Clinical trial NCT02756650
Conditions: Behcet Disease
Keywords: Behcet Disease Inflammation Immune system Arthritis
Sponsor: Novartis Pharmaceuticals
Start date: 2016-06-23; Completion date: 2019-01-31
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary objective of the study was to evaluate the safety and efficacy of canakinumab on the clinical and inflammatory findings of Behced Disease patients with neurologic and vascular involvement.

Detailed description:
Primary endpoint: Resolution of acute exacerbation findings related to Behçet's Disease (BD) based on achievements in any of the following items without deterioration on day 30:

For patients with parenchymal neurologic disease: Resolution of acute exacerbation of parenchymal neurologic findings based on improvements in any of the following items without deterioration on Day 30:

* Improvement of muscle strength, ataxia, or other relevant neurologic findings depending on the involved region on neurological examination (by Neuro-Behçet's Disease Score, Modified Expanded Disability Status Scale, and Modified Rankin Scores) cerebrospinal fluid
* Improvement in systemic inflammatory findings (CRP, Erythrocyte Sedimentation Rate , SAA)
* Any decrease in the size of the MRI lesion, or disappearance of contrast enhancement
* Improvement in patients' and physicians global assessment using a 10-cm visual analogue scale (VAS)

Complete response was defined as full clinical recovery to the pre-attack state, disappearance of MRI lesion(s), and normalisation of Cerebrospinal Fluid findings.

Partial response was defined as partial improvement in clinical findings, but with findings still worse than the pre-attack state, and MRI lesions, which become smaller with no or less enhancement, and a decrease in cerebrospinal fluid cell count.

Non-response was defined as no improvement in clinical findings, no change on MRI, no change in cerebrospinal fluid parameters, or worsening in those findings.

For patients with large vessel vascular disease: Resolution of acute vascular exacerbation findings related to Behçet's Disease based on achievements in any of the following items without deterioration at 1 month:

* Improvement in relevant symptoms (localised pain, abdominal pain, calf thickness, haemoptysis) by using physician and patient's global assessment with VAS
* Improvement in systemic inflammatory findings (CRP, ESR, SAA)
* Any improvement in radiological findings depending on the involved vessels (MR, CT or Doppler findings)
* Improvement in patients' and physicians global assessment using a 10-cm visual analogue scale (VAS)

Complete response was defined as clinical and laboratory improvement based on ≥50% improvements in patient's and physician's global assessments by using VAS, and ≥50% reduction in CRP values; along with stable or ≥20% reduced aneurysm size in patients with arterial involvement, and stable or ≥20% reduced calf swelling in patients with lower extremity venous thrombosis.

Partial response was defined as clinical and laboratory improvement based on observations of an improvement between 20-49% according to patient's and physician's global assessments by using VAS, 20-49% reduction in CRP values; along with stable or less than 20% reduced aneurysm size in patients with arterial involvement, and stable or less than 20% reduced calf swelling in patients with lower extremity thrombosis.

Non-response will be defined as observing no or less than 20% clinical improvement by patient's and physician's global VAS or worsening of clinical findings, no change or increase in acute phase response, increase in aneurysm size for patients with arterial involvement or progression of venous thrombosis in patients with venous involvement.

Arms: arm 1: Canakinumab was administered monthly
Interventions: intervention 1: Canakinumab
Intervention descriptions: intervention 1: 150 mg or 300 mg of canakinumab was administered monthly. IV (SC after month 6)

Protocol documents:
Prot_SAP_000.pdf: 
Global Clinical Development - General Medicine 
ACZ885/ Canakinumab 
 CACZ885NTR01 / NCT02756650 
 An open label, exploratory study to establish the efficacy and safety of 1 
year Canakinumab treatment in Behçet’s Disease Patients with 
Neurologic or Vascular Involvement 
Authors: 
Prof.Dr.
, Dr.
 
Document type: 
Synopsis/Clinical Trial Protocol  
EUDRACT number: 
N/A 
Version number: 
v1.00 (Original protocol)  
Development phase: 
II 
Release date: 
15 Aug 2016 
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 ........................................................................................................................ 4 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 5 
Glossary of terms ................................................................................................................. 6 
Protocol summary ................................................................................................................ 7 
1 
Introduction ....................................................................................................................... 11 
 
Background ............................................................................................................ 11 
 
Purpose .................................................................................................................. 11 
2 
Study objectives ................................................................................................................. 11 
 
Primary objective(s) ............................................................................................... 12 
 
Secondary objectives ............................................................................................. 13 
14 
3 
Investigational plan ........................................................................................................... 14 
 
Study design........................................................................................................... 14 
 
Rationale of dose/regimen, route of administration and duration of treatment ..... 15 
 
Rationale for choice of comparator ....................................................................... 15 
 
Purpose and timing of interim analyses/design adaptations .................................. 15 
 
Risks and benefits .................................................................................................. 15 
4 
Population .......................................................................................................................... 16 
 
Inclusion criteria .................................................................................................... 16 
 
Exclusion criteria ................................................................................................... 16 
5 
Treatment ........................................................................................................................... 18 
 
Protocol requested treatment ................................................................................. 18 
5.1.1 
Investigational treatment ....................................................................... 18 
5.1.2 
Additional study treatment .................................................................... 18 
 
Treatment arms ...................................................................................................... 18 
 
Treatment assignment, randomization ................................................................... 18 
 
Treatment blinding ................................................................................................. 18 
 
Treating the patient ................................................................................................ 19 
5.5.1 
Patient numbering ................................................................................. 19 
5.5.2 
Dispensing the investigational treatment .............................................. 19 
5.5.3 
Handling of study treatment .................................................................. 19 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 19 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 20 
5.5.6 
Rescue medication ................................................................................ 20 


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5.5.7 
Concomitant treatment .......................................................................... 21 
5.5.8 
Prohibited Treatment ............................................................................. 21 
5.5.9 
Discontinuation of study treatment ....................................................... 21 
5.5.10 
Withdrawal of consent .......................................................................... 22 
5.5.11 
Loss to follow-up .................................................................................. 22 
5.5.12 
Emergency breaking of assigned treatment code .................................. 22 
5.5.13 
Study completion and post-study treatment .......................................... 22 
5.5.14 
Early study termination ......................................................................... 23 
 
Information to be collected on screening failures .................................................. 25 
 
Patient demographics/other baseline characteristics ............................................. 25 
5.7.1 
Laboratory tests ..................................................................................... 25 
5.7.2 
Inflammation markers ........................................................................... 26 
5.7.3 
Hepatitis screen, HIV screen ................................................................. 26 
5.7.4 
Latent tuberculosis infection screening ................................................. 26 
5.7.5 
Chest X-ray ........................................................................................... 27 
 
