air space in a household or other enclosed 
environment for a prolonged period (days or weeks, not minutes or hours)) with a 
person with active pulmonary TB disease within the last year, or 
c. Evidence of TB infection (active or latent) determined by positive QuantiFERON 
(QFT-TB G In-Tube) test or positive Purified Protein Derivative (PPD) test (≥5 mm 
induration) at screening or within 2 months prior to the screening visit, according to 
the national guidelines. If presence of TB infection (active or latent) is established 
then treatment for TB as per national guidelines must have been initiated or 
completed prior to randomization. In the absence of national guidelines, the following 
has been demonstrated: TB has been treated adequately by antibiotics, cure can be 
demonstrated and risk factors resulting in TB exposure and contracting have been 
removed. 
9. 
Administration of any investigational drug or implantation of investigational device, or 
participation in another trial, within 30 days before screening (not applicable for patients 
rolling-over from CACZ885D2203/ CACZ885D2207M). 
10. Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 
3 months following the last dose 
11. Donation or loss of blood (amount depending on age and weight, 10-20% or more of 
volume, within 8 weeks prior to first dosing, or longer if required by local regulation 
12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test. 
13. 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 6.5.6. 
14. 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 


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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 
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. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Novartis will provide the following investigational treatment: 
1. Canakinumab solution for injection in vial which contains 150 mg/mL canakinumab in 1 
mL solution 
2. Placebo matching the canakinumab solution. 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
5.2 
Treatment arms 
In the randomized treatment epoch (Epoch 2), patients in each cohort will be assigned to one 
of the following 2 treatment arms in a ratio of 1:1 at Baseline: 
1. Canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) q4w 
2. Placebo 
Patients who will be eligible for blinded escape (see Section 3.1.2.2) will receive a single add-
on injection of canakinumab (150 mg [or 2 mg/kg for patients weighing ≤40 kg]) from Day 8 
to Day 28. Patients will then receive below treatment until investigational treatment 
discontinuation (TD)/ premature subject withdrawal (PSW): 


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1. Patients randomized to canakinumab 150 mg q4w will switch to canakinumab 300 mg (or 
4 mg/kg for patients weighing ≤40 kg) q4w 
2. Patients randomized to placebo switch to canakinumab 150 mg (or 2 mg/kg for patients 
weighing ≤40 kg) q4w 
Patients who require additional up-titration (open-label treatment arm as detailed in Section 
3.1.2.3) will switch to canakinumab 300 mg s.c. (or 4 mg/ kg for patients weighing ≤40 kg) 
q4w. 
In the randomized withdrawal epoch (Epoch 3), responders to canakinumab 150 mg (or 2 
mg/kg for patients weighing ≤40 kg) q4w (see Section 3.1.3 for details) will be re-randomized 
on Day 113 in a ratio of 1:1 to: 
1. Canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) q8w 
2. Placebo 
Patients who required up-titration during Epoch 2 will start their participation in Epoch 3 in 
the open-label treatment arm (canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) 
q8w or canakinumab 300 mg (or 4 mg/kg for patients weighing ≤40 kg) q8w. Any up-titration 
in case of lack of therapeutic effect will be allowed as outlined in Section 3.1.3.2. 
Patients from the non-randomized group (patients >28 days but <2 years old) and Japanese 
crFMF patients with non-exon 10 mutations) entering the study at Epoch 2 will receive open-
label canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) q4w. 
TRAPS patients previously participating in CACZ885D2203 or CACZ885D2207M entering 
the study at the beginning of Epoch 3 will be assigned to the open-label treatment arm at a 
dose of canakinumab 150 mg (or 2 mg/kg for patients weighing ≤40 kg) q8w or canakinumab 
300 mg (or 4 mg/kg for patients weighing ≤40 kg) q8w. 
Open-label treatment in Epoch 4 will be handled as detailed in Section 3.1.4. 
5.3 
Treatment assignment, randomization 
At Baseline, all eligible patients within each cohort will be randomized via Interactive 
Response Technology (IRT) to one of the treatment arms. The investigator or his/ her delegate 
will contact the IRT after confirming that the patient fulfills all the inclusion/ exclusion 
criteria. The IRT will assign a randomization number to the patient, which will be used to link 
the patient to a treatment arm and will specify a unique medication number for the first 
package of investigational treatment to be dispensed to the patient. The randomization number 
will not be communicated to the caller. 
At the beginning of the randomized withdrawal epoch (Epoch 3), all eligible patients within 
each cohort will be re-randomized via Interactive Response Technology (IRT) to one of the 
treatment arms. The investigator or his/ her delegate will contact the IRT after confirming that 
the patient qualifies for entering the withdrawal epoch. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 


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automates the random assignment of patient numbers to randomization numbers. 
 
 
 
 
  
Randomization will be stratified by disease cohort. 
 
 
 
Patients from the non-randomized cohort and roll-over TRAPS patients will be assigned to the 
open-label treatment in Epoch 2 and Epoch 3 respectively via IRT. 
In case of add-on injection from Day 8 to Day 28, IRT will assign a unique medication 
number for blinded administration. At the next scheduled visit, the new dosing regimen will 
be initiated by IRT automatically and medication number assigned accordingly. 
In case of up-titration from Day 29 onwards, the new dosing regimen will be initiated by IRT 
automatically at the next scheduled visit (including Day 29 visit) and medication number 
assigned accordingly. 
5.4 
Treatment blinding 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the randomized or re-randomized treatment assignment from the time 
of randomization until database lock, using the following methods: 
1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the following exceptions: 
a. Unblinded lab personnel charged with conducting the PD/ PK and/ or IG assays. 
2. The identity of the treatments will be concealed by the use of investigational treatment 
that are all identical in packaging, labeling, schedule of administration, appearance. 
Unblinding will only occur for placebo responders at the end of the randomized treatment 
epoch (Epoch 2), in the case of patient emergencies (see Section 5.5.12), in case of an interim 
analysis (see Section 9.6) and at the conclusion of the study. 
The randomization codes associated with patients from whom PK samples are taken will be 
disclosed to PK analysts who will keep PK results confidential until data base lock. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
 
 Once 
assigned to a patient, the Subject Number will not be reused.  


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Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site should 
select the CRF book with a matching Subject Number from the EDC system to enter data.  
The previous Subject-ID of TRAPS patients previously participating in CACZ885D2203 or 
CACZ885D2207M will be collected in the CRF. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered into the respective 
electronic CRF page. 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. 
The investigational treatment packaging/ kit has a 2-part label. A unique medication number 
is printed on each part of this label. The kit(s) dispensed will be the appropriate drug and 
quantity appropriate to the respective treatment arm and dose level. Investigator staff will 
identify the investigational treatment package(s) to dispense to the patient by contacting the 
IRT and obtaining the medication number(s). Immediately before dispensing the package to 
the patient, investigator staff will detach the outer part of the label from the packaging and 
affix it to the source document (Drug Label Form) for that patient’s unique subject number. 
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Investigational 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 have access. Upon receipt, all investigational treatment should 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 for the investigational treatment but no 
information about the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational 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 investigational treatment and packaging at the end 
of the study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 


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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 other investigational treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking investigational 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 and provided to each site. 
All patients will receive a first single s.c. injection of investigational treatment at Baseline. 
Following Baseline, patients will receive injections every 4 weeks until Day 113. Those 
patients who will be eligible for blinded escape (Section 3.1.2.2) will receive an additional s.c. 
injection of investigational drug between Day 8 and Day 28. 
Depending on a patient’s treatment assignment, i.e. blinded escape, or open-label treatment 
arm, patients will receive 1 or 2 injections per visit. 
Patients, who will be eligible for randomized withdrawal in Epoch 3, will receive injections 
every 8 weeks till Day 281. 
Patients in the open-label treatment arm (Epoch 2, Epoch 3 and or Epoch 4) will receive 1 or 
2 injections every 4 or 8 weeks, depending upon individual need until TD/ PSW. 
A graphical layout of the patient flow and administration of individual investigational 
treatment doses is shown in Figure 3-2 and Figure 3-3. Details about the doses administered 
are also described in Section 5.2. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
All kits of investigational treatment assigned by the IRT will be recorded/ databased in the 
IRT. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Any other investigational treatment dose adjustments than detailed in Section 3.1.2 (Epoch 2), 
Section 3.1.3 (Epoch 3) or Section 3.1.4 (Epoch 4) and/ or interruptions are not permitted. 
5.5.6 
Rescue medication 
Increase of corticosteroid maintenance dose or intermittent steroid treatment up to the dose 
detailed in Table 5-1 may be used as rescue therapy. 
Standard doses of NSAIDs can be used from Day 15 inclusive on an as needed basis to treat 
the sign and symptoms of TRAPS, HIDS or crFMF during acute flares at the discretion of the 
investigator. Before Day 15, NSAIDs should not be used for treating any signs or symptoms 
of the index flare. 


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Use of rescue medication must be recorded on the concomitant medications page in the CRF. 
5.5.7 
Concomitant treatment 
The investigator should 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 was enrolled into the study must be recorded. 
5.5.8 
Prohibited Treatment 
Use of the treatments displayed in Table 5-1 is NOT allowed after Screening. 
Table 5-1 
Prohibited treatment 
Medication 
Action to be taken 
Corticosteroid maintenance (prednisone 
equivalent > 0.2 mg/ kg/ day or greater than the 
maximum of 15 mg/ day for children over 60 kg). 
Investigational treatment does not need to be 
discontinued as a result of this protocol deviation 
(PD) 
Anakinra 
Investigational treatment to be discontinued2 
Rilonacept, tocilizumab, rituximab and any other 
biologics1 (investigational or marketed) 
Investigational treatment to be discontinued2 
Etanercept, adalimumab, infliximab, or any TNF 
inhibitor (investigational or marketed) 
Investigational treatment to be discontinued2 
Leflunomide, thalidomide, cyclosporine, or i.v. Ig 
Investigational treatment to be discontinued2 
Tofacitinib  
Investigational treatment to be discontinued2 
6-Merceptopurine, azathioprine, 
cyclophosphamide, or chlorambucil 
Investigational treatment to be discontinued2 
Intra-articular, peri-articular or intramuscular 
corticosteroid injections 
Investigational treatment to be discontinued2 
Any other investigational non-biological drug 
Investigational treatment to be discontinued2 
Any live vaccination1 
Investigational treatment to be discontinued2 
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 
Discontinuation of study treatment 
Patients may voluntarily discontinue investigational treatment for any reason at any time. 
The investigator should discontinue investigational treatment for a given patient if, on balance, 
he/she believes that continuation would be detrimental to the patient’s well-being. 
Investigational treatment must be discontinued under the following circumstances:  
• Emergence of the following adverse events: 
a. Absolute QTcF > 500 msec, confirmed by repeat ECG measurements 


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b. Serious infections combined with neutropenia 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 TB 
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 
The appropriate personnel from the site and Novartis will assess whether investigational 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason.  
Patients who discontinue investigational treatment should NOT be considered withdrawn 
from the study. They should return for the assessments indicated by an asterisk (*) in Table 6-
1 or Table 6-2. If they fail to return for these assessments for unknown reasons, every effort 
(e.g. telephone, e-mail, letter) should be made to contact them as specified in Section 5.5.11. 
The investigator must also contact the IRT to register the patient’s discontinuation from 
investigational treatment. 
5.5.10 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biologic material. 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. 
Investigational treatment must be discontinued and no further assessments conducted. All 
biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
5.5.11 
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred. 


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5.5.12 
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, investigational treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study patient who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the IRT. When the investigator contacts the system to break a treatment code for a patient, he/ 
she must provide the requested patient identifying information and confirm the necessity to 
break the treatment code for the patient. The investigator will then receive details of the 
investigational drug treatment for the specified patient and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Global Trial Lead (GTL) that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact his/ 
her backup in cases of emergency when he/ she is unavailable. The investigator will provide 
protocol number, investigational treatment name if available, patient number, and instructions 
for contacting the local Novartis Country Pharma Organization CPO (or any entity to which it 
has delegated responsibility for emergency code breaks) to the patient in case an emergency 
treatment code break is required at a time when the investigator and backup are unavailable. 
5.5.13 
Study completion and post-study treatment 
A patient who completes the baseline visit, is randomized to study drug, continues to 
participate in all required study visits post randomization up to Day 113 and completes all 
required assessments is considered a study completer. Site personnel will complete the 
randomized treatment epoch completion form recording the date the patient last took study 
medication and whether the patient completed or discontinued from the study. 
Enrollment in the screening portion of the study will be closely monitored when the 50th 
patient per cohort has been randomized. Patients still within the screening portion of the study 
will terminate their participation after the 60th, and last, patient per cohort has been 
randomized. 
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. 
5.5.14 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for 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. 


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6 
Visit schedule and assessments 
Table 6-1 (screening epoch [Epoch 1] and the randomized treatment epoch [Epoch 2]) and 
Table 6-2 (randomized withdrawal epoch [Epoch 3] and open-label treatment epoch [Epoch 4]) 
list all of the assessments and indicate with an “x” when the visits are performed.  
Patients are to be seen for all visits, preferably on the designated day. The proposed visit day 
is displayed in Table 6-1 and Table 6-2. 
Patients who prematurely withdraw from Epoch 2 for any reason should be scheduled for a 
visit when all the assessments listed for Day 113 will be performed. 
Patients who prematurely withdraw from Epoch 3 for any reason should be scheduled for a 
visit when all the assessments listed for Day 281 will be performed. 
Patients who prematurely withdraw from Epoch 4 for any reason should be scheduled for a 
visit when all the assessments listed for Day 785 will be performed. 
If a patient refuses to return for these assessments or is unable to do so, every effort should be 
made to contact him/ her by telephone to determine the reason for discontinuation.  
At a minimum, patients will be contacted for safety evaluations and a follow-up visit or phone 
call for SAEs must be performed 30 days following Investigational treatment discontinuation 
(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: 
Screening epoch (Epoch 1) and randomized treatment epoch (Epoch 2) 
Epoch 
Screening 
(Epoch 1) 
Randomized treatment epoch 
(Epoch 2) 
 
Visit 
1 
101 
102 
103 
104 
105 
199 and/ or 
PSW 
Safety 
follow-up 
Week 
 
1 
3 
5 
9 
13 
17 
 
Day 
-84 to -3 
1 
15 
29 
57 
85 
113 
PSW +30 or 8 
weeks after last 
injection1 
Informed consent 
X 
 
 
 
 
 
 
 
Informed consent for pharmacogenetic 
sampling2 
X 
 
 
 
 
 
 
 
Participation in previous study 
CACZ885D2203/ MPP treatment plan 
CAC/885D2207M 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Relevant medical history/ current medical 
conditions 
X 
 
 
 
 
 
 
 
Prior and concomitant medications 
(including vaccination status) 
X 
X 
X 
X 
X 
X 
X 
 
Surgical and medical procedures 
X 
X 
X 
X 
X 
X 
X 
 
Disease characteristics 
X 
 
 
 
 
 
 
 
Determination of TB status: 
QuantiFERON®-TB Gold in Tube (QFT-
GIT) assay, PPD skin test and/ or chest X-
ray (as stipulated by local guidelines) 
X 
 
 
 
 
 
 
 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
HIV screen 
X 
 
 
 
 
 
 
 


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Epoch 
Screening 
(Epoch 1) 
Randomized treatment epoch 
(Epoch 2) 
 
Visit 
1 
101 
102 
103 
104 
105 
199 and/ or 
PSW 
Safety 
follow-up 
Week 
 
1 
3 
5 
9 
13 
17 
 
Day 
-84 to -3 
1 
15 
29 
57 
85 
113 
PSW +30 or 8 
weeks after last 
injection1 
Pregnancy test – Serum* 
(for females of child bearing potential) 
X 
 
 
 
 
 
 
 
Pregnancy test – Urinalysis  
(for females of child bearing potential) 
 
X 
 
 
 
 
 
 
Physical examination* 
S 
S 
 
S 
S 
S 
S 
 
Height 
X 
 
 
 
X3 
 
X3 
 
Weight* 
X 
X 
X 
X 
X 
X 
X 
 
Blood pressure and pulse* 
X 
X 
X 
X 
X 
X 
X 
 
Body temperature* 
X 
X 
X 
X 
X 
X 
X 
 
ECG* 
X 
 
 
 
 
 
X 
 
Index flare onset 
 
X 
 
 
 
 
 
 
PGA 
X 
X 
X 
X 
X 
X 
X 
 
Physician’s severity assessment of key 
disease-specific signs and symptoms 
 
X 
X 
X 
X 
X 
X 
 
Review eDiary instructions 
S 
 
 
 
 
 
 
 
PPGA4 
X 
X 
X 
X 
X 
X 
X 
 
AIDAI4 
X 
X 
X 
X 
X 
X 
X 
 
SF-12® 
(to be completed by patients ≥18 years of 
age at Baseline) 
 
X 
 
X 
 
 
X 
 
CHQ-PF50© 
(to be completed by patients >5 <18 years 
of age at Baseline) 
 
X 
 
X 
 
 
X 
 


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Epoch 
Screening 
(Epoch 1) 
Randomized treatment epoch 
(Epoch 2) 
 
Visit 
1 
101 
102 
103 
104 
105 
199 and/ or 
PSW 
Safety 
follow-up 
Week 
 
1 
3 
5 
9 
13 
17 
 
Day 
-84 to -3 
1 
15 
29 
57 
85 
113 
PSW +30 or 8 
weeks after last 
injection1 
SDS v3 
 
X 
 
 
 
 
X 
 
Hematology* 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistry* 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis* 
X 
X 
X 
X 
X 
X 
X 
 
CRP (local lab)* 
X 
X 
X 
X 
X 
X 
X 
 
SAA* 
X 
X 
X 
X 
X 
X 
X 
 
PD sample (total IL-1β)* 
(pre-dose) 
 
X 
X 
X 
X 
X 
X 
 
PK sample (canakinumab)* 
(pre-dose) 
 
X 
X 
X 
X 
X 
X 
 
IG sample* (pre-dose) 
 
X 
 
X 
 
 
X 
 
Pharmacogenetic sample2 
 
X 
 
 
 
 
 
 
Contact IRT* 
X 
X 
X 
X 
X 
X 
X 
 
Administration of double-blind randomized 
treatment 
 
X 
 
X 
X 
X 
 
 
Administration of blinded-escape 
treatment5 
 
 
X 
X 
X 
X 
 
 
Administration of open-label treatment6 
 
 
 