Treatment exposure and compliance ..................................................................... 27 
 
Efficacy .................................................................................................................. 27 
5.9.1 
Resolution of Attacks ............................................................................ 27 
5.9.2 
Preservation of Remission within 12 months : ..................................... 28 
5.9.3 
Overall Disease Activity Measures ....................................................... 29 
5.9.4 
Steroid Tapering .................................................................................... 29 
5.9.5 
Improvement / Changes in Symptoms .................................................. 29 
5.9.6 
Imaging ................................................................................................. 29 
 
Safety ..................................................................................................................... 30 
5.10.1 
Physical examination ............................................................................ 30 
5.10.2 
Vital signs.............................................................................................. 30 
5.10.3 
Height and weight ................................................................................. 30 
5.10.4 
Electrocardiogram (ECG) ..................................................................... 31 
5.10.5 
Pregnancy and assessments of fertility ................................................. 32 
 
Other assessments .................................................................................................. 32 
5.11.1 
CSF Collection ...................................................................................... 32 
5.11.2 
Pharmacokinetics .................................................................................. 32 
5.11.3 
Pharmacodynamic (PD) assessments .................................................... 34 
 
 35 
6 
Safety monitoring .............................................................................................................. 37 
 
Adverse events ....................................................................................................... 37 
 
Serious adverse events ........................................................................................... 38 


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6.2.1 
Definition of SAE ................................................................................. 38 
6.2.2 
SAE reporting........................................................................................ 39 
 
Pregnancy reporting ............................................................................................... 40 
 
Prospective suicidality assessment ........................................................................ 40 
7 
Data review and database management ............................................................................. 40 
 
Site monitoring ...................................................................................................... 40 
 
Data collection ....................................................................................................... 41 
 
Database management and quality control ............................................................ 41 
 
Data Monitoring Committee .................................................................................. 42 
 
Adjudication Committee ........................................................................................ 42 
8 
Data analysis ...................................................................................................................... 42 
 
Analysis sets .......................................................................................................... 42 
 
Patient demographics and other baseline characteristics ....................................... 42 
 
Treatments ............................................................................................................. 42 
 
Analysis of the primary variable(s) ....................................................................... 43 
8.4.1 
Variable(s) ............................................................................................. 43 
8.4.2 
Statistical model, hypothesis, and method of analysis .......................... 43 
 
Analysis of secondary variables ............................................................................ 43 
8.5.1 
Efficacy variables .................................................................................. 43 
8.5.2 
Safety variables ..................................................................................... 43 
8.5.3 
Pharmacokinetics .................................................................................. 43 
 
Interim analyses ..................................................................................................... 44 
 
Sample size calculation .......................................................................................... 44 
9 
Ethical considerations ........................................................................................................ 44 
 
Regulatory and ethical compliance ........................................................................ 44 
 
Informed consent procedures ................................................................................. 44 
 
Responsibilities of the investigator and IRB/IEC .................................................. 45 
 
Publication of study protocol and results............................................................... 45 
10 Protocol adherence ............................................................................................................ 45 
 
Protocol Amendments ........................................................................................... 45 
11 References ......................................................................................................................... 46 
12 Names and addresses ......................................................................................................... 46 
13 Appendix 1: Blood collection Log .................................................................................... 47 
 
List of tables 
Table 5-1 
Assessment schedule ............................................................................. 23 
Table 13-1                 Blood Collection Log for PK/PD 
 Samples...…46 


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List of figures 
 
Figure 3-1 
Study design .......................................................................................... 14 
                           
 
List of abbreviations 
 
AE 
Adverse event 
BDCAF              Behçet’s Disease Current Activity Form 
SAE                    Serious adverse event 
CRF 
Case Report/Record Form (paper or electronic) 
CNS                   Central Nervous System 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CSF                    Cerebrospinal Fluid 
EDSS             Expanded Disability Status Scale 
 
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 
NBDS                 Neuro-Behçet's disease 
Modified EDSS    Modified  Expanded Disability Status Scale 
VAS                   Visual Analog Scale 
IV MP               Intravenous Methyl  Prednisolone 
PK/PD               Pharmacokinetics/ Pharmacodynamic 


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SAE                   Serious adverse eventGlossary of terms 
 
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 
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. 
Part  
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease. 
Period 
A subdivision of a cross-over study 
Premature subject/patient 
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  
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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Protocol summary 
  
Protocol number 
CACZ885NTR01 
Title 
An open label, exploratory study to establish the efficacy and safety 
of 1 year Canakinumab treatment in Behçet’s Disease Patients with 
Neurologic or Vascular Involvement 
Brief title 
 
Efficacy and Safety of Canakinumab in Behçet’s Disease Patients 
with Neurologic or Vascular Involvement 
Sponsor and Clinical 
Phase 
Novartis  
Phase 2 Exploratory Study 
Investigation type 
Drug 
Study type 
An open label Phase 2 Study 
Purpose and rationale 
Study objective is to evaluate efficacy and safety of canakinumab in 
neurologic and vascular subtypes of Behçet’s disease (BD). 
Primary Objective(s)  
Primary objective of the study is to evaluate the safety and efficacy 
of canakinumab on the clinical and inflammatory findings of BD 
patients with neurologic and vascular involvement. 
Secondary Objectives 
 
Secondary objectives include analyses measuring the effects of 
canakinumab on radiological findings (neurologic and vascular), 
cerebrospinal fluid (CSF) findings (neurologic), and 
 
 
 aiming to investigate the biology of inflammatory attacks 
and their response to IL-1 blockade in parallel with clinical 
findings. 
Study design 
The study will be conducted as an exploratory open-label pilot 
trial. There will be only one treatment arm. The improvement will 
be evaluated in comparison to the findings recorded at the 
baseline. 
Population 
Biologic naïve patients aged over 18 with BD fulfilling the 
International Study Group (ISG) criteria, who have a recent 
exacerbation of large-vessel vascular disease and/or parenchymal 
neurologic disease (within the last month). 
Inclusion criteria 
For NBS :1) Patients experiencing an acute exacerbation of 
parenchymal neurologic disease involving brainstem and/or 
diencephalic region with in last month.  
 
Exacerbation is defined based on the presence of both of the 
following: 
a. An acute/subacute neurological syndrome including any 
of hemiparesis, ataxia, dysarthria within the first month 


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of onset of neurologic manifestations (without any prior 
high dose steroid treatment) 
b. Compatible cranial MRI lesion involving brainstem 
and/or diencephalic region 
2) Patients aged over 18-60 BD fulfilling the International 
Study Group (ISG) criteria, who have exacerbation of large-vessel 
vascular disease and/or parenchymal neurologic disease with in last 
month.. 
For Vascular Disease : 
1)Patients experiencing an acute exacerbation of vascular disease 
within the last month, involving  
a. Large arteries (abdominal aorta, pulmonary arteries, 
extremity arteries) 
b. Large veins (deep vein thrombosis of extremities, caval 
vein thrombosis, dural sinus thrombosis) 
c. Compatible radiological findings (spiral CT, MR, or 
Doppler ultrasonography) 
 
 
 
2) Patients aged over 18-60 BD fulfilling the International Study 
Group (ISG) criteria, who have exacerbation of large-vessel 
vascular disease and/or parenchymal neurologic disease  with in 
last month.. 
 
 
 
Exclusion criteria 
For NBS:  
1. Presence of severe neurological sequelae from any previous 
attacks rendering the patient dependent on others physically 
or mentally 
2. Any other neurological cause underlying the picture 
including ischemic CNS lesion on MRI 
3. Any previous treatment with biological agents other than 
interferon-alpha 
or 
any 
previous 
treatment 
with 
cyclophosphamide 
 
 
 


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For Vascular disease  
 
4-Presence of severe vascular sequelae from any previous 
attacks rendering the patient dependent on others 
5-Any other vascular disease complication the evaluation of 
exacerbation 
6-Any previous treatment with biological agents other than 
interferon-alpha, 
or 
any 
previous 
treatment 
with 
cyclophosphamide 
 
General 
7- Presence or history of any other inflammatory rheumatic disease 
8- Use of the listed treatment  
a.  interferon-alpha in the last 6 months,  
b. IVMP in the past month 
 
9- Positive PPD test (according to local guidance) 
where an active TB infection cannot be excluded via 
Quantiferon (T-Spot or radiographic imaging if 
needed) If PPD test or Quantiferon-Gold assay result 
shows latent TB infection without signs of active 
tuberculosis disease, patient will be allowed to enter 
in the study, when the patient agrees to start taking 
isoniazid prophylaxis along with the study drug for 9 
months. 
10- Pregnancy or lactation 
11-Presence of any active or chronic infection or any major episode 
of infection requiring hospitalization or treatment with i.v. 
antibiotics within 30 days or oral antibiotics within 14 days prior to 
screening 
12-History or a malignancy within the last 5 years, except for 
successfully excised squamous or basal cell carcinoma of the skin 
13-Women of childbearing potential not using the contraception 
method(s) specified in this study, as well as women who are 
breastfeeding  
14-With known sensitivity to canakinumab 
15- Use of any other investigational agent in the last 30 days 
 


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Investigational and 
reference therapy 
Canakinumab 
Efficacy assessments 
Resolution of attacks 
Prevention of recurrent attacks 
Need for steroid usage 
Control of the symptoms 
Safety assessments 
All AEs and SAEs will be recorded appropriately. 
Other assessments 
PK/PD data will be collected.  
Canakinumab 
 will be measured in CSF. 
Data analysis 
All improvements in the 
 outcomes will be compared to 
the baseline, and statistical analyses will be conducted when 
possible. 
Key words 
Behcet’s disease, Neuro-Behcet Syndrome, Disease Exacerbation, 
IL-1 Blockade, Canakinumab, CNS inflammation, Vasculitis 


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1 
Introduction 
 
Background  
BD is a multisystem inflammatory disorder characterised by relapsing/remitting 
manifestations with variable vessel vasculitis as the underlying pathology. Prevalence of BD 
is in a wide range between 1-420 / 100,000 depending on geographic region in the world. 
 
Some courses of the disease carry a higher unmet need: 
a. Neurologic involvement: The patients experiencing parenchymal neurologic inflammatory 
attacks mainly affecting the brainstem have serious morbidity and increased mortality. There 
is no established treatment or a clinical trial conducted to evaluate the efficacy of any drug in 
Neuro-Behçet disease (NBD). 
b. Vascular disease: Depending on the involved large vessels (arteries and/or veins), vascular 
involvement has also been associated with increased morbidity and mortality. Similar to NBD 
there is no established treatment or a clinical trial conducted to evaluate the efficacy of any 
drug in large vessel vasculitis. 
 
In recent years, some case reports showed the efficacy of canakinumab in different BD 
manifestations. (1,2,3,4) 
 
Vitale et al. reported that the prompt and sustained clinical efficacy of canakinumab as a 
monotherapy in  patients with BD supports the opportunity of using this specific anti-IL-1β 
agent as a valid therapeutic option for those cases showing a disease course resistant or 
refractory to multiple treatments. (1) 
 
Cantarini et al. reported the results of canakinumab treatment in a refractory patient with BD, 
which was well-tolerated, and at the 6-month follow-up, no adverse events were noted. (2) 
 
Purpose  
Study objective is to evaluate the efficacy and safety of canakinumab in neurologic and 
vascular subtypes of BD. 
2 
Study objectives 
Primary objective: Primary objective of the study is to evaluate the safety and efficacy of 
canakinumab on the clinical and inflammatory findings of BD patients with neurologic and 
vascular involvement. 
 
Secondary objectives: Secondary objectives include analyses measuring the effects of 
canakinumab on radiological findings (neurologic and vascular), cerebrospinal fluid findings 
(neurologic), and 
 
aiming to investigate the biology of inflammatory attacks and their response to IL-1 blockade 
in parallel with clinical findings. 


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Primary objective(s) 
 
Primary endpoint: Resolution of acute exacerbation findings related to BD based on 
achievements in any of the following items without deterioration on day 30: 
 
For patients with parenchymal neurologic disease:  Resolution of acute exacerbation of 
parenchymal neurologic findings based on improvements in any of the following items 
without deterioration on Day 30: 
a. Improvement of muscle strength, ataxia, or other relevant neurologic findings depending 
on the involved region on neurological examination (by NBDS, Modified EDSS, and 
modified Rankin scores) 
b. Improvement in systemic inflammatory findings (CRP, ESR, SAA) 
c. Any decrease in the size of the MRI lesion, or disappearance of contrast enhancement 
d. Improvement in patients’ and physicians global assessment using a 10-cm visual 
analogue scale (VAS) 
 
Complete response will be defined as full clinical recovery to the pre-attack state, 
disappearance of MRI lesion(s), and normalisation of CSF findings.  
 