X 
X 
X 
 
 
Adverse events* 
 
X 
X 
X 
X 
X 
X 
 
Local tolerability* 
 
X 
X 
X 
X 
X 
X 
 
Screening phase disposition form 
 
X 
 
 
 
 
 
 
Study phase completion form 
 
 
 
 
 
 
X 
 


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Epoch 
Screening 
(Epoch 1) 
Randomized treatment epoch 
(Epoch 2) 
 
Visit 
1 
101 
102 
103 
104 
105 
199 and/ or 
PSW 
Safety 
follow-up 
Week 
 
1 
3 
5 
9 
13 
17 
 
Day 
-84 to -3 
1 
15 
29 
57 
85 
113 
PSW +30 or 8 
weeks after last 
injection1 
Follow-up visit or phone call for SAEs* 
 
 
 
 
 
 
 
X 
TD = Investigational treatment discontinuation 
PSW = Premature subject withdrawal 
X = assessment to be recorded on clinical data base 
S = assessment to be recorded on source documentation 
*These assessments are also to be conducted for patients who discontinue  
#These assessments are source documentation only and will not be entered into the CRF 
1 To be performed 30 days following Day 113 or PSW or 8 weeks after last injection of investigational drug, whichever is later for all patients not entering 
Epoch 3 
2 Only applicable for patients > 16 years of age 
3 Only applicable for pediatric patients 
4 The AIDAI and PPGA will be completed by the patient on an electronically diary daily from Screening till TD or PSW 
5 Applicable for patients whose index flare has not resolved by Day 15. Blinded-escape add-on treatment may be initiated from Day 8 to Day 28 
6 Applicable for patients on randomized treatment who flare on/ after Day 29 or patients on blinded-escape who will still have “mild”, “moderate” or 
“severe” disease activity (PGA ≥2 [clinical flare] and CRP ≥30 mg/L [serological flare]) or re-flare 


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Table 6-2 
Assessment schedule: 
Randomized withdrawal epoch (Epoch 3) and open-label treatment epoch (Epoch 4) 
Epoch 
Randomized withdrawal epoch 
(Epoch 3) 
Open-label treatment epoch 
(Epoch 4) 
 
Visit 
201
202
203
204
205
206
299/ 
PSW
301 
302 
303
304
305
306
307
308
309
399/ 
TD/ 
PSW
Safety 
follow-up 
Week 
17 
21 
25 
29 
33 
37 
41 
41 
49 
57 
65 
73 
81 
89 
97 
105
113 
 
Day 
113
141
169
197
225
253
281 
281 
337 
393
449
505
561
617
673
729
785 
TD/ PSW 
+30 or 8 
weeks 
after last 
injection1 
Prior and concomitant 
medications 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Surgical and medical 
procedures 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion/Exclusion Criteria 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test – Serum* 
(for females of child bearing 
potential) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Determination of TB status: 
QFT-GIT assay, PPD skin 
test and/ or chest X-ray (as 
stipulated by local 
guidelines) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Physical examination* 
S2 
S 
 
S 
S 
S 
S 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
Height 
X2 
 
X3 
 
X3 
 
X3 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
Weight* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood pressure and pulse* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body temperature* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Epoch 
Randomized withdrawal epoch 
(Epoch 3) 
Open-label treatment epoch 
(Epoch 4) 
 
Visit 
201
202
203
204
205
206
299/ 
PSW
301 
302 
303
304
305
306
307
308
309
399/ 
TD/ 
PSW
Safety 
follow-up 
Week 
17 
21 
25 
29 
33 
37 
41 
41 
49 
57 
65 
73 
81 
89 
97 
105
113 
 
Day 
113
141
169
197
225
253
281 
281 
337 
393
449
505
561
617
673
729
785 
TD/ PSW 
+30 or 8 
weeks 
after last 
injection1 
ECG* 
X2 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
PGA 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physician’s severity 
assessment of key disease-
specific signs and symptoms 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PPGA4 
X2 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
AIDAI4 
X2 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
SF-12® 
(to be completed by patients 
≥18 years of age at 
Baseline) 
X2 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CHQ-PF50© 
(to be completed by 
patients >5 <18 years of age 
at Baseline) 
X2 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
SDS v3 
X2 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistry* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CRP (local lab)* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SAA* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Epoch 
Randomized withdrawal epoch 
(Epoch 3) 
Open-label treatment epoch 
(Epoch 4) 
 
Visit 
201
202
203
204
205
206
299/ 
PSW
301 
302 
303
304
305
306
307
308
309
399/ 
TD/ 
PSW
Safety 
follow-up 
Week 
17 
21 
25 
29 
33 
37 
41 
41 
49 
57 
65 
73 
81 
89 
97 
105
113 
 
Day 
113
141
169
197
225
253
281 
281 
337 
393
449
505
561
617
673
729
785 
TD/ PSW 
+30 or 8 
weeks 
after last 
injection1 
PD sample (total IL-1β)* 
(pre-dose) 
X2 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
PK sample (canakinumab)* 
(pre-dose) 
X2 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
IG sample* (pre-dose) 
X2 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
Contact IRT* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administration of re-
randomized treatment 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of open-label 
treatment5 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Local tolerability* 
X2 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Screening phase disposition 
form 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study phase completion 
form* 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Follow-up visit or phone call 
for SAEs* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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TD = Investigational treatment discontinuation 
PSW = Premature subject withdrawal 
X = assessment to be recorded on clinical data base 
S = assessment to be recorded on source documentation 
*These assessments are also to be conducted for patients who discontinue  
#These assessments are source documentation only and will not be entered into the CRF 
1 To be performed 30 days following TD or PSW, or 8 weeks after last injection of investigational drug, whichever is later 
2 Only applicable for TRAPS patients rolling-over from CACZ885D2203/ CACZ885D2207M i.e. patients directly entering Epoch 3 following screening 
3 Only applicable for pediatric patients 
4 The AIDAI and PPGA will be completed by the patient on an electronically diary daily till Day 281 or PSW 
5 Patients up-titrated to q4w administration in Epoch 4, will come back every 4 weeks for unscheduled visits at Day 309, Day 365, Day 421, Day 477, Day 
533, Day 589, Day 645, Day 701 and Day 757 in addition to the scheduled visits 
 


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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 
serious adverse event (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: 
date of birth, age, sex, race, ethnicity, source of patient referral, 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. 
6.2.1 
Determination of tuberculosis status 
Determination of TB status will be required before administration of study treatment 
(Table  6-1) and needs to be re-assessed at Day 281 and Day 785 (Table 6-2). 
Selection of the most suitable test or combination of tests for detection of M. tuberculosis 
infection as listed in Section 6.2.1.1, Section 6.2.1.2 and Section 6.2.1.3 should be made as 
defined by local guidelines. 
Any significant findings at screening will be recorded in the “Relevant medical history/ 
Current medical conditions” section of the eCRF. 
Any significant findings after providing written informed consent for participation in the 
study must be recorded as Adverse Events. 
6.2.1.1 
QuantiFERON®-TB Gold In-Tube assay 
A QuantiFERON®-TB Gold In-Tube (QFT-GIT) assay may be carried out by the Central 
Laboratory to assess the TB status of patients. 
This blood-based assay is specific for Mycobacterium tuberculosis and is not influenced by 
previous Bacillus Calmette-Guérin (BCG) vaccination or exposure to other Mycobacteria 
species. This test, in contrast to the Purified Protein Derivative (PPD) skin test, is also 
insensitive to a booster effect since the patient is not exposed to the vaccine. The assay 
measures the production of interferon-gamma and puts it into relation to a negative and a 
positive control sample. Further information is given by (Manuel and Kumar 2008). 


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Details about sample processing are to be described in the Central Laboratory Manual. 
6.2.1.2 
PPD skin test 
A PPD skin test may be initiated to evaluate for an occult infection with TB if required by 
local regulations. The test dose is bioequivalent to 5 tuberculin units (or as according to local 
standard practice) of standard PPD usually injected intradermally into the volar surface of the 
forearm. The injection site will be cleansed and the PPD extract will then be injected into the 
most superficial layer under the skin. If given correctly, the injection should raise a small 
wheal of about 5 mm, which resolves within 10-15 minutes. 
A reaction will be measured in millimeters of induration (hard swelling) after 48h – 72h. A 
PPD skin induration >5 mm is interpreted as positive result. This will determine whether the 
patients have had a significant reaction to the PPD skin test. 
In case of a positive PPD skin test result and the absence of clinical signs of active 
tuberculosis and no history of BCG vaccination, the clinical investigator will, according to 
local guidance, decide whether this subject should undergo further clinical, laboratory and 
radiological examinations before deciding to initiate prophylactic treatment for latent TB 
infection. Level of TB risk is defined in Appendix 4. A chest x-ray or QFT-GIT assay is 
however required to further investigate the nature of the positive PPD skin test as 
recommended by many local guidelines. In case of a negative confirmatory test, the patient is 
eligible for participation/ continuation in the study and no further clinical investigations are 
needed. 
Patients with a positive PPD skin test result may be eligible for participation/ continuation 
only if they have a negative chest x-ray (Section 6.2.1.3) or negative QFT-GIT assay (refer to 
Section 6.2.1.1). 
The investigator will either obtain PPD skin tests on his own and be reimbursed by Novartis 
for its cost or be supplied with them by the Novartis affiliate, depending on the local Novartis 
policy. 
6.2.1.3 
Chest x-ray 
A chest x-ray may be performed if required for a complete TB workup per local regulations. 
6.2.2 
Hepatitis screen, HIV screen 
In order to exclude an active infection such as hepatitis or HIV infection, all patients will 
undergo appropriate testing at the Screening visit unless a negative serology is available 
within 3 months prior to screening.  
All subjects will be screened for Hepatitis B surface antigen (HBsAg) and Hepatitis C virus 
(HCV) antibodies unless negative serologies are available within 3 months prior to screening. 
A copy of the lab report must be placed in the patient’s file. 
Evaluation for HIV seropositivity will be performed, and if positive, confirmation by a second 
technique available at the laboratory site, e.g., Western blot. Appropriate subject counseling 
will be made available by the investigator in the event of a positive finding. Notification of 


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state and federal authorities, as required by law, will be the responsibility of the investigator. 
A copy of the lab report must be placed in the patient’s file. 
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 
Patients for whom study treatment must be permanently discontinued as detailed in 
Section 5.5.9 do not need to complete any of the efficacy assessments listed in this Section 6.4. 
6.4.1 
Physician’s global assessment of Disease activity (PGA) 
Physician’s global assessment of disease activity (PGA) will be assessed as shown in 
Table  6-1 and Table 6-2. 
PGA will be performed prior to the CRP results will be available from the local lab in order to 
prevent bias in the evaluation. 
It is encouraged that one investigator assess the same patient throughout the study to ensure 
consistency between assessments. 
The 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 symptoms 
6.4.2 
Physician’s severity assessment of key disease-specific signs and 
symptoms 
Physician’s severity assessment of key disease-specific signs and symptoms will be assessed 
as shown in Table 6-1 and Table 6-2. 
It is encouraged that one investigator assess the same patient throughout the study to ensure 
consistency between assessments. 
Key signs and symptoms will differ for each individual condition. The following signs and 
symptoms will be assessed:  
1. TRAPS: skin rash, musculoskeletal pain, abdominal pain, eye manifestations 
2. HIDS: lymphadenopathy, aphtous ulcers, abdominal pain 
3. crFMF: chest pain, abdominal pain, arthralgia/arthritis, skin rash 
Physician’s severity assessment of key disease-specific signs and symptoms will be based on 
a 5-point scale: 
• 0 = Absent 


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• 1 = Minimal 
• 2 = Mild 
• 3 = Moderate 
• 4 = Severe 
Fever (body temperature ≥38°C [100.4°F]), a key sign of disease activity will be assessed via 
the vital signs (see Section 6.5.2). 
6.4.3 
Inflammatory markers 
C-reactive protein (CRP) and serum amyloid A (SAA) protein will be measured as shown in 
Table 6-1 and Table 6-2 for all patients regardless of age. 
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. A back-up blood sample should be 
withdrawn and shipped to the central lab for storage for central CRP re-testing if deemed 
necessary. 
SAA will be measured at the central laboratory. 
6.4.4 
Resolution of the index flare 
Resolution of the index flare is defined as follows: 
• PGA <2, and CRP within normal range (≤10 mg/L) or reduction by at least 70% from 
baseline 
The resolution of the index flare will be assessed at Day 15. 
6.4.5 
New disease flare 
From Day 29 onwards, a new disease 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) 
For patients who achieved resolution of index flare at Day 15, this definition will be applied 
from Day 16. 
6.4.6 
Auto-inflammatory Disease Activity Index (AIDAI) 
The Auto-inflammatory Disease Activity Index (AIDAI) score is a valid and simple tool for 
assessing disease activity in TRAPS/ HIDS/ crFMF and CAPS. This tool is easy to use in 
clinical practice and has the potential to be used as a standard efficacy measure in clinical 
trials (Piram et al. 2013). 
The AIDAI will be collected on an electronic diary. 
This instrument needs to be filled out by the patient (for children a parent can assist when 
necessary) daily from Screening till TD/ PSW. Patients will be instructed to complete the 


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AIDAI in the evening. The same evaluator (same patient or parent) should perform the 
assessment throughout the study for consistency. 
The AIDAI diary contains 13 items as follows: (a) fever, ≥38°C (100.4°F); (b) overall 
symptoms; (c) abdominal pain; (d) nausea/vomiting; (e) diarrhea; (f ) headaches; (g) chest 
pain; (h) painful nodes; (i) arthralgia or myalgia; ( j) swelling of the joints; (k) eye 
manifestations; (l) skin rash; (m) pain relief drugs taken. 
All items have to be scored as either yes or no. 
6.4.7 
Patient/ Parent’s global assessment of disease activity (PPGA)  
Patient’s assessment of disease activity (PPGA) will be collected on an electronic diary. 
This instrument needs to be filled out by the patient (for children a parent can assist when 
necessary) daily from Screening till TD/ PSW. Patients will be instructed to complete the 
PPGA in the evening after having completed the AIDAI (Section 6.4.6). The same evaluator 
(same patient or parent) should perform the assessment throughout the study for consistency. 
The investigator or site staff will not be allowed to review the patient’s electronic diary to 
ensure for unbiased data collection. 
The PPGA is based on a 5-point scale: 
• 0 = None/absent (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 symptoms 
6.4.8 
Health-related Quality of Life 
Health-related quality of life (HRQoL) will be assessed by the following instruments: 
• SF-12 Health Survey – Acute version 2 (SF-12v2) to be completed by patients ≥18 years 
of age at Baseline 
• Child Health Questionnaire – Parent Form 50 (CHQ-PF50) to be completed by patients >5 
<18 years of age at Baseline 
• Sheehan Disability Scale version 3 (SDS v3) 
The questionnaires should be completed by the patient and/or parents at the scheduled visits 
before any other clinical assessments. The patient and/or parent should be given sufficient 
space and time to complete the questionnaires. The study coordinator should check the 
questionnaires for completeness and encourage the patient and/or parent to complete any 
missing responses. The questionnaires will be completed on an electronic device, e.g. tablet. 


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6.4.8.1 
Medical Outcome Short Form (12) Health Survey – Acute version 2 
(SF-12v2) 
The purpose of SF-12v2 in this study is to assess the physical and mental functioning of adult 
patients (patients ≥18 years of age at baseline) in this study.  
The SF-12v2 is a widely used instrument to measure generic health status. This 12-item 
questionnaire yields an 8-scale health profile as well as summary measures of individual 
patients. It has proven to be useful in monitoring general and disease-specific populations, 
comparing the relative burden of different diseases, differentiating the health benefits 
produced by different treatments, and in screening of individual patients. 
The SF-12® measures the impact of disease on overall quality of life and consists of eight 
subscales (physical function, pain, general and mental health, vitality, social function, 
physical and emotional health) which can be aggregated to derive a physical-component 
summary score and a mental-component summary score. Scores are determined with the use 
of norm-based methods which standardize scores based on an assessment of the general U.S. 
population free of chronic conditions. 
The SF-12v2 will be completed at visits shown in Table 6-1 and Table 6-2. 
6.4.8.2 
Child Health Questionnaire – Parent Form (CHQ-PF50) 
The CHQ-PF50 is an instrument used to measure HRQoL in children 5 to 17 years of age 
from a parent’s perspective. This questionnaire is to be completed by the parent with no input 
from the patient.  
The CHQ-PF50 has been shown to provide reliable and valid summary (physical and 
psychosocial health) scores for a 14-concept health status and for well-being concepts. This 
instrument is comprised of scales specifically developed for children and adolescents. The 
questionnaire measures the following concepts: Physical functioning, Role/social emotional, 
Role/social behavior, Role/social physical, Bodily pain, General behavior, Mental health, 
Self-esteem, General health perception, Change in health, Parental impact – emotional, 
Parental impact – time, Family activities, and Family cohesion. 
If during participation in this study, the patient turns 18, the parent would continue to 
complete the CHQ-PF50 until the time the patient completes this study. 
The CHQ-PF50 will be completed by the parent at visits shown in Table 6-1 and Table 6-2. 
6.4.8.3 
Sheehan Disability Scale (SDS) 
The Sheehan Disability Scale (SDS) was developed to assess functional impairment in three 
inter-related domains; work/ school, social and family life. It is used by researchers and 
practicing clinicians. 
The SDS is a brief self-reporting tool: The patient rates the extent to which work/ school, 
social life or family responsibilities are impaired by his or her symptoms on a 10-point visual 
analog scale. This 10-point visual analog scale uses spatiovisual, numeric and verbal 


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descriptive anchors simultaneously to assess disability. The range of anchor options addresses 
the various ways that individuals approach rating a continuum. 
The SDS will be completed at visits shown in Table 6-1 and Table 6-2. 
6.4.9 
Appropriateness of efficacy assessments  
The efficacy assessments selected are considered standard for this indication/ patient 
population and have previously been used in the respective canakinumab PoC studies or have 
been validated for use in hereditary recurrent fever syndromes (Piram et al. 2013). 
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 5.5.9. 
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 complete physical 
examination will be performed at Screening (Visit 1). 
A short physical exam will include the examination of general appearance and vital signs. A 
short physical exam will be at all visits starting from Randomization (Visit 101) except where 
a complete physical examination is required (see above).  
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 
Vital signs 
Vital signs will be obtained as shown Table 6-1 and Table 6-2. They will include blood 
pressure (BP), pulse and body temperature measurements. 
Systolic and diastolic BP and radial pulse rate will be assessed after the patient has rested in 
the supine position for at least 3 minutes. Blood pressure should be assessed on the same arm 
each time measurements are taken. These data will be recorded in the CRF. 
Measurement of blood pressure in the pediatric population should be done with the 
appropriate cuff size (see Appendix 1 for more details) and toward the end of the scheduled 
visit, thereby avoiding an increase in blood pressure which could be due to a white coat effect. 
Moreover, the investigator should check whether the pediatric patient is calm before taking 
the blood pressure reading. 