Partial response will be defined as partial improvement in clinical findings, but with 
findings still worse than the pre-attack state, and MRI lesions, which become smaller with 
no or less enhancement, and a decrease in CSF cell count. 
 
Non-response will be defined as no improvement in clinical findings, no change on MRI, 
no change in CSF parameters, or worsening in those findings. 
 
 
For patients with large vessel vascular disease: Resolution of acute vascular exacerbation 
findings related to BD based on achievements in any of the following items without 
deterioration at 1 month: 
 
a. Improvement in relevant symptoms (localised pain, abdominal pain, calf thickness, 
haemoptysis) by using physician and patient’s global assessment with VAS 
b. Improvement in systemic inflammatory findings (CRP, ESR, SAA) 
c. Any improvement in radiological findings depending on the involved vessels (MR, CT 
or Doppler findings)  
d. Improvement in patients’ and physicians global assessment using a 10-cm visual 
analogue scale (VAS) 
 
 


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Complete response will be defined as clinical and laboratory improvement based on ≥50% 
improvements in patient’s and physician’s global assessments by using VAS, and ≥50% 
reduction in CRP values; along with stable or ≥20% reduced aneurym size in patients with 
arterial involvement, and stable or ≥20% reduced calf swelling in patients with lower 
extremity venous thrombosis. 
 
 
Partial response will be defined as clinical and laboratory improvement based on 
observations of an improvement between 20-49% according to patient’s and physician’s 
global assessments by using VAS, 20-49% reduction in CRP values; along with stable or 
less than 20% reduced aneurym size in patients with arterial involvement, and stable or less 
than 20% reduced calf swelling in patients with lower extremity thrombosis. 
 
 
Non-response will be defined as observing no or less than 20% clinical improvement by 
patient’s and physician’s global VAS or worsening of clinical findings, no change or 
increase in acute phase response, increase in aneurysm size for patients with arterial 
involvement or progression of venous thrombosis in patients with venous involvement. 
 
Secondary objectives 
 
Secondary endpoints:  
General : 
Overall disease activity measures (BDCAF-Behçet’s Disease Current Activity Form) 
Reduced need for corticosteroid treatment (reduction of corticosteroid dosage) 
Course of other BD-related manifestations 
 
   
For NBS:  
Time to at least 50% resolution of the MRI lesion as defined above 
Assessment of parenchymal lesions by MR spectroscopy, and when possible with functional 
MRI (f-MRI) and MR-tractography 
Preservation of remission within first 12 months 
Number of exacerbations within 12 months 
 
For vascular disease: 
Radiological changes by PET-CT and/or MR imaging 
Time to resolution as defined above 
Preservation of remission within12 months 
Number of recurrent exacerbations within 12 months 
 
PK, PD evaluations in serum and CSF  


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Safety 
 
3 
Investigational plan 
 
Study design 
The study will be conducted as an exploratory open-label pilot trial. There will be only one 
treatment arm. The improvement will be evaluated in comparison to the findings recorded at 
the baseline.  
Figure 3-1 
Study design 
 
                      Start                           
 
 
 
                    End of Study 
 
 
                                             
 
 
 
 
 
 
 
 
 
 
 
 
   Baseline Epoch  
 
       (-7 to -0 day)  
 
 
 
 
  
      First dose    
 
 
 
 
 
                       300 mg IV   
 
 
 
 
 
    Canakinumab  
 
              6th month  
                  12th month 
----------- -----ı-----ı-----ı-----ı-----ı-----ı-----ı-----ı-----ı-----ı-----ı----I 
 
 
     150 mg canakinumab (IV)              150 mg canakinumab ( IV /s.c.) 
 
 
 
* Partial responders will be able take  
                                                  the 2nd canakinumab dose as 300 mg  
                                                 due to investigator decision 
                                                 IV infusion at the first month 
                                                then continue with 150 mg  
 
 
 
  
 
 
 
 
 
 
 
 
 


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Approximately10 subjects aged 18 to 60 years, who sign an informed consent and meet all 
inclusion and exclusion criteria in the screening period will enter into the study. The first dose 
of canakinumab will be administered as 300 mg IV.  
At the end of the first month, an analysis will be conducted to assess the complete, partial, and 
non-responders to canakinumab treatment by phsician. 
Partial responders will be able take the 2nd canakinumab dose as 300 mg IV infusion at the 
first month then  will continue the canakinumab treatment with 150 mg IV infusions at 
monthly intervals for 4 times. The complete responders will continue the canakinumab 
treatment with 150 mg IV infusions at monthly intervals for 5 times.  Non-responder or 
deteriorating patients will be dropped from the study at the first month evaluations. 
 
At month 6, the patients will be able to switch to SC injections or continue as IV infusions of 
150 mg canakinumab for additional 6 monthly administrations. Non-responder or 
deteriorating patients will be dropped from the study at the first month evaluations. 
 
Rationale of dose/regimen, route of administration and duration 
of treatment 
Canakinumab will be administered IV 300 mg initially. After the initial dose, complete 
responders will be given 150 mg IV infusions for every 4 week until month 6. A second 
canakinumab 300 mg IV dose will be used for patients with a partial response, and they will 
continue to receive 150 mg IV infusions for every 4 week until month 6.  
Depending on the response in the first 6-month period, 150 mg canakinumab will be given as 
SC injections or IV infusions for every 4 weeks during the second 6-month period. 
 
Rationale for choice of comparator 
There will be no active comparator.  
 
Purpose and timing of interim analyses/design adaptations 
At the end of 1st month primary end point will be assessed by the physician. Complete / 
Partial / Non responders will be determined.  
At 3rd and 6th months, there will be additional analyses to evaluate steroid tapering, 
prevention of disease exacerbation, and general disease activity by phsician. 
 
Risks and benefits  
The risk to subjects in this trial will be minimized by compliance with the inclusion/exclusion 
criteria, close clinical, laboratory and radiological monitoring, and application of good clinical 
practice principles. 


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4 
Population 
Key inclusion criteria : Biologic-naïve patients aged 18-60 years with BD fulfilling the ISG 
criteria, who have a recent exacerbation of large-vessel vascular disease and/or parenchymal 
neurologic disease.  
 
 
Inclusion criteria  
Key inclusion criteria : Biologic-naïve patients with BD fulfilling the ISG criteria, who have 
a recent exacerbation of large-vessel vascular disease and/or parenchymal neurologic disease 
within the last month.  
For NBS :1) Patients experiencing an acute exacerbation of parenchymal neurologic 
disease involving brainstem and/or diencephalic region with in last month.  
 