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Body temperature should be measured by validated thermometers as commonly used by sites 
in the respective patient population. The same type of thermometer should be used throughout 
the study. 
6.5.3 
Height and weight 
Height in centimeters (cm) and body weight [to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes] will be measured as shown in Table 6-1 and Table 6-2. 
6.5.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected with the exception of 
CRP which will be assessed locally. Details on the collections, shipment of samples and 
reporting of results by the central laboratory are provided to investigators in the laboratory 
manual. 
Clinically notable laboratory findings are defined in Appendix 1. 
6.5.4.1 
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. Absolute Neutrophil Count (ANC) will be 
calculated by the laboratory.  
Blood volume drawn for pediatric patients will be reduced according to age and weight and is 
specified in the central laboratory manual. 
Hematology samples are to be collected at visits shown in Table 6-1 and Table 6-2. 
6.5.4.2 
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), and uric acid. 
Blood volume drawn for pediatric patients will be reduced according to age and weight and is 
specified in the central laboratory manual. 
Clinical chemistry samples are to be collected at visits shown Table 6-1 and Table 6-2. The 
patient must be in a fasting state at the time of blood sampling. 
6.5.4.3 
Urinalysis 
A midstream urine sample (approx. 30 ml) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments. 


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Semi-quantitative ‘dipstick’ evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes and blood at visits 
shown in Table 6-1 and Table 6-2. Results of the ‘dipstick’ will be entered into the Urinalysis 
CRF. 
If the dipstick result is positive for albumin, nitrite, leucocytes and/ or blood, the sample will 
be sent for microscopic analysis of WBC, RBC and casts. 
6.5.5 
Electrocardiogram (ECG)  
ECGs will be obtained as shown Table 6-1 and Table 6-2. 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula 
(QTcF) should be used for clinical decisions. 
Single 12-lead ECGs are collected. The original ECGs on non-heat-sensitive paper and a 
certified copy on non-heat sensitive paper), appropriately signed, should be collected and 
archived at the study site. 
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs should be performed to confirm the safety finding. Clinically 
significant ECG findings at baseline must be discussed with the sponsor before administration 
with investigational treatment. 
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/ Current medical conditions/ AE eCRF page as appropriate. 
6.5.6 
Pregnancy and assessments of fertility  
6.5.6.1 
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 serum pregnancy test must be performed at the central lab on samples collected from these 
patients as shown in Table 6-1 and Table 6-2. Urine pregnancy testing may be conducted 
locally at the site at randomization. 
If a pregnancy test is positive, the patient must be discontinued from the study treatment and 
followed up according to Section 5.5.9. 
6.5.6.2 
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 


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activity, 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 #14 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. 
6.5.6.3 
Female pediatric patients (<12 years) 
No pregnancy tests are required. 
6.5.7 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments 
6.6.1 
Resource utilization 
No resource/ healthcare utilization information will be collected on patients entered into this 
study. 
6.6.2 
Pharmacokinetics 
Canakinumab concentrations will be analyzed in serum by means of a competitive ELISA 
assay 
 
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. 
For each scheduled PK sample, 2 mL of blood will be drawn into a plain barrier tube to obtain 
1 mL serum (the indicated blood volume will apply for patients > 16 years of age. For 
younger patients, a minimum of 1 mL of blood can be drawn in order to obtain 0.5 mL of 
serum). The sample will be allowed to clot during 45 minutes at room temperature. The serum 
will be obtained by centrifugation at approximately 2500 g for 10 minutes. The sample will be 
split into two aliquots to be transferred into polypropylene screw-cap tubes. Serum tubes will 
be frozen within 90 min of venipuncture and kept at ≤ -18°C pending shipment on dry ice. 
One of the two serum samples is to be kept at the study site as a backup while the other one 
will be shipped to the analytical center. 


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Actual time of dosing and actual times of blood collection have to be recorded on the PK 
blood collection eCRF page. PK samples will be collected as shown in Table 6-1 and 
Table  6-2. For a detailed description of blood sampling, handling, labeling and shipment 
instructions please refer to the Laboratory Manual and the Blood Sampling Log Appendix 3. 
If anaphylactic reactions occur after injection, two more samples (at the time of the event and 
8 weeks later) need to be taken. 
6.6.3 
Pharmacodynamics 
Total IL-1β (sum of free and bound to canakinumab) will be analyzed in serum by means of a 
competitive ELISA assay, 
  
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. 
For each scheduled PD sample, 3 mL of blood will be drawn into a plain barrier tube, to 
obtain 1.5 mL serum (the indicated blood volume will apply for patients > 16 years of age. 
For younger patients, a minimum of 1.5 mL blood can be drawn in order to obtain 0.7 mL of 
serum). The sample will be allowed to clot during 45 minutes at room temperature. The serum 
will be obtained by centrifugation at approximately 2500 g for 10 minutes. The sample will be 
split into two aliquots to be transferred into freezer-proof polypropylene screw-cap tubes. 
Serum tubes will be frozen within 90 min of venipuncture and kept at ≤ -18°C pending 
shipment on dry ice. One of the two serum samples is to be kept at the study site as a backup 
while the other one will be shipped to the central lab. 
Actual time of dosing and actual times of blood collection have to be recorded on the PD 
blood collection eCRF page. PD samples will be collected as shown in Table 6-1 and Table 6-
2.  
For a detailed description of blood sampling, handling, labeling and shipment instructions 
please refer to the Laboratory Manual and the Blood Sampling Log Appendix 3. 
If anaphylactic reactions occur after injection, two more samples (at the time of the event and 
8 weeks later) need to be taken. 
6.6.4 
Pharmacogenetics/pharmacogenomics 
6.6.4.1 
Pharmacogenetics 
The study includes an optional pharmacogenetic component which requires a separate 
signature if the patient agrees to participate. It is required as part of this protocol that the 
Investigator presents these options to the patient.   
 
 
 
 
 
 


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One 10 ml blood sample will be collected at study Baseline in an EDTA tube. After collection, 
the sample must be inverted several times to prevent clotting. If the blood draw at Baseline is 
missed, the sample should be taken at the next visit that a blood draw is already scheduled. 
Only one blood sample should be taken from patients > 16 years of age for this 
pharmacogenetic study. These samples will be shipped to the central lab for DNA extraction. 
The extracted DNA will then be transferred to 
 
Lab manuals will be provided with detailed information on sample collection, handling, and 
shipment. The sample collection date and exact time must be entered on the sample collection 
CRF page. 
 
 
 
6.6.4.2 
Pharmacogenomics 
Not applicable. 
6.6.5 
Immunogenicity 
Anti-ACZ885 antibody concentrations will be assessed in serum.  
For each scheduled IG sample, 2 mL of blood will be drawn into a plain barrier tube, to obtain 
1 mL serum (the indicated blood volume will apply for patients > 16 years of age. For 
younger patients, a minimum of 1 mL of blood can be drawn in order to obtain 0.5 mL of 
serum). The blood sample will be allowed to clot during 45 minutes at room temperature. The 
serum will be obtained by centrifugation at approximately 2500 g for 10 minutes. The sample 
will be split into two aliquots to be transferred into freezer-proof polypropylene screw-cap 
tubes. Serum tubes will be frozen within 90 minutes of venipuncture and kept at ≤ -18°C 
pending shipment on dry ice. 
Actual time of dosing and actual times of blood collection have to be recorded on the IG 
blood collection eCRF page. IG samples will be collected as shown in Table 6-1 and 
Table   6-2. 
For a detailed description of blood sampling, please refer to the Laboratory Manual and the 
Blood Sampling Log Appendix 3. 


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If anaphylactic reactions occur after injection, two more samples (at the time of the event and 
8 weeks later) need to be taken. 
6.6.6 
Other biomarkers 
No other biomarkers will be collected on patients entered into this study. 
7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. AEs also may be detected when they are volunteered by the 
patient during or between visits or through physical examination, laboratory test, or other 
assessments. 
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 should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 
AEs should be recorded in the AEs 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 
a. investigational treatment (no/yes), or 
b. other study treatment (non-investigational) (no/yes), or 
c. both and/ or indistinguishable 


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• its duration (start and end dates) or if the event is ongoing an outcome of not recovered/ 
not resolved should be reported. 
• whether it constitutes a serious AE (SAE – See Section 7.2 for definition of SAE) 
• action taken regarding investigational treatment. 
All AEs should be treated appropriately. Treatment may include one or more of the 
following:  
a. no action taken (i.e. further observation only)  
b. investigational treatment dosage adjusted/ temporarily interrupted  
c. investigational treatment permanently discontinued due to this adverse event  
d. concomitant medication given  
e. non-drug therapy given  
f. patient hospitalized/patient’s hospitalization prolonged  
• its outcome (not recovered/ not resolved; recovered/ resolved; recovering/ resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should 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. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new adverse 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 should 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 AE (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: 
a. routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 


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b. 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 form 
c. 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  
d. social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention. 
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 more severe (see Annex IV, ICH-E2D Guideline). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
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 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. 
If all AEs (serious and non-serious) are captured on the CRF, SAEs are monitored 
continuously and have also special reporting requirements; see Section 7.2.2. 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following TD or PSW, or 8 weeks after last 
injection of study drug, whichever is later must be reported to Novartis within 24 hours of 
learning of its occurrence.  
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form or the electronic Serious Adverse 
Event Form within the Oracle Clinical/Remote Data Capture (OC/RDC) system (where 


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available). The Investigator must assess the relationship to each specific component of the 
study treatment (if the study treatment consists of several components).  
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of awareness of the SAE to the local Novartis Drug Safety and Epidemiology 
Department.  The telephone and fax number of the contact persons in the local department of 
Drug Safety and Epidemiology, specific to the site, are listed in the investigator folder 
provided to each site.  The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a 
follow-up to a previously reported SAE   
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing SAE. These data will automatically be submitted to Novartis Drug Safety & 
Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first.  
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
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 investigational 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 
investigational 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: 
• 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 the standard base liver CRF pages 


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Please refer to Table 14-1 (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 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. 
For the liver laboratory trigger: 
• Repeating the LFT within the next week to confirm elevation. 
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages. 
• If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
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. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages. 
7.4 
Renal safety monitoring 
To ensure patient safety and enhance reliability in determining the nephrotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
renal events has to be followed. 
The following categories of renal AEs have to be considered during the course of the study: 
1. Serum event: confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to 
baseline during normal hydration status 
2. Urine event: New onset (≥1+) proteinuria, hematuria or glucosuria; or doubling in the 
urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine ratio (PCR) (if 
applicable). 
Every renal laboratory trigger or renal event as defined in Table 7-1 should be followed up by 
the investigator or designated personnel at the trial site as summarized below. 


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Table 7-1 
Specific Renal Alert Criteria and Actions 
Renal event 
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 drug 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 drug interruption / discontinuation 
New dipstick glucosuria ≥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: 
1. Document contributing factors in the CRF: co-medication, other co-morbid conditions, and 
additional diagnostic procedures performed 
2. Monitor patient regularly (frequency at investigator’s discretion) until either: 
• 
Event resolution: sCr within 10% of baseline or PCR within 50% of baseline, or 
• 
Event stabilization: sCr level with ±10% variability over last 6 months or PCR stabilization at a 
new level with ±50% variability over last 6 months. 
7.5 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on 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 investigational treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
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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 
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 Electronic 
Case Report Forms using fully validated software that conforms to US CFR 21Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. 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.  
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. 


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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 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. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO). 
Randomization codes and data about all investigational treatment dispensed to the patient and 
all dosage changes will be tracked using an Interactive Response Technology (IRT). The 
system will be supplied by a vendor, who will also manage the database. The database will be 
sent electronically to Novartis (or a designated CRO). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
8.5.1 
Infection Adjudication Committee 
An external, independent Infection Adjudication Committee (IAC) has been formed on a 
program level and will review pertinent data from this trial. 


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The mission of the canakinumab IAC is to independently and blindly review, evaluate and 
categorize new reports of pre-defined infections as they become available during the conduct 
of this trial. 
The members, detailed mission and procedures of the IAC are detailed in the IAC charter 
which is available upon request. 
8.5.2 
Malignancy Adjudication Committee  
An external, independent Malignancy Adjudication Committee (MAC) has been formed on a 
program level and will review pertinent data from this trial. 
The mission of the MAC is to independently and blindly review, evaluate and categorize 
reports of malignancy events across all potential indications and therapeutic areas in the 
canakinumab development program. 
The members, detailed mission and procedures of the MAC are detailed in the MAC Charter 
which is available upon request. 
9 
Data analysis  
All data will be analyzed separately for each independent cohort (TRAPS, HIDS, crFMF). 
Randomized treatment epoch (Epoch 2): 
Treatment arms for the primary efficacy analyses will include canakinumab 150 mg sc q4w 
and placebo.  
For some efficacy endpoints and specific safety endpoints (like AEs or laboratory 
abnormalities), treatment arms will include  
• canakinumab 150 mg q4w 
• placebo 
• canakinumab 150 mg– canakinumab 300  mg q4w 
• placebo – canakinumab 150 mg q4w 
In addition, patients in the canakinumab arm (150 mg q4w) flaring after Week 4 or placebo 
patients flaring after Week 4 or placebo patients flaring after receiving the first escape 
treatment will enter open-label escape and receive up to a maximum of 300 mg (or 4 mg/ kg) 
q4w until the end of study. Only descriptive safety data will be presented after patients enter 
open-label escape. 
Randomized withdrawal epoch (Epoch 3): 
Treatment arms for the safety and efficacy analyses will include, for canakinumab responders 
at the end of the epoch 2: 
• canakinumab 150 mg q8w 
• placebo. 
And the two open-label treatment arms: 


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• canakinumab 150 mg q8w 
• canakinumab 300 mg q8w 
Open-label treatment epoch (Epoch 4): 
Treatment arms for the safety and efficacy analyses will include (taken into account their 
regimen in Epoch 3): 
• placebo - canakinumab 150 mg q8w 
• placebo- canakinumab 150 mg q4w 
• canakinumab 150 mg q8w - canakinumab 150 mg q8w 
• canakinumab 150 mg q8w - canakinumab 150 mg q4w 
• canakinumab 150 mg q8w 
• canakinumab 300 mg q8w 
• canakinumab 300 mg q8w – canakinumab 300 mg q4w 
Safety data for the subgroup of patients coming from ACZ885D2203 and/or the subsequent 
Multiple Patient Program (MPP) treatment plan CACZ885D2207M collected in Epoch 3 and 
4 will separately be reported from the other patients who will be screened and randomized in 
Epoch 2. 
Safety data for the subgroup of canakinumab naïve Japanese crFMF patients with non-exon 
10 mutations, and patients >28 days but <2 years old, collected in Epoch 2, 3 and 4 will 
separately be reported from the other patients who will be screened and randomized in 
Epoch 2. Summary statistics for continuous variables will include N, mean, standard deviation, 
minimum, lower quartile, median, upper quartile, maximum. Summary statistics for discrete 
variables will be presented in contingency tables and will include absolute and relative 
frequencies. 
If not otherwise specified, p-values will be presented as two-sided p-values and two-sided 
confidence intervals will be displayed. 
9.1 
Analysis sets 
The Randomized Set Epoch 2, respectively Epoch 3 will consist of all patients who are 
randomized in the randomized treatment epoch (Epoch 2), respectively in the randomized 
withdrawal epoch (Epoch 3). Unless otherwise specified, mis-randomized patients (mis-
randomized in IRT) will be excluded from the randomized set. Mis-randomized patients are 
defined as cases where IRT contacts were made by the site either prematurely or 
inappropriately prior to confirmation of the patient’s final randomization eligibility and no 
study medication was administered to the patient. 
The Full Analysis Set (FAS) Epoch 2, respectively Epoch 3 will consist of all randomized 
patients in the randomized treatment epoch, respectively in the randomized withdrawal epoch 
who received at least one dose of study drug. Following the intent-to-treat principle, patients 
will be analyzed according to the treatment they were assigned to at randomization in each 
epoch. 