Exacerbation is defined based on the presence of both of the following: 
a. An acute/subacute neurological syndrome including any of hemiparesis, ataxia, 
dysarthria within the first month of onset of neurologic manifestations (without any 
prior high dose steroid treatment) 
b. Compatible cranial MRI lesion involving brainstem and/or diencephalic region 
2) Patients aged over 18-60 BD fulfilling the International Study Group (ISG) criteria, 
who have exacerbation of large-vessel vascular disease and/or parenchymal neurologic 
disease with in last month. 
 
For Vascular Disease : 
1)Patients experiencing an acute exacerbation of vascular disease within the last month, 
involving  
d. Large arteries (abdominal aorta, pulmonary arteries, extremity arteries) 
e. Large veins (deep vein thrombosis of extremities, caval vein thrombosis, dural sinus 
thrombosis) 
f. Compatible radiological findings (spiral CT, MR, or Doppler ultrasonography) 
2) Patients aged over 18-60 BD fulfilling the International Study Group (ISG) criteria, who 
have exacerbation of large-vessel vascular disease and/or parenchymal neurologic disease  
with in last month.. 
 
 
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. 
Key exclusion criteria  
    For NBS:  
1-Presence of severe neurological sequelae from any previous attacks rendering the patient 
dependent on others physically or mentally 


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2-Any other neurological cause underlying the picture including ischemic CNS lesion on MRI 
3-Any previous treatment with biological agents other than interferon-alpha or any previous 
treatment with cyclophosphamide 
 
 
For Vascular disease  
4-Presence of severe vascular sequelae from any previous attacks rendering the patient 
dependent on others 
5-Any other vascular disease complication the evaluation of exacerbation 
6-Any previous treatment with biological agents other than interferon-alpha, or any previous 
treatment with cyclophosphamide 
 
General 
7- Presence or history of any other inflammatory rheumatic disease 
8- Use of the listed treatment  
c.  interferon-alpha in the last 6 months,  
d. IVMP in the past month 
 
9- Positive PPD test (according to local guidance) where an active TB infection cannot be 
excluded via Quantiferon (T-Spot or radiographic imaging if needed) If PPD test or 
Quantiferon-Gold assay result shows latent TB infection without signs of active tuberculosis 
disease, patient will be allowed to enter in the study, when the patient agrees to start taking 
isoniazid prophylaxis along with the study drug for 9 months. 
10- Pregnancy or lactation 
11-Presence of any active or chronic infection or any major episode of infection requiring 
hospitalization or treatment with i.v. antibiotics within 30 days or oral antibiotics within 14 
days prior to screening 
12-History or a malignancy within the last 5 years, except for successfully excised squamous 
or basal cell carcinoma of the skin 
13-Women of childbearing potential not using the contraception method(s) specified in this 
study, as well as women who are breastfeeding  
14-With known sensitivity to canakinumab 
15- Use of any other investigational agent in the last 30 days 


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5 
Treatment 
 
Treatment 
Arm 
# 
of 
Patients 
Entered 
Treatment 
Type 
of 
Study Drug 
Compound 
Min 
Dose 
Max 
Dose 
Frequency 
Admin. 
Route 
Generic 
Acceptable? 
( 
Canakinumab 
10 
Investigational 
ACZ 
150 
mg 
300 
mg 
Monthly 
IV  
(SC 
after 
month 
6) 
- 
 
 
 
 
 
 
 
 
 
Protocol requested treatment 
5.1.1 
Investigational treatment 
 
Canakinumab 150 mg powder for solution for infusion/injection contains nominally 150 
mg canakinumab. The vials contain an overfill of 20% i.e. resulting in a total amount of 180 
mg canakinumab per vial. The overfill will allow for complete withdrawal of the labeled 
amount of canakinumab. 
Canakinumab will be used as 300 mg  IV  infusions for subjects over 18 years and diagnosed 
as Behcet disease. The dose will be down-titrated to 150 mg IV after first dose. And there will 
be a switch to 150 mg SC injections after 6 months (if investigators confirm)  
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
 
Treatment arms 
This is a open-label, single-arm active treatment study design. 
 
Treatment assignment, randomization  
At Screening (Day -7 to -0) an eligible patient will be given the lowest available number. The 
investigator will enter the patient number on the CRF. 
 
Treatment blinding  
This will be an open-label, single arm study. 


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Treating the patient 
5.5.1 
Patient numbering  
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused.  
If an enrolled patient fails to be treated for any reason, the reason will be entered on the 
Screening Study Disposition CRF.  
5.5.2 
Dispensing the investigational treatment  
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. 
5.5.3 
Handling of study treatment  
5.5.3.1 
Handling of investigational treatment  
Study drug will be supplied to the study site by Novartis as open labelled bulk medication. 
Study drugs 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 designated study person 
has access. Upon receipt, all study drugs should be stored according to the instructions 
specified on the drug labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. 
Medication labels will be in the local language and comply with the legal requirements of 
country. They will include storage conditions for the drug, but no information about the 
patient except for the patient number. 
The investigator or authorized site staff  must maintain an accurate record of the shipment and 
dispensing of study drug in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability log to the monitor or to the Novartis address provided in 
the investigator folder at each site. 
5.5.3.2 
Handling of other study treatment  
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment  
All patients will receive study medication every four weeks. Patients will receive IV infusions 
of canakinumab in open label study treatment period. Please refer to for study schema 
description. 
All study treatments assigned to the patient during the study will be recorded. 
Each reconstituted vial provides 150 mg of canakinumab per 1 mL.  
 


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From a microbiological point of view, once the canakinumab solution for infusion has been 
compounded in the infusion bag or the solution for injection has been prepared, it should be 
used immediately. If not used immediately, it should be administered within 24 hours (end of 
infusion included). If the infusion solution/solution for injection is not used within 60 minutes 
of preparation, it should be kept at 2-8 °C. The bags and the solution for injection should be 
allowed to come to room temperature for 5-10 minutes but not more than 15 minutes before 
administration. 
Detailed instructions on the preparation and administration of the study drug will be described 
in the Pharmacist Manual and provided to the site. 
Patients should remain at the study site for observation for 1 hour following study drug 
administration. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
The first dose will be started as 300 mg IV.. At the end of the first month, an analysis will be 
conducted to assess the complete, partial, and non-responders to canakinumab treatment by 
phsician. 
Partial responders will be able take the 2nd canakinumab dose as 300 mg IV infusion at the 
first month then  will continue the canakinumab treatment with 150 mg IV infusions at 
monthly intervals for 4 times. The complete responders will continue the canakinumab 
treatment with 150 mg IV infusions at monthly intervals for 5 times.  Non-responder or 
deteriorating patients will be dropped from the study at the first month evaluations. 
 At the end of the 6th month the administration route can be switched to subcutaneous 
injection.  
5.5.6 
Rescue medication  
A rescue treatment with increased doses of prednisolone or intravenous methyl prednisolone 
pulses could be used depending on worsening of BD manifestations at the discretion of the 
investigator. 
If no response or worsening of neurologic/vascular manifestations were observed in the first 
week, rescue treatment decision should be given with the repeated CSF and MRI (neurologic) 
or CT/Doppler (vascular) analyses. 
 