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The Per-protocol Set (PPS) Epoch 2 will consist of all patients in the FAS Epoch 2 who do 
not fulfill any criteria that could potentially confound the interpretation of analyses conducted 
on the FAS. 
The Safety Set Epoch 2, Epoch 3, Epoch 4 will consist of all patients that received study 
treatment in Epoch 2, resp. Epoch 3, resp. Epoch 4 and had at least one post-baseline safety 
assessment. Patients will be analyzed according to treatment received. Of note, the statement 
that a subject had no AEs also constitutes a safety assessment. 
9.2 
Patient demographics and other baseline characteristics 
Summary statistics will be provided for demographic and baseline characteristics by study 
cohort and treatment group in the randomized treatment epoch (Epoch 2), the randomized 
withdrawal epoch (Epoch 3) and open-label treatment epoch (Epoch 4).  
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term. 
9.3 
Treatments 
The exposure to investigational treatment (number of doses) and duration of exposure (days) 
during this study will be summarized by cohort, epoch, treatment group and listed for the 
Safety Set. 
The number and percentage of patients taking concomitant medication, rescue medication will 
be summarized by cohort, epoch, treatment group and ATC class. 
9.4 
Analysis of the primary variable(s) 
All efficacy evaluations will be performed on the FAS. 
9.4.1 
Variable(s) 
Each cohort (TRAPS, HIDS, crFMF) of the study will have its own primary efficacy variable 
analyzed separately and independently of the other cohorts. The primary efficacy variable of 
the randomized treatment epoch (Epoch 2) and for the overall study is the proportion of 
responders within each cohort, where a responder is defined as a patient who has resolution of 
its index disease flare at Day 15 and does not experience a new flare during the 16 weeks 
following randomization. 
Resolution of the index flare (initial flare at the time of the randomization) is defined at the 
Day 15 visit as: 
• PGA < 2, and 
• CRP within normal range (≤10 mg/L) or reduction ≥70% from baseline. 
Absence of new flares over the first 16 weeks, where new flare is defined from the time of the 
resolution of the index flare as: 
• Physician’s Global Assessment (PGA) ≥2, and 


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• CRP ≥30 mg/L. 
In the randomized treatment epoch (Epoch 2), patients needing dose escalation in the 
canakinumab arms, or crossed-over from Placebo arms to canakinumab, or discontinued from 
the study due to any reason prior to evaluating the primary endpoint will be considered as 
non-responders. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary hypothesis tested will be the superiority of canakinumab dose (150 mg sc [or 
2mg/kg] q4w) relative to placebo with respect to the proportion of responders in the 
randomized treatment epoch (Epoch 2), where a responder is defined as a patient who has 
resolution of its index disease flare and does not experience a new flare during the 16 weeks 
following randomization. The hypothesis within each cohort will be tested at a one-sided 
2.5% level. 
The statistical hypothesis is that there is no difference in the proportion of patients with 
responder rate at Week 16 in canakinumab dose 150 mg s.c. (or 2 mg/kg) q4w versus placebo. 
Let pjk denote the proportion of responders at Week 16 for treatment group j and cohort k, k = 
1, 2, 3 for each of the cohorts and j=0, 1 where 
• 0 corresponds to placebo, 
• 1 corresponds to canakinumab 150mg q4w. 
The following hypotheses will be tested 
• H1k: p1k – p0k = 0 versus HA1k: p1k – p0k > 0, 
In other words: 
• H1: canakinumab 150mg q4w is not different to placebo with respect to responder rate at 
Week 16. 
Canakinumab treatment group will be compared to placebo with respect to the proportion of 
responders at Week 16 using the Fisher’s exact test. The proportion of responders, as well as 
the odds ratio and risk difference with corresponding 97.5% confidence interval will be 
presented. 
9.4.3 
Handling of missing values/censoring/discontinuations 
Patients needing dose escalation in the canakinumab arms, or who crossed-over from placebo 
arms to canakinumab in the randomized treatment epoch (Epoch 2), or discontinued from the 
study due to any reason prior to evaluating the primary endpoint will be considered as non-
responders. 
9.4.4 
Supportive analyses 
The primary analysis in the randomized treatment epoch will be repeated where definition of 
the resolution of the index flare and new flare definition will be derived from the centralized 
SAA values. 


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Resolution of the index flare (initial flare at the time of the randomization) is defined at the 
Day 15 visit as: 
• PGA <2, and 
• SAA within normal range (≤10 mg/L) or reduction of ≥70% from baseline. 
Absence of new flares over the first 16 weeks, where new flare is defined from the time of the 
resolution of the index flare as: 
PGA ≥2, and SAA ≥30 mg/L 
9.4.5 
Sensitivity analyses 
The primary analysis in the randomized treatment epoch will be repeated on the Full Analysis 
Set where patients receiving a single add-on injection before Day 15 will be excluded; i.e., 
• patients receiving add-on injection based on criterion from Day 8 to Day 14 (persistent 
PGA ≥2, or CRP persistent >10 mg/L with less than 40% reduction from baseline from 
Day 8 to Day 14), 
• patients receiving a single add-on injection despite they don’t fulfill criterion for add-on 
injection from Day 8 to Day 14. 
A second sensitivity analysis will be performed where the primary analysis in the randomized 
treatment epoch will be repeated on the per-protocol set; i.e., excluding patients receiving a 
single add-on injection before day 15 despite they don’t fulfill criterion for add-on injection 
from Day 8 to Day 14. 
A third sensitivity analysis will be performed where the primary analysis in the randomized 
treatment epoch will be repeated on Full Analysis Set where patients receiving a single add-on 
injection before Day 15 will be considered as responder except if new flare occurs from Day 
15 onward in Epoch 2. 
9.5 
Analysis of secondary variables 
9.5.1 
Secondary efficacy variables 
The secondary efficacy objectives will be evaluated by assessing the efficacy of canakinumab 
(q4w in the randomized treatment epoch, and q8w in the randomized withdrawal epoch) as 
compared to placebo and will be analyzed by cohort. All secondary efficacy objectives will be 
including in the closed testing procedure. 
• To evaluate the percentage of patients who achieve a PGA < 2 at Week 16 
• To evaluate the percentage of patients with the serologic remission at Week 16 (defined as 
C-reactive protein [CRP] ≤10 mg/L) 
• To evaluate the percentage of patients with normalized Serum Amyloid A (SAA) level at 
Week 16 (defined as SAA ≤10 mg/L) 
• To evaluate the percentage of canakinumab responders in Epoch 2 who maintain clinically 
meaningful response (absence of new flares) when switched to a canakinumab every 8 
weeks regimen compared to placebo (Epoch 3). 


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Testing strategy 
If the primary objective is achieved, all secondary endpoints in the randomized treatment 
epoch (Epoch 2) will be assessed in a hierarchical testing procedure to evaluate the superiority 
of canakinumab s.c. q4w over placebo. This is performed in order to control the overall Type 
I error rate (α = 0.025, one sided tests) in the evaluation of these secondary efficacy variables. 
Testing was continued as long as each test showed statistical significance at the 2.5% level. 
The following hypotheses will be included the closed testing procedure: 
Primary objective: H1 (see Section 9.4.2). 
Secondary objectives: 
• H2: Canakinumab 150 mg q4w is not different to placebo with respect to the percentage of 
patients with PGA < 2 at Week 16. 
• H3: Canakinumab 150 mg q4w is not different to placebo with respect the percentage of 
patients with CRP ≤10 mg/L at Week 16. 
• H4: Canakinumab 150 mg q4w is not different to placebo with respect the percentage of 
patients with SAA ≤10 mg/L at Week 16. 
If all secondary objectives are achieved in the randomized treatment epoch, then the 
secondary objective in the randomized withdrawal epoch will be tested. 
H5: Canakinumab 150 mg q8w is not different to placebo with respect to the percentage of 
responders (absence of new flares) at Week 40. 
Physician’s global assessment of disease activity 
Between-treatment differences for the proportion of patients with PGA < 2 at Week 16 will be 
analyzed using a logistic regression model with treatment group and baseline PGA as effect 
for each cohort. Patients needing dose escalation in the canakinumab arms, or who crossed-
over from placebo arms to canakinumab in the randomized treatment epoch (Epoch 2), or 
discontinued from the study due to any reason prior to evaluating the endpoint at week 16 will 
be considered as having PGA ≥2. In case of convergence issues then Firth’s method will be 
used in the logistic regression model. If convergence issue is still not resolved then 
Canakinumab treatment group will be compared to placebo with respect to the proportion of 
patients with PGA <2 at Week 16 will be analyzed using the Fisher’s exact test. 
Serological remission 
Serological remission is defined as CRP ≤10mg/L. 
Between-treatment differences for the proportion of patients with CRP ≤10 mg/L at Week 16 
will be analyzed using a logistic regression model with treatment group, and baseline CRP 
values (log(e) transformation) as effect for each cohort. Patients needing dose escalation in the 
canakinumab arms, or who crossed-over from placebo arms to canakinumab in the 
randomized treatment epoch (Epoch 2), or discontinued from the study due to any reason 
prior to evaluating the endpoint at week 16 will be considered as having CRP >10 mg/L. In 
case of convergence issues then Firth’s method will be used in the logistic regression model. 


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If convergence issue is still not resolved then Canakinumab treatment group will be compared 
to placebo with respect to the proportion of patients with CRP ≤10 mg/L at Week 16 will be 
analyzed using the Fisher’s exact test. 
Normalization of SAA 
Normalization of SAA is defined as SAA ≤10mg/L. 
Between-treatment differences for the proportion of patients with SAA ≤10 mg/L at Week 16 
will be analyzed using a logistic regression model with treatment group and baseline SAA 
values as effect for each cohort. Patients needing dose escalation in the canakinumab arms, or 
who crossed-over from placebo arms to canakinumab in the randomized treatment epoch 
(Epoch 2), or discontinued from the study due to any reason prior to evaluating the endpoint 
at week 16 will be considered as having SAA >10 mg/L. In case of convergence issues then 
Firth’s method will be used in the logistic regression model. If convergence issue is still not 
resolved then Canakinumab treatment group will be compared to placebo with respect to the 
proportion of patients with SAA ≤10 mg/L at Week 16 will be analyzed using the Fisher’s 
exact test. 
Maintenance of clinically meaningful response 
Responder in the randomized withdrawal epoch is defined as no flare between week 16 and 
week 40. The canakinumab 150 mg q8w treatment group will be compared to placebo with 
respect to the proportion of responders at Week 40 using the Fisher’s exact test. Only 
canakinumab responders in Epoch 2 and re-randomized at week 16 will be considered in the 
analysis. The proportion of responders, as well as the odds ratio (if estimable) and risk 
difference with corresponding 97.5% confidence interval will be presented. 
9.5.2 
Exploratory efficacy variables 
Exploratory efficacy variables will be analyzed separately for each independent cohort 
(TRAPS, HIDS, crFMF). Continuous variables will be summarized by mean, standard 
deviation, median, minimum, maximum, 25% and 75% quartiles, and number of patients with 
non-missing data. Categorical variables will be summarized by absolute frequencies and 
percentages. 
Inflammatory parameters (CRP, SAA) 
CRP and SAA will be summarized descriptively by visit for each cohort, epoch and by 
treatment arm.  
In addition, the number and percentage of patients with CRP ≤10 mg/L, SAA ≤10 mg/L will 
also be presented. 
PGA and PPGA Disease Activity, Key disease specific signs and symptoms 
The efficacy outcomes measured on Likert scale, such as physician’s global assessment of 
response to treatment, investigator’s global assessment of disease control, patient/parent 
global assessment of disease control, patient/parent global assessment of disease activity, 


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patient/parent assessment of flare severity, patient/parent severity assessment of the key 
disease-specific signs and symptoms will be presented in frequency tables by visit for each 
cohort and treatment group. 
Between-treatment differences for the proportion of patients with no PGA disease activity, no 
PPGA disease activity at Week 16 will be analyzed using a Fisher’s exact test for each cohort. 
Episodes of Fever 
Number and duration of fever episodes collected in patient’s diaries will be summarized 
within each cohort and treatment group. Plots of fever episodes per patient over time and 
treatment group will also be presented.  
Rescue medication (Corticosteroids and NSAIDs) 
Corticosteroids and NSAIDs levels will be summarized descriptively by visit for each cohort 
and by treatment group. 
In addition, the number and percentage of patients who reduce their corticosteroids 
maintenance dose at Week 16 compared to baseline, patients who take corticosteroids rescue 
medication and patients who take only NSAIDs rescue medication during the study will also 
be presented. Between-treatment differences for the proportion of patients who are able to 
reduce their corticosteroids at Week 16 will be analyzed using a Fisher’s exact test for each 
cohort. 
Blinded escape 
The number and percentage of patients who require blinded escape from Days 8 to 28 will be 
summarized by cohort and treatment group. 
Auto-Inflammatory Disease Activity Index (AIDAI) 
Symptoms evaluated in the AIDAI diary will be summarized with each cohort and epoch.  
Time to first new flare in the randomized withdrawal epoch (Epoch 3) 
The two treatment groups (150 mg q8w and placebo) will be compared using a one-sided log-
rank test at the 2.5% significance level. The hazard ratio and its associated 95% two-sided 
confidence intervals will be estimated. Kaplan-Meier estimates of the probability to 
experience a flare event will be calculated from the start of the randomized withdrawal epoch. 
95% confidence intervals using Greenwood’s formula will be provided. 
SF-12 Health Survey (SF-12)  
SF-12 scores will be summarized by epoch, visit and treatment arms within each cohort. Only 
patients ≥18 years of age at baseline will be part of the analyses. 


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Child Health Questionnaire – Parent Form 50 (CHQ-PF50)  
Descriptive statistics will be used to summarize patient responses on the CHQ-PF50© 
Questionnaire by epoch, treatment, total score and by domain within each cohort. Only 
patients >5 - <18 years of age at Baseline are included. 
Sheehan Disability Scale (SDS v3) 
SDS score by domains and global functional impairment score will be summarized by epoch, 
visit and treatment arms within each cohort. 
Number of flares 
The number of flares by patient will be summarized by epoch and treatment arms within each 
cohort. 
9.5.3 
Safety variables 
All safety evaluations will be performed on the Safety set. 
9.5.3.1 
Adverse events 
Adverse events will be coded using the MedDRA dictionary that provides the primary system 
organ class and preferred term information.  
Adverse events will be summarized by presenting, for each cohort, epoch and treatment group, 
the number and percentage of patients having any adverse event, having any adverse event in 
each primary system organ class and having each individual adverse event based on the 
preferred term. Exposure adjusted incidence rate of AEs will also be provided. All other 
information collected (e.g. severity, relationship to study treatment) will be tabulated and 
listed as appropriate. 
Adverse events will also be summarized by SMQ. Adverse event analyses will be adjusted for 
treatment group exposure in each epoch. 
Deaths, serious adverse events, and adverse events leading to discontinuation of study 
treatment will be summarized by primary system organ class and preferred term and listings 
will be provided. 
9.5.3.2 
Laboratory data 
Laboratory parameters will be summarized by presenting descriptive statistics for the absolute 
values, change from baseline for each cohort, epoch and treatment group. Change from 
baseline will only be summarized for patients with both baseline and post baseline values in 
each epoch. All information collected will be listed by patient and abnormal values will be 
flagged. In addition, shift tables based on normal ranges and incidence rates of notable 
abnormalities will be presented. 
In addition, laboratory values collected during the open-label escape period in the randomized 
treatment epoch will separately be listed. 


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9.5.3.3 
Vital signs 
Vital signs will be summarized by presenting descriptive statistics for the absolute values and 
changes from baseline for each cohort, epoch and treatment group. All information collected 
will be listed by patient and abnormal values will be flagged. 
9.5.3.4 
ECG 
Listings and table will be provided for notable ECG abnormalities. Summary statistics will be 
presented for ECG variables by epoch, visit and treatment group for each cohort. 
9.5.3.5 
Immunogenicity 
A listing for each cohort will be presented for patients who develop immunogenicity. 
9.5.4 
Resource utilization 
No resource/ healthcare utilization information will be collected on patients entered into this 
study. 
9.5.5 
Pharmacokinetics 
Summary statistics (e.g. mean, standard deviation) and individual subject listing of serum 
concentration measurements of canakinumab at the assigned time points will be provided as 
surrogates of systemic exposure. 
9.5.6 
Pharmacogenetics/pharmacogenomics 
9.5.6.1 
Pharmacogenetics 
The exploratory pharmacogenetic studies are designed to investigate the association between 
 
 
 
 
 
 
 
 
 
 
9.5.6.2 
Pharmacogenomics 
Not applicable 
9.5.7 
Biomarkers 
Samples for biomarker analyses are not to be taken as part of this study. 


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9.5.8 
PK/PD 
A mixed effects modeling approach may be used to characterize the PK of canakinumab and 
its binding to IL-1β. The relationship between the population parameters such as CL/F and 
covariates (demographics, disease) may be investigated using graphical methods and simple 
regression models. Quality of individual fits to the dataset will be assessed, and individual 
model parameters (post-hoc estimates) may be obtained for each patient. Alternatively, in case 
the population based modeling may not be feasible, the analysis will be limited to the 
methodology based on predictive check, where the measures of systemic drug exposure (pre-
dose trough levels) will be plotted against the data collected in previous trials. 
9.6 
Interim analyses 
If there is any delay in the enrollment of the patients in one of the cohorts in the randomized 
treatment epoch i.e. it takes more than 24 weeks to recruit patients in one of the cohorts, then 
an interim analysis performed within each cohort would be considered. The decision to 
perform this interim analysis would be taken jointly between the indication-specific lead 
investigators and Novartis. 
• If overall enrollment time has surpassed 24 weeks, AND 
• If >2/3 patients are enrolled in the slowest enrolling cohort. 
However, due to the low number of patients in the slowest enrolling cohort, the interim 
analysis will not be sufficiently powered to detect statistically significant differences. Thus 
only descriptive analysis would be performed in this cohort and these results will complete the 
dossier with the final results of the two cohorts where all patients have been recruited. 
In order to support regulatory filing, the analyses of the primary and all Week 16 secondary 
efficacy variables will be performed after all subjects have completed the final visit of the 
randomized treatment epoch (Epoch 2) of the study (Day 113). These results will be presented 
in a first Clinical Study Report (CSR) (see also Section 10.4). 
An interim analysis is planned at the end of the randomized withdrawal epoch (Epoch 3). An 
Interim Analysis CSR may be prepared to support health authority interactions, as necessary 
(see also Section 10.4). 
The final long-term safety analyses involving data from all 4 epochs will be performed after 
all patients have completed the final visit of the trial (Day 785) and will be presented in the 
final CSR (see also Section 10.4). 
9.7 
Sample size calculation 
The primary efficacy objective in the randomized treatment epoch and for the overall study is 
to compare canakinumab treatment to placebo with respect to the proportion of responders at 
Week 16 using the Fisher’s exact test. The proportion of responders, as well as the odds ratio 
(if estimable) and risk difference with corresponding 97.5% confidence interval will be 
presented. 
 
 


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Since a 20% screening failure rate is expected, it is estimated 
that approximately 
 patients have to be screened. 
Nquery Advisor® software version 7.0 was used. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US 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 should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/ IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/ IEC approval. 
The study includes an optional pharmacogenetic component which requires a separate 
signature if the patient agrees to participate. It is required as part of this protocol that the 
Investigator presents this option to the patient. The process for obtaining consent should be 
exactly the same as described above for the main informed consent. 
Declining to participate in these pharmacogenetic assessments will in no way affect the 
patient’s ability to participate in the main research study. 
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained. 


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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 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. 
For this study, the following CSRs will be prepared: 
1. The first CSR will report all efficacy and safety data collected during the randomized 
double-blind treatment epoch (Epoch 2) up to 16 weeks 
2. An Interim Analysis CSR may be prepared to support health authority interactions, as 
necessary. This CSR will report all efficacy and safety data collected during the 
randomized withdrawal/ dose-reduction epoch (Epoch 3) 
3. The final CSR will report cumulative long term safety and efficacy data collected during 
all 4 epochs 
Upon study completion and finalization of the final CSR the results of this trial will be either 
submitted for publication and/ or posted in a publicly accessible database of clinical trial 
results. 
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 should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
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. All significant protocol deviations will be recorded and reported in the CSR. 