Following protocol will be used as rescue treatment in patients with worsening symptoms: 
 
For patients with neurologic involvement: 5-10 days of 1000 mg intravenous methyle 
prednisolone, followed by 1 mg/kg/day prednisolone, if still an insufficient response is 
observed, 1000 mg intravenous cyclophosphamide 
 
For patients with vascular involvement:  3 days of 1000 mg intravenous methyle 
prednisolone, followed by 1 mg/kg/day prednisolone, if still an insufficient response is 
observed, 1000 mg iv cyclophosphamide. 


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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 
The following treatments are NOT allowed prior to baseline (time intervals prior to baseline 
are detailed below) AND during the entire study: 
• Etanercept in the 4 weeks prior to the baseline visit (Day 0) and thereafter 
• Rilonacept in the 3 weeks prior to the baseline visit (Day 0) and thereafter 
• Adalimumab in the 8 weeks prior to the baseline visit (Day 0) and thereafter 
• Infliximab in the 12 weeks prior to the baseline visit (Day 0) and thereafter 
• Rituximab in the 26 weeks prior to the baseline visit (Day 0) and thereafter 
• Any other investigational biologics in the 8 weeks prior to the baseline visit (Day 0) and 
thereafter (with the exception of anakinra therapy –see below) 
• Kineret (anakinra therapy) 3 days prior to the baseline visit (Day 0) and thereafter 
• Leflunomide in the 4 weeks prior to the baseline visit (Day 0) and thereafter. After the 
completion of leflunomide treatment a cholestiramine in dose 8 g 3 times per day for 14 
days is recommended. 
• Thalidomide in the 2 weeks prior to the baseline visit (Day 0) and thereafter 
• Cyclosporine in the 2 weeks prior to the baseline visit (Day 0) and thereafter 
• i.v. immunoglobulin (i.v. Ig) in the 8 weeks prior to the baseline visit (Day 0) and thereafter 
• 6-Mercaptopurine, , cyclophosphamide, or chlorambucil in the 12 weeks prior to the 
baseline visit (Day 0) and thereafter 
• Dapsone,  in the 3 weeks prior to the baseline visit (Day 0) and thereafter 
• Corticosteroids ≥20mg/day or >0.4 mg/kg, whichever applies, in the 1 week prior to the 
baseline visit (Day 0) and thereafter 
• Live vaccinations within 3 months prior to the start of the trial, during the trial, and up to 3 
months following the last dose. 
• Use of other investigational non-biological drugs at the time of enrollment, within 30 days or 
5 half-lives of enrolment, whichever is longer. 
 Intravenous methyl prednisolone pulse treatment within the last month 
 
 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug. All medications and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient  
starts treatment with study drug must be listed on the Concomitant medications/Significant 
non-drug therapies after start of study drug. 
5.5.9 
Discontinuation of study treatment  
 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant safety risk for that patient. The following 
circumstances require study drug discontinuation: 


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Protocol No. CACZ885NTR01 
 
 
• Emergence of the following adverse events: 
• in the case of any severe or serious adverse event that is not compatible with 
administration of study medication, including adverse events that require treatment 
with an unacceptable co-medication, 
• in the case of onset of malignancy, 
• in the case of an uncontrolled life-threatening infection. 
• Pregnancy 
• Use of the prohibited concomitant medications  
• Withdrawal of informed consent 
5.5.10 
Withdrawal of consent  
 
Subjects also should be withdrawn at any time if the investigator concludes that it would be in 
the patient’s best interest for any reason. Protocol deviations should not lead to patient 
withdrawal unless they indicate a significant risk to the patient’s safety.  
Subjects may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason.  
If premature withdrawal occurs for any reason, the investigator must determine the primary 
reason for a patient’s premature withdrawal from the study and record this information on the 
Study Completion CRF. For subjects who are lost to follow-up (i.e., those subjects 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 documenting in the source documents steps taken to contact the 
patient, e.g., dates of telephone calls, registered letters, etc. 
Every patient has the right to discontinue study participation at any time, and every patient 
may be discontinued from the study for any reason beneficial to his/her wellbeing. All data 
generated up to the time of discontinuation from the study will be analysed and the reason(s) 
for discontinuation will be recorded.  
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. 
5.5.12 
Emergency breaking of assigned treatment code  
Not applicable 
5.5.13 
Study completion and post-study treatment  
Information on the date the subject last took drug, the subject’s completion or discontinuation 
of the study and the reason for discontinuation of the study will be recorded on the Study 
Completion CRF page. 


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Synopsis/Clinical Trial Protocol v1.00  
 
Protocol No. CACZ885NTR01 
 
 
Study Completion evaluations must also be performed when a subject prematurely withdraws 
from the study for whatever reason. 
The investigator also 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 may include initiating another treatment outside of the study as deemed appropriate by 
the investigator. 
At the end of the study, all subjects will be evaluated for serious adverse event 8 weeks (+/- 1 
week) after their last injection and may require an additional contact. 
At the End of Study, subjects will have the option to continue study medication.  The decision 
regarding treatment continuation will be at the discretion of the investigator and subject. 
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 The investigator may be informed of additional 
procedures to be followed in order to assure that adequate consideration is given to the 
protection of the patient’s interests. The investigator will be responsible for informing IRBs 
and/or ECs of the early termination of the trial. 
Table 5-1 
Assessment schedule 
Visit 
Screening 
*** 
1*** 
2 3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Day 
-7 to 0 
0 
7 14 
30 
60 
90 
120 
150 
180 
210 
24
0 
270 
300 
330 
360 
Inf consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(**)PPD test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Background 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital findings 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Virology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Synopsis/Clinical Trial Protocol v1.00  
 
Protocol No. CACZ885NTR01 
 
 
Visit 
Screening 
*** 
1*** 
2 3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Day 
-7 to 0 
0 
7 14 
30 
60 
90 
120 
150 
180 
210 
24
0 
270 
300 
330 
360 
Blood 
biochemistry 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X  
 