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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 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 should be followed. 
12 
References 
References are available upon request 
Aksentijevich I, Kastner DL (2011). Genetics of monogenic autoinflammatory diseases: past 
successes, future challenges. Nat. Rev. Rheumatol. 7, 469–478; published online 5 July 2011; 
doi:10.1038/nrrheum.2011.94. 
De Benedetti F, Brunner HI, Ruperto N, et al (2012). Randomized trial of tocilizumab in 
systemic juvenile idiopathic arthritis. N Engl J Med. 2012 Dec 20;367(25):2385-95. 
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. 2012 Aug;11(8):633-52. 
Drenth JP, van der Meer JW (2001). Hereditary periodic fever. N Engl J Med. 2001 Dec 
13;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. 2012 64(10) S322-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. 2012 Mar;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. 2012 64(10) S322-S322 
abstract 750. 
Hoffman HM, Simon A (2009). Recurrent febrile syndromes: what a rheumatologist needs to 
know. Nat Rev Rheumatol. 2009 May;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. 2011;13(6):R202. doi: 10.1186/ar3535. 
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 


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patients with cryopyrin-associated periodic syndrome across different severity phenotypes. 
Ann Rheum Dis. 2011 Dec;70(12):2095-102. 
Kuemmerle-Deschner JB, Ramos E, Blank N, Roesler J, 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. 2011 Feb 
28;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. 2009 Jun 4;360(23):2416-25. 
Livneh A, Langevitz P, Zemer D, et al.(1997) Criteria for the diagnosis of familial 
Mediterranean fever. Arthritis Rheum 40:1879-85. 
Manuel O, Kumar D (2008). QuantiFERON-TB Gold assay for the diagnosis of latent 
tuberculosis infection. Expert Rev Mol Diagn 8(3):247-55. 
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. 2011 Feb;70(2):309-14. 
doi: 10.1136/ard.2010.132613. 
Piram M, Koné-Paut I, Lachmann HJ, et al (2013). Validation of the Auto-Inflammatory 
Diseases Activity Index (AIDAI) for ereditary recurrent fever syndromes. Ann Rheum Dis. 
2013 Sep 11. doi: 10.1136/annrheumdis-2013-203666. 
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. 2012 Feb;64(2):557-67. doi: 
10.1002/art.33342. 
Schwartz GJ, Muñoz A, Schneider MF, et al (2009). New Equations to Estimate GFR in 
Children with CKD. J Am Soc Nephrol 20: 629–637, 2009. doi: 10.1681/ASN.2008030287 
Stojanov S, Kastner DL (2005). Familial autoinflammatory diseases: genetics, pathogenesis 
and treatment. Curr Opin Rheumatol. 2005 Sep;17(5):586-99. 
Ter Haar N, Lachmann H, Ozen S, et al (2012). Treatment of autoinflammatory diseases: 
results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2012 Jun 29.  
Touitou I, Koné-Paut I (2008). Autoinflammatory diseases. Best Pract Res Clin Rheumatol. 
2008 Oct;22(5):811-29. 


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13 
Appendix 1: Clinically notable laboratory values and vital 
signs 
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): > 3x, 5x, 10x, and 20x Upper Limit of Normal (ULN)1 
2. AST (SGOT): > 3x, 5x, 10x, and 20x ULN1 
3. Elevation of AST and/ or ALT (>3x ULN) accompanied by elevated bilirubin (> 1.5x 
ULN, >2x ULN)1 
4. Any elevations of bilirubin; elevated total bilirubin (TBL) to >2x ULN1 
5. Any elevations of ALP >1.5x ULN1 
6. Gamma-Glutamyltransferase (GGT): >3x ULN 
7. Creatinine (serum): ≥3x ULN 
8. Creatinine clearance (CrCl) (Cockroft-Gault formula)2: ≥ 25% decrease from baseline 
9. Triglycerides: >5x ULN 
Hematology 
1. Hemoglobin: ≥20 g/L decrease from baseline or <100 g/L 
2. Platelet count3 
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: <25x 109/L 
3. White blood cell count3 
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 neutrophils3 
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: ≥ 2.5x, ≥ 3x ULN 
Urinalysis 
a. Protein urine dipstick: ≥ ++ 


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Notable vital signs abnormalities in adult patients (≥ 18 years of age) 
Post-baseline vital signs will be flagged as notable abnormalities as follows: 
1. Systolic/Diastolic blood pressure: ≥25% decrease or ≥25 % increase from baseline 
2. Pulse: ≥110 bpm with ≥15% change from baseline, or < 50 bpm with ≥15% change from 
baseline 
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): > 3x, 5x, 10x, and 20x Upper Limit of Normal (ULN)1 
2. AST (SGOT): > 3x, 5x, 10x, and 20x ULN1 
3. Elevation of AST and/ or ALT (>3xULN) accompanied by elevated bilirubin (> 1.5x 
ULN, >2xULN)1 
4. Any elevations of bilirubin; elevated total bilirubin (TBL) to >2x ULN1 
5. Any elevations of ALP >1.5x ULN1 
6. GGT: ≥3x, 5x ULN 
7. Creatinine (serum): ≥1.5x ULN 
8. Creatinine clearance (Schwartz formula§): ≥25% decrease from baseline, ≥2 consecutive 
visits 
9. Total Cholesterol: ≥1.5xULN 
10. Triglycerides: ≥5.7 mmol/L 
11. Creatinine clearance (Schwartz formula4): ≥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 count3 
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: <25x 109/L 
3. White blood cell count3 
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 neutrophils3 


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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 
• Protein urine dipstick: ≥+ for ≥3 months in duration 
Notable vital signs abnormalities in pediatric patients (< 18 years of age) 
Post-baseline vital signs in pediatric patients (at the time of the assessment) will be flagged as 
notable abnormalities as follows: 
1. Systolic blood pressure (mmHg): >ULN and increased >20 in change from baseline or 
<LLN and decreased >20 in change from baseline 
Normal ranges: LLN = 100, ULN = 115 (2 – 5 years of age), LLN = 110, ULN = 125 (6 – 
12 years of age), LLN = 120, ULN = 135 (13 < 18 years of age) 
2. Diastolic blood pressure (mmHg): >ULN and increased >20 in change from baseline and 
<LLN and decreased >20 in change from baseline 
Normal ranges: LLN=65, ULN = 75 (2 – 5 years of age), LLN = 70, ULN = 80 (6 – 12 
years of age), LLN = 75, ULN = 85 (13 < 18 years of age) 
3. Pulse (bpm): >ULN and increased >20 in change from baseline or <LLN and 
decreased >20 in change from baseline 
Normal ranges: LLN=80, ULN = 130 (2 – 5 years of age), LLN = 70, ULN = 115 (6 – 12 
years of age), LLN = 60, ULN = 100 (13 < 18 years of age) 
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/1.73m2) = [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 
• 3x ULN < ALT / AST ≤5 x ULN 
•  1.5x ULN < TBL ≤2 x 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 casea 
• Discontinue the study drug 
immediately 
• Hospitalize, if clinically appropriate 
• Establish causality 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
ALT or AST 
> 8 × ULN 
• Discontinue the study drug 
immediately 
• Hospitalize if clinically appropriate 
• Establish causality 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and 
INR > 1.5 
• Discontinue the study drug 
immediately 
• Hospitalize, if clinically appropriate 
• Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
• Complete liver CRF 
> 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 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN 
accompanied by 
symptomsb 
• Discontinue the study drug 
immediately 
• Hospitalize if clinically appropriate 
• Establish causality 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(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 
• Complete liver CRF 
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 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(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 drug 
immediately 
• Hospitalize the patient 
• Establish causality 
• Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE 
potentially 
indicative of a 
liver toxicity* 
• Consider study drug interruption or 
discontinuation  
• Hospitalization if clinically 
appropriate 
• Establish causality 
• Complete liver CRF 
Investigator discretion 


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Criteria 
Actions required 
Follow-up monitoring 
*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 
aElevated 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 
cResolution 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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16 
Appendix 4: Level of TB risk 
High risk TB patients are defined as follows: 
• HIV positive patients 
• Patients on concomitant immunosupressants/ immunodeficiency 
• Patients who have been in close contact with active TB 
• Chest x-ray suggestive of prior TB infection 
• Patients with a history of lack of compliance with anti-tuberculosis drug intake for a prior 
infection/prophylaxis 
Moderate risk TB patients are defined as follows: 
• Patients living in or coming from countries with a high prevalence of TB 
• Healthcare workers 
• Patients with diabetes/ silicosis/ chronic renal failure/ malignancies 
• Patients exposed to high-risk patients (as described above) 
• Infants < 4 years 
• Intravenous substance abusers 
Low risk TB patients are defined as follows: 
• Induration size of 5-9 mm following PPD skin test 
• None of the risks listed for high and moderate risk patients 

SAP_001.pdf: 
Clinical Development
Canakinumab / ACZ885
ACZ885N2301 / NCT02059291 
A randomized, double-blind, placebo controlled study of canakinumab in 
patients with Hereditary Periodic Fevers (TRAPS, HIDS, or crFMF), with 
subsequent randomized withdrawal/ dosing frequency reduction and 
open-label long term treatment epochs
Statistical Analysis Plan
Author:
Document type:
Statistical Analysis Plan
Document status:
Final analysis
Release date:
10 Jan 2017
Number of pages:
37
Property of Novartis
Confidential May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Amendment 
1.0
12.12.2014
Incorporate changes from protocol amendment 1: adding analysis 
statement for patients >28 days but <2 years old who enter the study 
directly into the open-label arm of Epoch 2; Update Notable Blood 
pressure normal range to include patients less than 2 years old. 
Adding Sensitivity analyses section.
Amendment 
2.0
09.10.2015
Additional analysis added for primary and secondary endpoints.
Shift analysis for CKD categories added.
Amendment 
3.0
24.10.2015
Imputation rule for missing standardized local CRP value is added.
Detailed definition of duration of exposure added.
Detailed summary around CRP categories before day 29 added.
Details around rescue medication analysis added.
Addendum
01.12.2015
Updated to include AEs and concomitant medications occurred 
during safety follow period after epoch 2 in listings and add two 
additional sensitivity analysis
Addendum 2
07.01.2015
Adding time to first resolution of fever analysis; Adding plot analysis; 
Adding gene analyses.
Amendment 
1.0 Epoch 3
26.02.2016
Updated definition of safety set Epoch 3
Treatment label update for epoch 3
Added method to calculate cumulative dose in epoch 3 and 4
AIDAI weekly scores changed to AIDAI monthly scores
Addendum
1.0 Epoch 3
Final 
analysis
26.04.2016
10.01.2017          
Clarification on derivation of AIDAI monthly score is added.
Added dose distribution over time from epoch 2 to epoch 4, 
summary tables of CRP, SAA, PGA starting from epoch 2 to epoch 
4. AE/SAE combing epoch 2 to epoch 4 data after patients taking 
ACZ885. Additional two safety summary tables are added for Health 
Authority data disclosure requirements (EudraCT and CT.gov).


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Table of contents
Table of contents .................................................................................................................3
1
Statistical methods planned in the protocol and determination of sample size...................6
1.1
Statistical and analytical plans.................................................................................6
1.2
Subjects and treatments ...........................................................................................7
1.3
Treatment group definitions ....................................................................................9
1.4
Summary of the analyses .......................................................................................15
1.5
Patient demographics and other baseline characteristics.......................................16
1.6
Patient disposition..................................................................................................17
1.7
Medical history......................................................................................................17
1.8
Study medication ...................................................................................................17
1.9
Concomitant medication........................................................................................18
1.10
Efficacy evaluation ................................................................................................18
1.10.1
Analysis of the primary endpoint..........................................................18
1.10.2
Analysis of secondary variables............................................................21
1.10.3
Subgroup analyses.................................................................................23
1.10.4
Exploratory efficacy variables ..............................................................24
1.11
Pharmacokinetic ....................................................................................................27
1.12
Pharmacodynamics................................................................................................28
1.12.1
Pharmacogenetics..................................................................................28
1.13
Safety evaluation ...................................................................................................28
1.13.1
Adverse events ......................................................................................28
1.13.2
Local injection site tolerability..............................................................29
1.13.3
Laboratory data .....................................................................................29
1.13.4
Vital signs..............................................................................................32
1.13.5
Immunogenicity ....................................................................................33
1.13.6
Liver safety monitoring.........................................................................33
1.14
Interim analyses .....................................................................................................33
1.15
Determination of sample size ................................................................................34
2
Clinical Study Report -  Appendix 16.1.9  Documentation of statistical methods ...........35
2.1
Analysis visit windows..........................................................................................35


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List of abbreviations
AE
Adverse Event
AIDAI
Auto-Inflammatory Disease Activity Index
ALT
Alanine Aminotransferase (SGPT)
AST 
Aspartate Aminotransferase (SGOT)
BMI
Body Mass Index
CHQ-PF50
Child Health Questionnaire
CRP
C-reactive Protein
CSR
Clinical Study Report
ECG
Electrocardiogram
eCRF 
Electronic case report/record form
FAS
Full Analysis Set
crFMF
colchicine resistant Familial Mediterranean Fever
HIDS
Hyper IgD Syndrome
IL-1β
Interleukin-1β
LLN 
Lower Limit of Normal
MedDRA 
Medical dictionary for regulatory activities
PD
Pharmacodynamic(s)
PGA
Physician’s global assessment
PhS
CHQ-PF50 physical component summary measure 
PK
Pharmacokinetic(s)
PPGA
Patient/ Parent’s global assessment
PsS
CHQ-PF50 psychosocial component summary measure
SAA 
Serum Amyloid A
SAE 
Serious Adverse Event
s.c. 
subcutaneous(ly)
SDS
Sheehan Disability Scale
SF-12 
Short Form (12) Health Survey
SGOT
Serum Glutamic Oxaloacetic Transaminase, same as AST
SGPT
Serum Glutamic Pyruvic Transaminase, same as ALT
TBL
Total Bilirubin
TRAPS
TNF-receptor Associated Periodic Syndrome


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ULN 
Upper Normal Limit
VAS 
Visual Analog Scale


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1
Statistical 
methods 
planned 
in 
the 
protocol 
and 
determination of sample size
Data will be analyzed by Quanticate according to the data analysis section 9 of the study 
protocol which is available in Appendix 16.1.1 of the Clinical Study Report (CSR).  Important 
information is given in the following sections and details will be provided, as applicable, in 
Appendix 16.1.9 of the CSR.
1.1
Statistical and analytical plans
The planned analysis is described in Section 9 (Data Analysis) of the study protocol which is 
available in Appendix 16.1.1 of the CSR.  
This document covers statistical and analytical plans for the primary endpoint analysis i.e. the 
resolution of the index flare at the time of randomization and the absence of incident flares over 
the first 16 weeks after randomization, at Week 16 interim analysis but also covers the analyses 
for the Week 40 interim analysis and the final analysis after database lock. The data collected 
in this study up to the time of the Week 16 interim analysis will be part of the marketing 
authorization submission package of the ACZ885N project. All data collected up to Week 16
will be analyzed in the Week 16 interim analysis.
This study consists of 3 cohorts (one cohort per condition: TNF-receptor Associated Periodic 
Syndrome (TRAPS), Hyper IgD Syndrome (HIDS) and colchicine resistant Familial 
Mediterranean Fever (crFMF)), and 4 study epochs. 
Each cohort will follow the same study design across the 4 epochs:

A screening epoch to assess patients’ eligibility of up to 12 weeks duration (Epoch 1)

A randomized treatment epoch (Epoch 2) of 16 weeks which will provide efficacy and 
safety data in a double-blind placebo-controlled parallel-arm setting. This randomized
treatment epoch will include 2 possible escape options: Blinded escape (from Day 8 to Day 
28), Open-label treatment (from Day 29 to Day 112)

A randomized withdrawal epoch (Epoch 3) of 24 weeks where Canakinumab responder 
patients will be re-randomized to canakinumab 150 mg q8w or Placebo

An open-label treatment epoch (Epoch 4) of 72 weeks to collect long-term safety data for 
canakinumab.
In order to provide access to treatment, roll-over TRAPS patients previously participating in 
clinical study CACZ885D2203 and/or the subsequent Multiple Patient Program (MPP) 
treatment plan CACZ885D2207M will be allowed to enter the study in randomized withdrawal 
epoch (Epoch 3) and the Japanese crFMF patients with non-exon 10 mutations or patients >28 
days but <2 years old (with bodyweight ≥3.75 kg) will enter the study in the open-label arm of
randomized treatment epoch (Epoch 2). The non-randomized patient group including Japanese 
crFMF patients with non-exon 10 mutations and patients >28 days but <2 years old will follow 
the following study design across the 4 epochs:
a.
A screening epoch to assess patients’ eligibility of up to 12 weeks duration (Epoch 1)
b. An open-label epoch of 16 weeks (Epoch 2)
c.
An open-label epoch of 24 weeks (Epoch 3)


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d. An open-label treatment epoch of 72 weeks to collect long-term safety data for 
canakinumab (Epoch 4)
All data will be analyzed separately for each independent cohort (TRAPS, HIDS, crFMF).
The purpose of the study is to provide evidence supporting answers to following questions. The 
data will be analyzed by Epoch:
1. Whether canakinumab at a starting dose of 150mg s.c. (or 2mg/kg for patients ≤40 kg) 
administered every 4 weeks is able to induce and maintain 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 in a greater proportion of patients with TRAPS, HIDS, or 
crFMF compared to placebo (Data from Epoch 2)
2. Whether, in patients responding to the initial dosing regimen of every 4 weeks, 
canakinumab will maintain its clinical efficacy if administered at a reduced dosing interval 
of 150mg s.c. (or 2mg/kg for patients ≤40 kg) every 8 weeks. (Data from epoch 3 and 4)
Safety data for the subgroup of patients coming from ACZ885D2203 and/or the subsequent
Multiple Patient Program (MPP) treatment plan CACZ885D2207M collected in Epoch 3 and 4 
will separately be reported from the other patients who will be screened and randomized in
Epoch 2.
Safety data for the subgroup of canakinumab naïve Japanese crFMF patients with non-exon 10 
mutations, and patients >28 days but <2 years old, collected in Epoch 2, 3 and 4 will separately 
be reported from the other patients who will be screened and randomized in Epoch 2. 
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum, and number of patients with non-missing 
data (n). Summary statistics for discrete variables will be presented in contingency tables and 
will include absolute and relative frequencies.
If not otherwise specified, p-values will be presented as two-sided p-values and two-sided 
confidence intervals will be displayed.
All listings will be presented by cohort and treatment sequence.
1.2
Subjects and treatments 
The following analysis sets will be used for the data analysis.
The Randomized Set Epoch 2 will consist of all patients who are randomized in the randomized 
treatment epoch (Epoch 2). 
The Randomized Set Epoch 3 will consist of all patients who received canakinumab drug in 
epoch 2 and are responders at week 16 and who are re-randomized in the randomized
withdrawal epoch (Epoch 3). 
Unless otherwise specified, mis-randomized patients (mis-randomized in IRT) will be excluded 
from the randomized set. (Mis-randomized patients are defined as cases where IRT contacts 
were made by the site either prematurely or inappropriately prior to confirmation of the patient’s 
final randomization eligibility and no study medication was administered to the patient).


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The Full Analysis Set (FAS) Epoch 2 will consist of all randomized patients in the randomized 
treatment epoch who received at least one dose of study drug in epoch 2. Following the intent-
to-treat principle, patients will be analyzed according to the treatment they were assigned to at 
randomization.
The Full Analysis Set (FAS) Epoch 3 will consist of all patients in the randomized withdrawal 
epoch who received at least one dose of study drug.
The Safety Set Epoch 2 will consist of all patients that received study treatment in Epoch 2. 
Patients will be analyzed according to treatment received. Of note, the statement that a subject 
had no AEs also constitutes a safety assessment.
The Safety Set Epoch 3 will consist of all patients that received study treatment in Epoch 3. 
Patients will be analyzed according to treatment received. Of note, the statement that a subject 
had no AEs also constitutes a safety assessment.
The Safety Set Epoch 4 will consist of all patients that received study treatment in Epoch 4. 
Patients will be analyzed according to treatment received. Of note, the statement that a subject 
had no AEs also constitutes a safety assessment.
The Per-protocol Set (PPS) Epoch 2 will consist of all patients in the FAS Epoch 2 who do 
not fulfill any criteria that could potentially confound the interpretation of analyses conducted 
on the FAS.
The protocol deviation (PD) population codes leading to exclusion from Per-protocol set are 
presented in Table 1-1. In addition, subjects receiving a single add-on injection before day 15 
despite they don’t fulfill criterion for add-on injection from Day 8 to Day 14 were excluded 
from Per-protocol set.
An analysis based on the per-protocol set will be performed as additional sensitivity analysis.
Protocol deviations for exclusion from a per-protocol analysis are defined in Table 1-1.


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Table 1-1
Subject classification rules
Analysis set
PD Categories Codes that 
cause subject to be excluded
Non-PD criteria that cause a 
subject to be excluded
Randomization set
INC01,INC02,INC20
Mis-randomized subject
FAS Epoch 2(Full Analysis Set) 
INC01,INC02,INC20, TRT02
NA
FAS Epoch 3(Full Analysis Set)
INC01,INC02,INC20, TRT02
NA
Safety Epoch 2
INC02, TRT02
NA
Safety Epoch 3
INC02, TRT02
NA
Safety Epoch 4
INC02, TRT02
NA
Per-protocol Epoch 2
See notes*
1) subjects receiving a single add-
on injection before day 15 despite 
they don’t fulfill criterion for add-
on injection from Day 8 to Day 14
2) subjects taking biologics after 
taking study medication and don’t 
discontinue study drug
*the following are used to define Per-protocol analysis set:
Exclude the following
INCLXX: TRAPs (INC01,INCL02, INCL06, INCL07, INC20), HIDs(INC01, INCL02, INCL11, INCL12, INC20), 
crFMF(INC01, INCL02, INCL15, INCL18, INCL19, INC20)
TRTXX: TRT02, TRT07, TRT26
Definition of responders
Definition of responders in epoch 2: canakinumab treated patients in Epoch 2 who maintain a 
clinically meaningful response (absence of new flares) until week 16 from the time of the 
resolution of the index flare at day 15. All patients randomized to placebo at baseline and 
completing the randomized treatment epoch (Epoch 2) without any re-flare will be considered 
placebo-responders.
Definition of non-responders in epoch 2: In the randomized treatment epoch (Epoch 2), patients 
needing dose escalation in the canakinumab arms, or escape from Placebo arms to canakinumab, 
or discontinued from the study due to any reason prior to evaluating the primary endpoint at 
week 16 will be considered as non-responder in epoch 2.
Definition of responders in epoch 3: Responder in the Randomized withdrawal epoch (epoch 3) 
is defined as patients having no flare(s) between week 16 and week 40.
Definition of responders in epoch 4: Responders in the epoch 4 are defined as patients having 
no flare(s) between week 40 and end of the study.
1.3
Treatment group definitions
The following study epoch will be considered for analysis:

Epoch 2: A randomized treatment epoch of 16 weeks. This randomized treatment epoch 
will include 2 possible escape options: Blinded escape, Open-label treatment

Epoch 3: A randomized withdrawal epoch of 24 weeks


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
Epoch 4: An open-label treatment epoch of 72 weeks.
Treatment groups for analysis will include:
Randomized treatment epoch (Epoch 2):
Treatment arms for the primary and secondary efficacy analyses will only include canakinumab 
150 mg sc q4w and placebo.
Other efficacy and safety data will be displayed in Epoch 2 in the following way:
o
Patients being randomized and not having a flare in epoch 2 (and not having 
received add-on dose or any up-titration)
o
Patients being randomized and having at least one flare in epoch 2 and having 
been up-titrated only once (or received add-on dose) (150mg q4->300mg q4;
Placebo->150mg q4)
o
Patients being randomized and having at least one flare in epoch 2 and having 
been up-titrated at least twice (Placebo->300mg q4)
  ------- No flare---------      ----------------------- >= 1 Flare ----------------------------
             Randomized                          Open –label arm
150mg q4      Placebo       150mg q4->300mg q4  Pla->150mg q4  Pla->150mg q4->300mg q4
Randomized withdrawal epoch (Epoch 3):
As one of the objectives in epoch 3 is to look at the maintenance of efficacy, patients will be 
categorized in two groups: those being randomized and keeping their initial treatment arm until 
the end of epoch 3 (i.e. no having a flare) and the other patients where the cumulative dose (in 
mg) over the 24 weeks will be analyzed.
Safety and efficacy data will be displayed in Epoch 3 in the following way:
- Re-randomized & no up-titration     ----    Cumulative dose in mg over 24 weeks  ----
150mg q8    Placebo                   <600mg
600mg - <1200mg     ≥1200mg
The cut-offs of 600mg, 1200mg were decided based on all options for cumulative dose over 24 
weeks depending on the number of flares and initial dose regimen at start of epoch 3. 
Example on how the cumulative dose is calculated over the 24 weeks:
Considering a patient taking initially 150 mg q8w at start of epoch 3 and having only one flare 
in epoch 3 then the patient will up titrate to 150 mg q4w. Here are the different cases. The first 
line shows the initial schedule with no flare. If no flare, the patient receives 3 injections of 150 
mg each so a total of 450 mg over 24 weeks, from Day 113 to Day 281, with no dose at day 
281( belongs to epoch 4).


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Day 113
Day 141
Day 169
Day 197
Day 225
Day 253
Cumulative 
dose in mg
Dose: 
150mg 
q8 with 
no flare
X
150mg
X
150mg
X
150mg
450mg
1 flare  
between 
D225-
D253 
X
150mg
X
150mg
X
150mg
X
150mg
600mg
1 flare  
between 
D197-
D225 
X
150mg
X
150mg
X
150mg
X
150mg
600mg
1 flare  
between 
D169-
D197 
X
150mg
X
150mg
X
150mg
X
150mg
X
150mg
750mg
1 flare  
between 
D141-
D169
X
150mg
X
150mg
X
150mg
X
150mg
X
150mg
750mg
1 flare  
between 
D113-
D141
X
150mg
X
150mg
X
150mg
X
150mg
X
150mg
X
150mg
900mg
Therefore for a patient taking initially 150mg q8w at the start of epoch 3 and having one flare 
in epoch 3, the range of cumulative dose over 24 weeks will be [600 mg-900 mg].


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Cumulative dose calculation for epoch 3:
For Patients weighing ≥7.5 kg and ≤40 kg, the dose is derived in mg/kg ie. Actual total dose 
(ml) x150mg / Weight(kg) at visit.

If the sum of the dose (mg/kg) in Epoch 3 is ≤7mg/kg then the patient will be assigned 
to the dose level category <600mg.

If the sum of the dose (mg/kg) in Epoch 3 is >7mg/kg -≤15mg/kg then the patient will 
be assigned to the dose level category ≥600mg-<1200mg.

If the sum of the dose (mg/kg) in Epoch 3 is >15mg/kg then the patient will be assigned 
to the dose level category ≥1200mg.
For Patients weighing <7.5 kg, the dose is derived in mg/kg ie. Actual total dose (ml) x75mg / Weight(kg) 
at visit.

If the sum of the dose (mg/kg) in Epoch 3 is ≤7mg/kg then the patient will be assigned to the 
dose level category <600mg.

If the sum of the dose (mg/kg) in Epoch 3 is >7mg/kg -≤15mg/kg then the patient will be 
assigned to the dose level category ≥600mg-<1200mg.

If the sum of the dose (mg/kg) in Epoch 3 is >15mg/kg then the patient will be assigned to the 
dose level category ≥1200mg.
Open-label treatment epoch (Epoch 4):
As few patients are expected having no flare in epoch 4 for 72 weeks, then safety and efficacy 
data will be displayed using the cumulative dose over the 72 weeks in Epoch 4 in the following 
way:


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       -----    Cumulative dose in mg over 72 weeks  ----
         <2700mg         ≥2700mg- <5400mg          ≥5400 mg
The cut-offs of 2700mg, and 5400mg were decided based on all options for cumulative dose 
over 72 weeks depending on the number of flares and initial dose regimen at start of epoch 4. 
The first group could be considered as patients taking initially 150mg q8w at start of epoch 4 
with or without flare over 72 weeks, the second one grouping patients taking initially 150mg 
q4w or 300mg q8w at start of epoch 4 with or without flare over 72 weeks and the last one 
patients taking initially 300mg q4 with or without flare over 72 weeks.
Roll-over patients from ACZ885D2203/ CACZ885D2207M and naïve Japanese 
crFMF patients with non-exon 10 mutations and patients >28 days but <2 years 
old
Data for the subgroup of patients coming from ACZ885D2203 and/or the subsequent Multiple 
Patient Program (MPP) treatment plan CACZ885D2207M collected in Epoch 3 as well as 
canakinumab naïve Japanese crFMF patients with non-exon 10 mutations and patients >28 days 
but <2 years old collected in Epoch 2 and Epoch 3, will separately be reported from the other 
patients who will be screened and randomized in Epoch 2. For subgroup 1: Roll-over patients 
from ACZ885D2203/ CACZ885D2207M:
In epoch 3, for this subgroup of patients safety and efficacy data will be tabulated as follows:
       ----    Cumulative dose in mg over 24 weeks  ----
          <600mg            600mg - <1200mg           ≥1200mg
In epoch 4, this subgroup of patients will be reported together with the other patients as follows:


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       -----    Cumulative dose in mg over 72 weeks  ----
          <2700mg         ≥2700mg- <5400mg          ≥5400 mg
For subgroup 2: Naïve Japanese crFMF patients with non-exon 10 mutations and patients >28 
days but <2 years old:
Patient Demographics & other baseline characteristics and Adverse events data for this 
subgroup will be tabulated under one treatment group ACZ885. All other safety and efficacy 
data will be listed under one treatment group ACZ885 in epoch 2 and epoch 3. This subgroup 
of patients will also be reported together with the other patients in epoch 4 using same 
cumulative dose categories.


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1.4
Summary of the analyses
Table 1-2
Analysis by Epoch
Endpoint/analysis
Epoch
Epoch 2 
(restricted to 
initial 
randomized 
treatment 
arms)
Epoch 2
Epoch 3
Epoch 4
Patient disposition 
X
X
X
X
Demography & baseline characteristics
X
X
X
X
Medical history
X
Previous & concomitant medication
X
X
X
X
Surgeries and medical procedures
X
X
X
Rescue medications
X
X
X
X
Study medication: duration of exposure
X
X
X
X
Proportion of responders at week 16
X
Supportive analysis using SAA
X
patients who achieve a PGA < 2 at Week 16
X
Serologic remission at week 16
X
Normalized SAA
X
Responder in epoch 3 (only for canakinumab 
responder in epoch 2)
X
CRP 
X
X
X
PGA 
X
X
X
PPGA 
X
X
X
Physician’s severity assessment of disease signs 
and symptoms over time
X
X
X
Fever
X
X
X
Blinded escape
X
Time to new flare
X
AIDAI
X
X
X
SF-12
X
X
X
CHQ-PF50
X
X
X
SDS v3
X
X
X
Total IL-1β
X
X
X
Adverse events
X
X
X
Laboratory data
X
X
X
Vital signs
X
X
X
ECG
X
X
X


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1.5
Patient demographics and other baseline characteristics
Summary statistics will be provided for demographic and baseline characteristics for the below 
treatment groups, and by epoch:
1. In Epoch 2, by initial randomized treatment arms (canakinumab 150mg sc q4w, placebo,
all subjects) and according to treatment groups defined in section 1.3
2. In Epoch 3, according to treatment groups defined in section 1.3
3. In Epoch 4, according to treatment groups defined in section 1.3
Demographics for subgroup of patients coming from ACZ885D2203 and/or the subsequent 
Multiple Patient Program (MPP) treatment plan CACZ885D2207M enrolled in Epoch 3 as well 
as canakinumab naïve Japanese crFMF patients with non-exon 10 mutations and patients >28 
days but <2 years old enrolled in Epoch 2, will be presented separately from the other patients 
who will be screened and randomized in Epoch 2.
The following common background and demographic variables will be presented:
Continuous variables:
o
Age at Baseline
o
Height at screening
o
Weight at screening
o
Body mass index (BMI) at screening
o
Time since first symptoms (years)
o
number of flares per year
o
average duration of flare (days)
o
local standardized CRP (mg/l) at baseline
o
SAA (mg/l) at baseline
Categorical variables:
o
Age categories (≥2-<4 , ≥4-<6, ≥6-<12,≥12-<18, ≥18-<65, ≥65)
o
Gender (Male/Female)
o
Race (White, Black or African American, Asian, Native Hawaiian or other,
Pacific Islander, Unknown, Other)
o
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Not 
reported)
o
Prior use of any biologics (No/Yes)
o
Prior use of Anakinra (No/Yes)
o
Prior use of Tociluzimab (No/Yes)
o
Prior use of Etanercept (No/Yes)
o
Confirmed gene mutation (TNFRSF1A gene for TRAPS, MEFV gene exon 10 
for crFMF, MVK gene for HIDS) (No/Yes)
o
Active disease at maximum colchicine dose (for crFMF patients) (No/Yes)
o
Intolerance to effective doses of colchicine (for crFMF patients) (No/Yes)


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o
Type of mutation (display the first 3 most common mutation types then the rest 
in “Other” category) and allele
o
Physician’s global assessment of disease activity at baseline (None, Minimal, 
Mild, Moderate, Severe) 
o
Physician’s severity assessment of disease signs and symptoms at baseline
(Absent, Minimal, Mild, Moderate, Severe)
for TRAPS: skin rash, 
musculoskeletal pain, abdominal pain, eye manifestations, for HIDS: 
lymphadenopathy, aphtous ulcers, abdominal pain, for crFMF: chest pain, 
abdominal pain, arthralgia/arthritis, skin rash
o
Patient’s global assessment of disease activity at baseline (None, Minimal, Mild, 
Moderate, Severe)
Body Mass Index (BMI) will be calculated using the following formula:
BMI = (body weight in kilograms) / (height in meters)2
1.6
Patient disposition
The number of patients screened will be presented. In addition, the reasons for screen failures 
will be provided in listing and will be tabulated. The number and percentage of patients in the 
randomized set who completed study epochs, and who discontinued the study prematurely 
(including the reason for discontinuation) will be presented by epoch, initial randomized 
treatment and treatment sequence (defined in section 1.3) and for all patients.
For each protocol deviation, the number and percentage of patients for whom the deviation
applies will be tabulated over the study (not by epoch) and will be presented according to 
randomization treatment in epoch 2.
1.7
Medical history
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term by initial randomized treatment groups in epoch 
2 for the safety set.
1.8
Study medication
The exposure to investigational treatment (number of doses) and duration of exposure (days) 
during this study will be summarized by cohort, epoch, initial randomized treatment and
treatment sequence (defined in section 1.3) and listed for the Safety Set.
Duration of exposure will be defined as the time from the first dose of study medication in that 
epoch to the last visit in the epoch (e.g., treatment epoch 2) +1 in days. For subjects who 
discontinue, the last visit in the corresponding treatment epoch will be taken into account.
For the final analysis, dose distribution from baseline to end of epoch 4 for each cohort will be 
displayed.