 
 
 
Inflammatory 
markers 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK markers 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
 
 
X 
PD samples 
 
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
 
 
X 
MR-Doppler 
Imaging (PET-CT 
when necessary) 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
 
X 
(*)CSF Puncture 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
Neurological 
evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BDCA 
(BD 
Current Activity)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VAS 
for 
symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
Assessment 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
Attack 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Steroid 
usage 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phsician&Patient 
Global 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug 
Administration 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Optional 
** PPD test could be used within 6 months before patient study entry  
*** If needed, in Patient’s emergency situation, Screening and Visit 1 assessment could 
be combining by the physician decisions.  There is no need to be repeated same test for 
each visit (screening and visit 1)  
 


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Information to be collected on screening failures  
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, and 
SAE data collected. Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data. 
For all patients who have signed informed consent and are entered into the next epoch of the 
study will have all adverse events occurring after informed consent is signed recorded on 
the Adverse Event CRF. 
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. 
 
Patient demographics/other baseline characteristics  
 
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, ethnicity, patient referral source, relevant medical history/current 
medical condition present before signing informed consent. Where possible, diagnoses will be 
recorded, not symptoms.   
Subjects should be seen for all post-baseline visits on the designated day with the allowance 
of a ±7 day window for all visits. Subjects who discontinue study drug before completing the 
study, and those who prematurely withdraw from the study for any reason, should be 
scheduled for a visit 8 weeks (±1 week) after their last infusion /injection, at which time all of 
the assessments listed for the final visit will be performed. 
Subjects who discontinue study drug also should return for a last assessment. If they refuse to 
return for this or are unable to do so, every effort should be made to contact them or a 
knowledgeable informant by telephone to determine the reason for discontinuation. At a 
minimum, they will be contacted for safety evaluations during the 30 days following the last 
dose of study drug, including final contact at the 30-day point. Documentation of attempts to 
contact the patient should be recorded in the patient record.  
Information that will be collected on subjects who are screened but not enrolled includes 
patient demographics (age, gender, and ethnicity) and primary reason for not continuing. 
If a patient discontinues before entering Visit 1,only the demographic information and 
Screening Log entry with the primary reason for discontinuation should be completed on the 
CRF. It is not necessary to complete all the required evaluations at the time of discontinuation 
unless medically indicated. 
At screening visit information on age, sex, will be collected. Relevant medical 
history/current medical conditions, family medical history, will be recorded on the respective 
CRF page. The following should be recorded on the respective CRF page. 
 
5.7.1 
Laboratory tests 
The investigator will evaluate the clinical significance of each laboratory value outside of the 
reference range. This decision should be based upon the nature and degree of the observed 
abnormality. The investigator may choose to repeat any abnormal result ONCE, in order to 
rule out laboratory error. "NCS" will be entered on the original laboratory sheet to the right of 


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all laboratory values, which are outside the reference range, but are judged "not clinically 
significant." The physician making these assessments should date and initial each form. A 
copy of each laboratory report must be placed in the patient’s file. Clinically relevant 
deviations of laboratory test results occurring during or at completion of the study must be 
reported and discussed with Novartis. Repeated evaluations are mandatory until normalization 
or until the change is no longer clinically relevant. In case of doubt, Novartis must be 
contacted. 
All laboratory tests will be performed in the study site except PK/PD, 
 
 
 
 
 
 
 
5.7.2 
Inflammation markers 
 
The following markers of inflammation, Erythrocyte Sedimentation Rate (ESR), C-reactive 
protein (CRP) and serum amyloid A (SAA), will be performed at all scheduled visits. 
 
5.7.3 
Hepatitis screen, HIV screen 
In order to exclude an active hepatitis B or C or HIV infection, all subjects will undergo 
appropriate testing at the screening visit and. All subjects will be screened for Hepatitis B 
surface antigen (HBsAg). Screening for Hepatitis C will be based on HCV antibodies. A copy 
of the lab report must be placed in the patient’s file. Evaluation for HIV seropositivity will 
consist of ELISA and, if positive, confirmation by Western blot will be required. Appropriate 
subject counselling will be made available by the investigator in the event of a positive 
finding. Notification of 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. 
5.7.4 
Latent tuberculosis infection screening 
 
Latent tuberculosis infection screening will be performed by a PPD skin test by intradermal 
injection of  5 tuberculin units of standard PPD, and/or interferon-gamma release assay such 
as Quantiferon-Gold assay at screening visit or within 6 months before patient study entry, and the 
results will be evalauted at screening visit before the first dose of study medication. A PPD 
skin induration at 72 hours of  ≥ 5 mm is interpreted as a positive result. If PPD test or 
Quantiferon-Gold assay result shows latent TB infection without signs of active tuberculosis 
disease, patient will be allowed to enter the study in the study, if the patient is taking isoniazid 
prophylaxis before the study drug administration and agrees to continue the prophylaxis for 9 
months. 
 


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Also because of natural life threatening course of neurological and vascular involvements, in 
patients who need an urgent intervention, drug administration can be started without waiting 
test results of PPD or Quantiferon assay if there are no findings of active tuberculosis disease. 
If but  test results confirm a latent TB infection without signs of active tuberculosis, patients 
should start taking INH prophylaxis treatment for 9 months along with the study drug 
administration. 
 
5.7.5 
Chest X-ray 
In the event of a positive PPD skin test result at screening, or prior BCG immunization, or 
history of treated tuberculosis, a chest X-ray will be obtained, if one has not been 
administered during the 12 months before the first dose of study medication to assess the 
tuberculosis status of the patient. If a chest X-ray has been obtained in the previous 12 
months, a chest X-ray may be ordered at the investigator’s discretion, based on the patient’s  
clinical picture and local standard of medical care. Any significant findings will be recorded 
in the “Relevant medical history/Current medical conditions” section of the CRF as necessary. 
 
Treatment exposure and compliance  
Any deviations from the protocol regarding the administration of study medication must be 
described on the Dose Administration Record CRF. 
Concomitant medications/ non-drug therapy before the first dose of study medication and 
after start of study drug will be collected, including medication name and reason. 
 
Efficacy 
5.9.1 
Resolution of Attacks 
The definition of the attack  
 
For Vascular Disease: Recent Onset symptomatic Venous Thrombosis or Arterial 
Aneurysm. 
For Neurologic Disease: An acute/subacute neurological syndrome including any of 
hemiparesis, ataxia, dysarthria within the first month of onset of neurologic 
manifestations. 
 