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1.9
Concomitant medication
The number and percentage of patients taking prior/concomitant medication will be 
summarized by cohort, treatment group in each epoch and ATC class for the safety set. The 
number and percentage of patients with surgeries and medical procedures will be summarized 
by cohort, treatment group in each epoch and MedDRA preferred term for the safety set. Prior 
and concomitant medications will be summarized by treatment group in separate tables. Prior 
medications will be summarized by initial randomized treatment groups in epoch 2.
Concomitant medications will be summarized by epoch and treatment groups (defined in 
section 1.3). Concomitant medication occurring in follow-up period after discontinuation of 
study will be listed but not summarized in tables.
Prior medications are defined as treatments taken and stopped prior to first dose of study
treatment in epoch 2. Any medication given at least once between the day of first dose of 
randomized study treatment and the date of the last study visit will be a concomitant medication, 
including those which were started pre-baseline and continued into the period where study 
treatment is administered.
Rescue medications (Corticosteroids and NSAIDS) will also be separately summarized by 
cohort, epoch, initial randomized treatment and treatment sequence (defined in 
section 1.3) and ATC class.
Colchicine positive subjects, will be summarized using counts and percentages of subjects who 
took colchicine at baseline and stopped before or at the end of epoch 2 and subjects who started 
taking colchicine after day 1 and stopped before or at the end of epoch 2. Subjects will be 
defined as colchicine positive according to the following: 
-
Patient who took colchicine continuing after receiving 1st ACZ drug
-
Patient who took colchicine after 1st dose of ACZ drug and stopped it after 4 weeks 
(>4weeks)
Colchicine information for crFMF cohort will be listed.
1.10
Efficacy evaluation
All efficacy evaluations will be performed on the full analysis set (FAS). For the overall 
analysis from baseline to epoch 4, patients who randomized to Placebo group at the beginning 
of epoch 2, only data after the first dose of ACZ885 will be included. 
1.10.1
Analysis of the primary endpoint
1.10.1.1 Variable(s)
Each cohort (TRAPS, HIDS, crFMF) of the study will have its own primary efficacy variable 
analyzed separately and independently of the other cohorts. The primary efficacy variable of 
the randomized treatment epoch (Epoch 2) and for the overall study is the proportion of 
responders within each cohort, where a responder in epoch 2 is defined as a patient who has 


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resolution of its index disease flare at Day 15 and does not experience a new flare during the 16 
weeks following randomization.
Resolution of the index flare (initial flare at the time of the randomization) is defined at the Day
15 visit as:

PGA < 2 and CRP within normal range (≤10 mg/L) or reduction of ≥ 70% from baseline
Absence of new flares over the first 16 weeks, where new flare is defined from the time of the 
resolution of the index flare as:

Physician’s Global Assessment (PGA) ≥2, and

CRP ≥ 30 mg/l
In the randomized treatment epoch (Epoch 2), patients needing dose escalation in the 
canakinumab arms, or escape from Placebo and receive open-label canakinumab, or are 
discontinued from the study due to any reason prior to evaluating the primary endpoint will be 
considered as non-responders. Local standardized CRP results shall be used for responder 
evaluation. For all visits, if local standardized CRP result is missing then the central 
standardized CRP result should be considered (except when patient discontinued)”. Note: the 
central lab values have to be standardized before they are used for the analysis and standardized 
value shall be conducted based on the SI normal range of 0.0-10.0 mg/l. Values in the original 
measurement unit (OMU), denoted x have been transformed into standardized values, denoted 
xref, as xref= 10 × [(x – minOMU) / rangeOMU], where minOMU and rangeOMU are 
minimum value and range on the OMU respectively.
Patient receiving an add-on dose before day 15 will not be considered as having resolution of 
the index flare at day 15.
1.10.1.2 Statistical model, hypothesis, and method of analysis
The primary hypothesis tested will be the superiority of canakinumab dose (150mg sc [or
2mg/kg] q4w) relative to placebo with respect to the proportion of responders in the randomized 
treatment epoch (Epoch 2), where a responder is defined as a patient who has resolution of its 
index disease flare and does not experience a new flare during the 16 weeks following 
randomization. The hypothesis within each cohort will be tested at a one-sided 2.5% level.
The statistical hypothesis is that there is no difference in the proportion of patients who respond 
at Week 16 with the canakinumab dose 150 mg s.c. (or 2mg/kg) q4w versus placebo. Let pjk 
denote the proportion of responders at Week 16 for treatment group j and cohort k, k = 1, 2, 3 
for each of the cohorts and j=0, 1 where 

0 corresponds to placebo,

1 corresponds to canakinumab 150mg q4w.
The following hypotheses will be tested

H1k: p1k – p0k = 0 versus HA1k: p1k – p0k > 0,
In other words:


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
H1: canakinumab 150 mg q4w is not different to placebo with respect to responder rate at 
Week 16.
Canakinumab treatment group will be compared to placebo with respect to the proportion of 
responders at Week 16 using the Fisher’s exact test. The proportion of responders, as well as 
the odds ratio and risk difference with corresponding 95% confidence interval will be presented.
The 95% confidence interval for the proportions will be calculated using exact (Clopper –
Pearson) method.
1.10.1.3 Handling of missing values/censoring/discontinuations
Patients needing dose escalation in the canakinumab arms, or who escape from placebo to 
canakinumab in the randomized treatment epoch (Epoch 2), or discontinued from the study due 
to any reason prior to evaluating the primary endpoint will be considered as non-responders in 
epoch 2.
1.10.1.4 Supportive analyses
The primary analysis in the randomized treatment epoch will be repeated where definition of
the resolution of the index flare and new flare definition will be derived from the centralized
SAA values. Resolution of the index flare (initial flare at the time of the randomization) is 
defined at the Day 15 visit as:

PGA < 2, and SAA within normal range (≤10 mg/L) or reduction of ≥ 70% from baseline 
Absence of new flares over the first 16 weeks, where new flare is defined from the time of the
resolution of the index flare as:

PGA ≥2, and SAA ≥ 30 mg/l
If SAA value is missing for the response assessment at scheduled visit then no imputation will 
be applied and response will be missing.
1.10.1.5 Sensitivity analyses
The primary analysis in the randomized treatment epoch will be repeated on the Full Analysis 
Set where patients receiving a single add-on injection before Day 15 will be excluded.  This 
implies that the following patients will be excluded; 

patients receiving add-on injection based on criterion from Day 8 to Day 14(persistent 
PGA ≥2, or CRP persistent >10 mg/L with less than 40% reduction from baseline 
from Day 8 to Day 14),

patients receiving a single add-on injection despite they don’t fulfill criterion for add-on 
injection from Day 8 to Day 14.
A second sensitivity analysis will be performed on the Full Analysis Set where patients 
receiving a single add-on injection despite they don’t fulfill criterion for add-on injection from 
Day 8 to Day 14 will be excluded.
A third sensitivity analysis will be performed where the primary analysis in the randomized 
treatment epoch will be repeated on Full Analysis Set where patients receiving a single add-on 


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injection before Day 15 will be considered as responders except if new flare occurs from Day 
15 onward in Epoch 2.
In additionally, two more sensitivity analysis will be performed where the primary efficacy
analysis on week 16 in the randomized treatment epoch will be repeated on Full Analysis Set 

Where only local values will be used and if missing local CRP values at visit 102 then 
no resolution of the index flare will be considered.

Where only central values will be used and if missing central CRP values at visit 102 
then no resolution of the index flare will be considered.
1.10.2
Analysis of secondary variables
Secondary efficacy variables will be analyzed separately for each independent cohort (TRAPS, 
HIDS, crFMF). 
The secondary efficacy objectives will be evaluated by assessing the efficacy of canakinumab
(q4w in the randomized treatment epoch, and q8w in the randomized withdrawal epoch) as
compared to placebo and will be analyzed by cohort. All secondary efficacy objectives will be
included in the closed testing procedure.

to evaluate the percentage of patients who achieve a PGA < 2 at Week 16

to evaluate the percentage of patients with the serologic remission at Week 16 (defined as
C-reactive protein [CRP] ≤10 mg/L)

to evaluate the percentage of patients with normalized Serum Amyloid A (SAA) level at
Week 16 (defined as SAA ≤10 mg/L)

to evaluate the percentage of canakinumab responders in Epoch 2 who maintain clinically
meaningful response (absence of new flares) when switched to a canakinumab every 8
weeks regimen compared to placebo (Epoch 3).
1.10.2.1 Testing strategy
The following hypotheses will be included in the closed testing procedure, and type-I-errors 
will be set such that a family-wise type-I-error rate of 2.5% is kept (one sided tests)

Primary objective: H1.
Secondary objectives:

H2: Canakinumab 150mg q4w is not different to placebo with respect to the percentage of
patients with PGA < 2 at Week 16.

H3: Canakinumab 150mg q4w is not different to placebo with respect the percentage of
patients with CRP ≤10mg/L at Week 16.

H4: Canakinumab 150mg q4w is not different to placebo with respect the percentage of
patients with SAA ≤10mg/L at Week 16.

H5: Canakinumab 150mg q8w is not different to placebo with respect to the percentage of 
responders (absence of new flares) at Week 40.


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If the primary objective is achieved, all secondary endpoints in the randomized treatment epoch 
(Epoch 2) will be assessed. If all secondary objectives are achieved in the randomized treatment 
epoch (Epoch 2), then the secondary objective in the randomized withdrawal epoch will be 
tested. The 95% confidence interval for the proportions will be calculated using exact (Clopper 
–Pearson) method.
Physician’s global assessment of disease activity (PGA)
PGA is based on a 5-point scale for disease associated signs and symptoms:
0 (=none/no), 1 (=minimal), 2 (=mild), 3 (=moderate), and 4 (severe). 
Frequency tables will be provided by analysis visit and randomized treatment groups for each 
cohort. Between-treatment differences for the proportion of patients with PGA < 2 at Week 16 
will be analyzed using a logistic regression model with treatment group, and baseline PGA as 
explanatory variables for each cohort. All randomized patients at start of Epoch 2 will be 
considered for this analysis. Patients needing dose escalation in the canakinumab arms, or who 
escape from placebo arms to canakinumab in the randomized treatment epoch (Epoch 2), or 
discontinued from the study due to any reason prior evaluating the endpoint at week 16, will be
considered as having PGA ≥ 2. If the logistic regression model has difficulty converging due 
low or high response rates, then Firth’s method will be used in the logistic regression model. If 
the convergence issue is still not resolved then Canakinumab treatment group will be compared 
to placebo with respect to the proportion of patients with PGA < 2 at Week 16 will be analyzed 
using the Fisher’s exact test.
Serological remission
Serological remission is defined as CRP ≤10mg/L. Between-treatment differences for the
proportion of patients with CRP ≤10mg/L at Week 16 will be analyzed using a logistic 
regression model with treatment group, and baseline CRP values as explanatory variables for 
each cohort. All randomized patients at Epoch 2 will be considered for this analysis. Patients 
needing dose escalation in the canakinumab arms, or who crossed-over from placebo arms to 
canakinumab in the randomized treatment epoch (Epoch 2), or discontinued from the study due 
to any reason prior evaluating the endpoint at week 16, will be considered as having CRP > 
10mg/L. If the logistic regression model has difficulty converging due low or high response 
rates, then Firth’s method will be used in the logistic regression model. If the convergence issue 
is still not resolved then the canakinumab treatment group will be compared to placebo with 
respect to the proportion of patients with CRP ≤10mg/L at Week 16 will be analyzed using the 
Fisher’s exact test.
Normalization of SAA
Normalization of SAA is defined as SAA ≤10mg/L. Between-treatment differences for the 
proportion of patients with SAA ≤10mg/L at Week 16 will be analyzed using a logistic 
regression model with treatment group, and baseline SAA values as effect for each cohort. All
randomized patients at Epoch 2 will be considered for this analysis. Patients needing dose 
escalation in the canakinumab arms, or who crossed-over from placebo arms to canakinumab 


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in the randomized treatment epoch (Epoch 2), or discontinued from the study due to any reason 
prior evaluating the endpoint at week 16, will be considered as having SAA > 10mg/L. If the 
logistic regression model has difficulty converging due low or high response rates, then Firth’s 
method will be used in the logistic regression model. If the convergence issue is still not 
resolved then the Canakinumab treatment group will be compared to placebo with respect to 
the proportion of patients with SAA ≤10mg/L at Week 16 will be analyzed using the Fisher’s 
exact test.
Maintenance of clinically meaningful response
Responder in the Randomized withdrawal epoch (epoch 3) is defined as no flare between week 
16 and week 40. The canakinumab 150mg q8w treatment group will be compared to placebo 
with respect to the proportion of responders at Week 40 using the Fisher’s exact test. Only
canakinumab responders in Epoch 2 and re-randomized at week 16 will be considered in the
analysis. The proportion of responders, as well as the odds ratio (if estimable) and risk
difference with corresponding 97.5% confidence interval will be presented. Canakinumab 
responders at end of epoch 2 needing dose escalation in the canakinumab arm, or who crossed-
over from placebo arm to canakinumab in Epoch 3, or discontinued from the study due to any 
reason in epoch 3 will be considered as non-responders in epoch 3.
1.10.3
Subgroup analyses
Primary and secondary efficacy analyses will be repeated by subgroup of prior use of any 
biologics (No/Yes) and by age groups (<18 years old and ≥18 years old).
Primary and secondary efficacy endpoints based on week 16 will be repeated by Colchicine 
subgroup as defined below for crFMF cohort only. Colchicine is defined with ATC code: 
M04AC01.
Two groups will be defined:
Colchicine negative defined as :
-
Colchicine Naïve patients (no colchicine before or after treatment)
-
Patient who took colchicine before and stopped before receiving ACZ drug
-
Patient who took colchicine before and stopped within 4 weeks after 1 st dose of ACZ 
drug (≤4weeks)
Colchicine positive defined as :
-
Patient who took colchicine continuing after receiving 1st ACZ drug
-
Patient who took colchicine after 1st dose of ACZ drug  and stopped it after 4 weeks 
(>4weeks)
1.10.3.1 Additional analyses
Number and percentage of patients with resolution of index flare at day 15 based on status of 
receiving add-on dose before day 15 will be presented by initial randomized treatment. In 
addition, number and percentage of responders at day 29 for non-responders at day 15 based on 
their value at day 15 and by status of up-titration before day 29 will be presented.


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1.10.4
Exploratory analysis
An exploratory analysis will be performed where the primary and secondary efficacy analysis
on week 16 in the randomized treatment epoch will be repeated on Full Analysis Set where 
patients initially randomized to ACZ will be considered as responder if : Resolution of index 
flare at day 15 and no flare after day 15 or for those who have been up-titrated to 300 mg before 
day 29, have resolution of index flare at day 29 (PGA < 2 and CRP within normal range (≤10 
mg/L) or reduction of ≥ 70% from baseline) and no flare after day 29.
1.10.5
Exploratory efficacy variables
Exploratory efficacy variables will be analyzed separately for each independent cohort (TRAPS, 
HIDS, crFMF). 
Inflammatory parameters (CRP, SAA)
CRP and SAA will be summarized descriptively by analysis visit for each cohort, by epoch and 
treatment groups (as defined in section 1.3).
In addition, the number and percentage of patients with CRP ≤10mg/L, SAA ≤10mg/L will also 
be presented.
Number and percentage of patients with CRP ≤10mg/L, CRP > 10- <15 mg/L, CRP ≥15-<30 
mg/L, CRP≥30 mg/L at day 15 will be presented by status of resolution of index flare and initial 
randomized treatment.
Number and percentage of patients with CRP ≤10mg/L, CRP > 10- <15 mg/L, CRP ≥15-<30 
mg/L, CRP≥30 mg/L at day 29 will be presented for patients initially receiving ACZ and having 
up-titration before day 29  by disease cohorts. 
In addition, number and percentage of patients with the following categories will be 
summarized for CRP assessment before day 15, at day 15 and day 29 by initial randomized 
treatment by disease cohorts.

CRP ≤10mg/L

CRP reduction less than 40% from baseline

CRP reduction of ≥ 70% from baseline

CRP reduction of ≥ 40% from baseline
In the final analysis, summary tables of CRP and SAA after patients taking ACZ885 will be 
shown by visit, from Baseline to last visit in Epoch 4. 
PGA and PPGA Disease Activity, Key disease specific signs and symptoms
The efficacy outcomes measured on Likert scale, such as physician’s global assessment of
disease activity, physician’s severity assessment of disease signs and symptoms, will be 
presented in frequency tables by analysis visit for each cohort, epoch and treatment groups (as 
defined in section 1.3).


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Between-treatment differences for the proportion of patients with no disease activity based on 
PGA (PGA<1), no disease activity (rate overall severity<1) based on PPGA at Week 16 will be 
analyzed using a Fisher’s exact test for each cohort, by randomized treatment group.
Patients needing dose escalation in the canakinumab arms, or who escape from placebo arms to 
canakinumab in the randomized treatment epoch (Epoch 2) or discontinued from the study due 
to any reason prior evaluating the endpoint at week 16, will be considered as having PGA ≥1
and PPGA≥1.Patient/parent’s global assessment of disease activity (PPGA) will also be 
summarized for weekly averages using summary statistics. Week 0 will be average of PPGA 
score from day -7 to day 1, week 1 will be average of score from day 2 to day 7, week 2 will be 
average of score from day 8 to day 14 and so on.
In addition, Spaghetti plot will be provided by subject and cohort and initial randomized 
treatment for PGA assessment and Physician’s severity assessment of disease signs and 
symptoms
In the final analysis, shifts in PGA score from baseline to end of Epoch 4 by treatment group 
for each cohort will be shown in figures. , Summary tables of PGA after patients taking ACZ885 
will be shown by visit, from Baseline to last visit in Epoch 4. 
Episodes of Fever
Number and duration of fever episodes collected in patient’s diaries will be summarized
within each cohort, epoch and treatment group (as defined in section 1.3). Plots of fever 
episodes per patient over time (displaying frequency and duration) and treatment group will 
also be presented. Treatment difference for time to first resolution of fever will be analyzed 
using a Cox proportional hazard regression model. The Kaplan-Meier estimates of the 
proportion of patients with first resolution of fever along with the associated 95% confidence 
intervals using the Greenwood’s formula will be provided.
Rescue medication 
Corticosteroids levels will be summarized descriptively by analysis visit for each cohort and by 
treatment group (as defined in section 1.3). In addition, the number and percentage of patients 
who reduce their corticosteroids maintenance dose at Week 16 compared to baseline, patients 
who take corticosteroids rescue medication and patients who take only NSAIDs rescue 
medication during the study, patients who take steroid  level >0.2 mg/kg/day will also be 
presented. Between-treatment differences for the proportion of patients who are able to reduce 
their corticosteroids at Week 16 will be analyzed using a Fisher’s exact test for each cohort.
The analysis will only include subjects who were receiving corticosteroids at baseline.
Rescue medications are not collected visit wise in the study and are collected in summary page 
as part of concomitant medications. Rescue medications will be mapped to visits. Rescue 
medications shall be assigned to visit based on start and end date of the medication and 
corresponding visit date. For example, if visit date for visit 103 lies between start and end date 
of “VALISONE-G” corticosteroid then dose level of this concomitant medication will be 
assigned to visit 103. If there are more than one dose that are assigned to same visit then these 


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doses shall be added after converting the units to mg/kg/day. If there are no records of rescue 
medication for any visit then it shall be considered as 0 mg/kg/day dose.
Blinded escape
The number and percentage of patients who require blinded escape from Days 8 to 28 will be 
summarized by cohort and randomized treatment group.
Auto-Inflammatory Disease Activity Index (AIDAI)
Symptoms evaluated in the AIDAI diary will be summarized with each cohort and epoch (2 and 
3) and by treatment group (as defined in section 1.3) for monthly score as sum of scores over a 
month. Spaghetti plot will be provided by subject and cohort and initial randomized treatment.
 
 
 
 
Time to first new flare in the randomized withdrawal epoch (Epoch 3)
Time to first new flare in Epoch 3 will be analyzed for patients re-randomized at the start of 
epoch 3. The two treatment groups (150mg q8w and placebo) will be compared using a one-
sided log-rank test at the 2.5% significance level. The hazard ratio and its associated 95% two-
sided confidence intervals will be estimated. Kaplan-Meier estimates of the probability to
experience a flare event will be calculated from the start of the randomized withdrawal epoch.
95% confidence intervals using Greenwood’s formula will be provided.
Patients who discontinued the study in epoch 3, or having an up-titration or escape from placebo 
group to canakinumab arm will be counted as having a flare in epoch 3. In this case the date of 
the premature subject withdrawal (PSW) visit, or resp. time of up-titration or escape is 
considered as the end date for the calculation of time to flare.
SF-12 Health Survey (SF-12)
SF-12 scores will be summarized (descriptively) by epoch (2 and 3), analysis visit, initial
randomized treatment and treatment sequence (as defined in section 1.3) within each 
cohort. Only patients ≥18 years of age at baseline will be part of the analyses.
SF-12 measurements consists of 12 questions over eight subscales (physical function, pain, 
general and mental health, vitality, social function, physical and emotional health). The 
subscales can be aggregated to derive a physical-component summary score (PCS) and a 
mental-component summary score (MCS).
The score will be summarized for each subscale and for PCS and MCS.
Child Health Questionnaire – Parent Form 50 (CHQ-PF50)
Descriptive statistics will be used to summarize patient responses on the CHQ-PF50©
Questionnaire by epoch (2 and 3), analysis visit, initial
randomized treatment and
treatment sequence (as defined in section 1.3), total score (Physical (PhS) and Psychosocial 


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(PsS) scores) and by domain within each cohort. Only patients >5 <18 years of age at baseline 
are included.
Sheehan Disability Scale (SDS v3)
SDS score by domain and global functional impairment score will be summarized by epoch (2 
and 3), analysis visit, initial randomized treatment and treatment sequence (as 
defined in section 1.3) within each cohort.
Number of flares 
The number of new flares by patient will be summarized by epoch and treatment arms within 
each cohort.
Disease-associated genetic mutations
Relationships between disease-associated genetic mutations and CRP/SAA/PGA values at Day 
15 on patients randomized to Canakinumab will be analyzed by cohort. T-test will be used for 
mean comparison between genetic mutations for CRP and SAA, and wilcoxon rank sum test
will be used for mean comparison between genetic mutations for PGA. Mean CRP, SAA, PGA 
at Day 15 were compared between
For cr-FMF cohort
(i)
all M694V gene vs overall cr-FMF canakinumab treated patients
(ii) all M694V gene vs non-M694V gene
(iii) M694V heterozygous vs homozygous
For HIDS cohort
(i)
all V377I gene vs overall HIDS canakinumab treated patients 
(ii) all V377I gene vs non-V377I gene
(iii) V377I heterozygous vs homozygous
For TRAPS cohort
(i) all R92Q gene vs overall TRAPS canakinumab treated patients
(ii) all R92Q gene vs non-R92Q gene
(iii) R92Q heterozygous vs homozygous
In the T-test procedure, Pooled and Satterthwaite methods for the p-value were used depending 
on the test on equality of variances. 
In the Npar1way procedure, p-value from Exact test was taken given the relatively small sample 
size of patients.
1.11
Pharmacokinetic  
Pharmacokinetic (PK) concentrations will be summarized by epoch by means of arithmetic and 
geometric mean, median, standard deviation, minimum and maximum, coefficient of variation 
for arithmetic and geometric mean, the number of non-missing data points and the number of 
data points greater than zero. Sample number, date, scheduled timepoint, actual time of sample 
and days post dose (elapsed time) will also be listed.


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1.12
Pharmacodynamics 
Total IL-1β
Total Interleukin-1 beta (IL-1β) summary statistics (arithmetic and geometric mean, median, 
standard deviation, minimum and maximum, coefficient of variation for arithmetic and 
geometric mean, the number of non-missing data points and the number of data points greater 
than zero) will be displayed by epoch. Sample number, date, scheduled timepoint and actual 
time of sample will be listed.
1.12.1
Pharmacogenetics 
Sample number, date, scheduled timepoint and actual time of sample will be listed.
1.13
Safety evaluation
All safety evaluations will be performed on the Safety set. For the overall analysis from baseline 
to epoch 4, patients who randomized to Placebo group at the beginning of epoch 2, only data 
after the first dose of ACZ885 will be included.
1.13.1
Adverse events
Adverse events will be coded using the MedDRA dictionary that provides the primary system
organ class and preferred term information. 
Adverse events will be summarized by presenting, for each cohort, epoch,
initial
randomized treatment and treatment sequence (as defined in section 1.3), the number 
and percentage of patients having any adverse event, having any adverse event in each primary 
system organ class and having each individual adverse event based on the preferred term. All 
other information collected (e.g. severity, relationship to study treatment) will be tabulated and 
listed as appropriate.
Adverse events will also be summarized by standardized MedDRA query (SMQ).
Exposure adjusted incidence rate of adverse events by primary system organ class and preferred 
term will be presented by epoch and according to the actual dose the patient receives.
Deaths, serious adverse events, and adverse events leading to discontinuation of study treatment 
will be summarized by primary system organ class and preferred term and listings will be 
provided.
Adverse events of special interest including identified and potential risks and adjudicated 
malignancy and infection events will be listed and summarized for each cohort, epoch and 
treatment group (as defined in section 1.3).
In addition, summary of adverse events and serious adverse events will be presented in 
combining the three cohorts. Adverse events occurring in follow-up period after discontinuation 
of study will be listed but not summarized in tables.
For the final analysis, AE/SAE will be reported using data after patients taking ACZ885 starting 
from epoch 2 to end of epoch 4.


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For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on any ACZ 
group adverse events which are not serious adverse events with an incidence greater than 5% 
and on any ACZ group serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
-
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
-
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective".
1.13.2
Local injection site tolerability
Local injection site tolerability will be assessed on the injection site (separately from the adverse 
event page). Each patient will be classified into one of the following four categories (based on 
AE ATC grade):
1.
No tolerability reactions at any time in the trial.
2.
A mild reaction (grade 1) observed on at least one occasion but no moderate or severe/
potentially life threatening reactions.
3.
A moderate reaction (grade 2) observed on at least one occasion but no severe/ potentially 
life threatening reactions.
4.
A severe (grade 3) or potentially life threatening (grade 4) reaction observed on at least 
one occasion.
The number and percentage of patients in each category will be presented for each cohort, epoch,
initial randomized treatment and treatment sequence (as defined in section 1.3). In
addition, 
summary 
of 
pre-specified 
symptoms 
(Erythema/Redness, 
Tenderness, 
Induration/Swelling, Pain) will be provided. All details of injection site reactions will be listed.
1.13.3
Laboratory data
Laboratory parameters will be summarized by presenting descriptive statistics for the absolute 
values, change from baseline (and from each start of epoch) for each cohort, epoch, analysis 
visit and treatment group (as defined in section 1.3). Change from baseline (resp. start of epoch)
will only be summarized for patients with both baseline (resp. start of epoch) and post baseline 
values in each epoch. There will be multiple “baseline” as one will be defined for each start of 
epoch. All information collected will be listed by patient and abnormal values will be flagged. 
In addition, shift tables based on normal ranges and incidence rates of notable abnormalities 
will be presented.


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Creatinine clearance will be also be summarized by subgroup of Colchicine for crFMF disease 
cohort. Creatinine clearance will also be summarized by subgroup of CKD categories defined 
at baseline derived using eGFR value as below:
CKD Stage 1: >=90 ml/min/1.73m2 
CKD Stage 2: 60-<90 ml/min/1.73m2 
CKD Stage 3a-b: 30-<60 ml/min/1.73m2 
CKD Stage 4-5: <30 ml/min/1.73m2
Shift in CKD stage from baseline to end of epoch 2, epoch 3 and epoch 4 will be summarized 
for crFMF disease cohort patients.
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): >3x, 5x, 10x, and 20x Upper Limit of Normal (ULN)1
2. AST (SGOT): > 3x, 5x, 10x, and 20x ULN1
3. Elevation of AST and/ or ALT (> 3xULN) accompanied by elevated bilirubin (> 1.5xULN,
> 2xULN)1
4. Any elevations of bilirubin; elevated total bilirubin (TBL) to > 2x ULN1
5. Any elevations of ALP >1.5x ULN
6. Gamma-Glutamyltransferase (GGT): > 3x ULN
7. Creatinine (serum): ≥ 3x ULN
8. Creatinine clearance (CrCl) (Cockroft-Gault formula)2: ≥ 25% decrease from baseline
9. Triglycerides: >5x ULN
Hematology
1. Hemoglobin: ≥20 g/L decrease from baseline,
<100 g/L
2. Platelet count3
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: <25x 109/L
3. White blood cell count3
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
a. CTC Grade 1: <LLN – 1.5 x 109/L


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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 109/L
5. Absolute lymphocytes: <LLN
6. Absolute eosinophils: ≥ 2.5x, ≥ 3x ULN
Urinalysis
Protein urine dipstick: ≥ ++ 
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): > 3x, 5x, 10x, and 20x Upper Limit of Normal (ULN)1
2. AST (SGOT): > 3x, 5x, 10x, and 20x ULN1
3. Elevation of AST and/ or ALT (> 3xULN) accompanied by elevated bilirubin (> 1.5xULN,
> 2xULN)1
4. Any elevations of bilirubin; elevated total bilirubin (TBL) to > 2x ULN1
5. Any elevations of ALP >1.5x ULN1
6. GGT: ≥ 3x, 5x ULN
7. Creatinine (serum): ≥ 1.5x ULN
8. Creatinine clearance (Schwartz formula§): ≥ 25% decrease from baseline, ≥2 consecutive
visits
9. Total Cholesterol: ≥ 1.5xULN
10. Triglycerides: ≥ 5.7 mmol/L
11. Creatinine clearance (Schwartz formula4): ≥ 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,  
<85 g/L (patients < 16 years of age) or <100 g/L (patients ≥ 16 years of age)
2. Platelet count3

CTC Grade 1: <Lower Limit of Normal (LLN) – 75 x 109/L

CTC Grade 2: <75 – 50 x 109/L

      CTC Grade 3: <50 – 25 x 109/L

CTC Grade 4: <25x 109/L
3. White blood cell count3

CTC Grade 1: <LLN – 3 x 109/L

CTC Grade 2: <3 – 2 x 109/L


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
CTC Grade 3: <2 – 1 x 109/L

CTC Grade 4: <1 x 109/L
4. Absolute neutrophils

CTC Grade 1: <LLN – 1.5 x 109/L

CTC Grade 2: <1.5 – 1 x 109/L

CTC Grade 3: <1 – 0.5 x 109/L

CTC Grade 4: <0.5 x 109/L
5. Absolute lymphocytes: <LLN
6. Absolute Eosinophils: ≥ 1.1 x ULN, ≥0.45 x 109/L
Urinalysis

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/1.73m2) = [0.413 x length (cm)/ (serum creatinine mg/dl)] (Schwartz et al. 2009).
1.13.4
Vital signs
Vital signs will be summarized by presenting descriptive statistics for the absolute values and
changes from baseline (and from each start of epoch) for each cohort, epoch, analysis visit and 
treatment group (as defined in section 1.3). All information collected will be listed by patient 
and abnormal values will be flagged
Notable vital signs abnormalities in adult patients (≥ 18 years of age)
Post-baseline vital signs will be flagged as notable abnormalities as follows:
1. Systolic/Diastolic blood pressure: ≥25% decrease or ≥25 % increase from baseline
2. Pulse: ≥ 110 bpm with ≥15% change from baseline, or < 50 bpm with ≥15% change from
baseline
Notable vital signs abnormalities in pediatric patients (< 18 years of age)
Post-baseline vital signs in pediatric patients (at the time of the assessment) will be flagged as 
notable abnormalities as follows:


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1. Systolic blood pressure (mmHg): >ULN and increased >20 in change from baseline or
<LLN and decreased >20 in change from baseline
2. Diastolic blood pressure (mmHg): >ULN and increased >20 in change from baseline or 
<LLN and decreased >20 in change from baseline
3. Pulse (bpm): >ULN and increased >20 in change from baseline or <LLN and decreased
>20 in change from baseline
Blood pressure normal range for patients >28 days but <18 years old are listed in below table:
Table 1-3
Blood pressure normal range in pediatric population according to 
current age
Age is age at the time of the visit. 
#Reference values according to website: http://www.sickkids.ca/Nursing/Education-and-learning/Nursing-Student-
Orientation/module-two-clinical-care/vitals/.
ECG
Listings and table will be provided for notable ECG abnormalities. Summary statistics will be
presented for ECG variables by epoch, analysis visit and treatment group for each cohort.
1.13.5
Immunogenicity
A listing for each cohort will be presented for patients who develop immunogenicity.
1.13.6
Liver safety monitoring
A listing for each cohort will be presented for patients with liver events.
1.14
Interim analyses
Contingency Analysis
If there is any delay in the enrollment of the patients in one of the cohorts in the randomized 
treatment epoch i.e. it takes more than 24 weeks to recruit patients in one of the cohorts, then
an interim analysis performed within each cohort would be considered. The decision to perform 
Age
SBP
DBP
Pulse
0 - 1 months
#
45-80
33-52
93-182
>1 - 3 months
#
65-85
35-55
120-178
>3 - 6 months
#
70-90
35-65
107-197
>6 -12 months
#
80-100
40-65
108-178
>12 months- 2 years
#
80-100
40-70
90-152
> 2 years - 5 years
100-115
65-75
80-130
> 5 years -12 years
110-125
70-80
70-115
> 12 years -18 years
120-135
75-85
60-100


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this interim analysis would be taken jointly between the indication-specific lead investigators 
and Novartis.

If overall enrollment time has surpassed 24 weeks, 

AND If >2/3 patients are enrolled in the slowest enrolling cohort.
However, due to the low number of patients in the slowest enrolling cohort, the interim analysis 
will not be sufficiently powered to detect statistically significant differences. Thus only 
descriptive analysis would be performed in this cohort and these results will complete the
dossier with the final results of the two cohorts where all patients have been recruited.
Primary efficacy analysis
In order to support regulatory filing, the analyses of the primary and all Week 16 secondary
efficacy variables will be performed after all subjects have completed the final visit of the
randomized treatment epoch (Epoch 2) of the study (Day 113). These results will be presented
in a first Clinical Study Report (CSR).
40-week interim analysis
An interim analysis is planned at the end of the randomized withdrawal epoch (Epoch 3). An
Interim Analysis CSR may be prepared to support health authority interactions, as necessary.
The final long-term safety analyses involving data from all 4 epochs will be performed after all 
patients have completed the final visit of the trial (Day 785) and will be pres ented in the final 
CSR.
1.15
Determination of sample size
The primary efficacy objective in the randomized treatment epoch and for the overall study is 
to compare canakinumab treatment to placebo with respect to the proportion of responders at 
Week 16 using the Fisher’s exact test. The proportion of responders, as well as the odds ratio 
(if estimable) and risk difference with corresponding 97.5% confidence interval will be 
presented.
 
 
 
 
 Since a 20% screening failure rate is expected, it is estimated 
that approximately 
 patients have to be screened.
Nquery Advisor® software version 7.0 was used.


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2
Clinical Study Report -
Appendix 16.1.9  Documentation of statistical methods
2.1
Analysis visit windows
Baseline/ First day in Epoch 2
For canakinumab naïve Japanese crFMF patients with non-exon 10 mutations and patients >28 
days but <2 years old, the date of baseline is equal to the first date of dosing. 
For patients who are randomized in epoch 2 then date of baseline is equal to the first date of 
dosing on or after the date of randomization (Visit 101). 
For laboratory and vital signs evaluations the latest value before start of treatment in Epoch 2
was taken as baseline in case of missing baseline.
First day in Epoch 3
For patients who roll-over from study ACZ885D2203/D2207M, the date of baseline is equal to 
the first date of dosing.
For canakinumab patients in epoch 2 who are responder at week 16, the first day in epoch 3 is 
equal to the first date of dosing on or after the date of re-randomization (Visit 201).
For the other patients, the first day in epoch 3 is equal to the first date of dosing at visit 201.
First day in Epoch 4
For all patients, the first day in epoch 4 is equal to the first date of dosing at visit 301.
Time visit window
The visit numbers as reported in the CRF were used except for end of study/epoch visit 
(visit=199, 299, 399), which were mapped according to Table 2-1.


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Table 2-1
Visit window definition
Epoch
Analysis Visit
Visit window (days) 
for patients who 
entered epoch 2
Visit window (days) 
for patients who 
directly entered 
epoch 3
2
Day 15 (Week 3)
2 – 18
–
2
Day 29 (Week 5)
19 – 32
–
2
Day 57 (Week 9)
33 – 60 
–
2
Day 85 (Week 13) 
61 – 88 
–
2
Day 113 (Week 17)
89 – 116    
–
3
Day 141 (Week 21)
117 – 144 
2 – 32
3
Day 169 (Week 25)
145 – 172 
33 – 60
3
Day 197 (Week 29)
173 – 200 
61 – 88 
3
Day 225 (Week 33)
201 – 228
89 – 116    
3
Day 253 (Week 37)
229 – 256 
117 – 144 
3
Day 281 (Week 41)
257 – 284  
145 – 172
4
Day 337 (Week 49) 
285 – 340
173 – 228
4
Day 393 (Week 57)
341 – 396
229 – 284
4
Day 449 (Week 65)
397 – 452
285 – 340
4
Day 505 (Week 73)
453 – 508
341 – 396
4
Day 561 (Week 81)
509 – 564
397 – 452
4
Day 617 (Week 89)
565 – 620
453 – 508
4
Day 673 (Week 97)
621 – 676
509 – 564
4
Day 729 (Week 105)
677 – 732
565 – 620
4
Day 785 (Week 113)
>733
>620
For subjects who prematurely discontinue between two scheduled visits, the data at the end of 
study/epoch visit will be re-aligned to the visit which belongs to the associated visit window. If 
the early termination visit is mapped to a visit for which the scheduled visit was already 
performed, then the assigned visit number will be set to the next one. For example if a patient 
discontinued prematurely at week 8 (assigned based on the visit window above) but already has 
a value for week 8, then the end of study visit will be set to week 12.