Primary endpoint: Resolution of acute exacerbation findings related to BD based on 
achievements in any of the following items without deterioration on day 30: 
 
1-For Neuro Behcet Attack 
 
A     Improvement of muscle strength (Measured by MRC, and VAS) 
B     Ataxia (Measured by global assessment of Physician) 
C   Modified EDSS (Modified Expanded Disability Status Scale) , Neuro-Behçet’s 
Disability Score (NBDS) ranging from 0-8 and the modified Rankin scores (0-6) 
D     Improvement in systemic inflammatory findings (CRP, ESR, SAA) 
E     Any decrease in the size of the MRI lesion, or disappearance of contrast enhancement 


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Complete response will be defined as full clinical recovery to pre-attack state, 
disappearance of MRI lesion(s), CSF becomes normal.  
 
Partial response will be defined as partial improvement in clinical findings, but with 
findings still worse than pre-attack state, MRI lesions which become smaller with no or less 
enhancement, and a decrease in CSF cell count. 
Non-response will be defined as no improvement in clinical findings, no change on MRI, 
no change in CSF parameters, or worsening in those findings. 
 
2-For patients with large vessel vascular disease 
 
A Improvement in relevant symptoms   
a. Localised pain (by using physician and patient’s global assessment with visual 
analog scale (VAS)  
b. Abdominal pain, (by using physician and patient’s global assessment with visual 
analog scale (VAS) 
c. Calf thickness, (by measuring) 
d. Hemoptysis    (yes/no) 
B  Improvement in systemic inflammatory findings (CRP, ESR, SAA) 
C  Any improvement in radiological findings depending on the involved vessels (MR, CT 
or Doppler findings)  
 
Complete response will be defined as clinical and laboratory improvement based on >50% 
improvements in patient’s and physician’s global assessments by using VAS, and >50% 
reduction in CRP values; along with stable or >20% reduced aneurysm size in patients with 
arterial involvement, and stable or >20% reduced calf swelling in patients with lower 
extremity venous thrombosis. 
 
 
 
Partial response will be defined as clinical and laboratory improvement based on 
observing an improvement between 20-50% according to patient’s and physician’s global 
assessments by using VAS, 20-50% reduction in CRP values; along with stable or less than 
20% reduced aneurysm size in patients with arterial involvement, and stable or less than 
20% reduced calf swelling in patients with lower extremity thrombosis. 
 
 
 
Non-response will be defined as observing no or less than 20% clinical improvement by 
patient’s and physician’s global VAS or worsening of clinical findings, no change or 
increase in acute phase response, increase in aneurysm size for patients with arterial 
involvement or progression of venous thrombosis in patients with venous involvement. 
5.9.2 
Preservation of Remission within 12 months :  
Investigators will question absence / presence of attack during each visit. Normalization of 
inflammatory markers, improvements in symptoms will be recorded during each visit. 


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5.9.3 
Overall Disease Activity Measures 
Using Behcet Disease Current Activity Form (BDCAF) to collect general information about 
the disease course and progress. The patient will fill the form starting from baseline till the 
end of the study in every treatment day. The scores will be analysed at Day 30, 90, 180 and 
360.  
 
5.9.4 
Steroid Tapering 
Prednisolone dosage should be 20 mg or less at baseline, and it should not be increased during 
the trial.  
At the end of Day 30, complete responders begin to decrease the steroid doses. Tapering 
target will be 2,5 mg for every 2 weeks. At Day 120, patients expected to use prednisolone no 
more than 5 mg / day. 
5.9.5 
Improvement / Changes in Symptoms 
 
Headache; will be assessed by Visual Analog Scale, ranging from 0 to 10 cm, 0 indicating the 
best score and 10 the worst score, and it will be assessed by the patients and physicians during 
each visit. 
Localized Pain; will be assessed by Visual Analog Scale, ranging from 0 to 10 cm, 0 
indicating the best score and 10 the worst score, and it will be assessed by the patients and 
physicians during each visit. 
Abdominal Pain will be assessed by Visual Analog Scale, ranging from 0 to 10 cm, 0 
indicating the best score and 10 the worst score, and it will be assessed by the patients and 
physicians during each visit. 
 
Ataxia Improvements / Changes will be assessed by Physician Global Assessment. 
Calf thickness / swelling will be calculated by tape measure. 
Hemoptysis will be assessed by  (Yes / No) scale.  
 
 
5.9.6 
Imaging 
 
Different imaging techniques can be used for the assessment of vascular involvement 
depending on the localization and types of the involved vessels.  
For Deep Vein Thrombosis, Doppler ultrasound investigation and/or MRI will be used. 
For the assessment of arterial aneurysms, including pulmonary artery aneurysms, CT and/or 
MR imaging will be performed. 
 
 


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For Neurologic Involvement, cranial MR imaging will be preferred. MR imaging is extremely 
useful in differentiating NBD from its mimics. The brainstem–thalamic–basal ganglia lesions, 
in the proper clinical context can strongly support the diagnosis of acute/subacute 
parenchymal NBD.  
 
 
 
Safety  
5.10.1 
Physical examination 
A complete physical examination will be performed at all study visits. It 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.  
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions screen on the subject’s 
CRF. Significant findings made after the start of study drug, which meet the definition of an 
AE must be recorded on the AE screen of the subject’s CRF. 
 
5.10.2 
Vital signs 
Vital signs will be assessed at Screening, at all study visits. This will include measurement of 
subject’s body temperature, blood pressure (BP) and pulse.  
Body temperature will be measured by the investigator at each visit using established methods 
such as timpanic measurements. In addition, subject will measure the subject’s body 
temperature (timpanic or axillary) during occurrence of fever and record it in the subject’s 
diary if they experience fever. 
Systolic and diastolic blood pressure and radial pulse rate will be assessed after the subject 
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. 
 
5.10.3 
Height and weight 
Height will be measured in centimeters at Screening. 
Body weight (in indoor clothing, but without shoes) will be measured to the nearest 0.1 
kilogram (kg) at , Screening, Visit 5, and Visit 15.Laboratory evaluations clinics  laboratory 
will be used for analysis of all specimens collected except for CRP and urine dipstick  as 
outlined in the laboratory test section.  
The investigator will evaluate the clinical significance of each laboratory value outside of the 
reference range. This decision should be based upon the nature and degree of the observed 
abnormality. The investigator may choose to repeat any abnormal result ONCE, in order to 
rule out laboratory error. "NCS" will be entered on the original laboratory sheet to the right of 
all laboratory values, which are outside the reference range, but are judged "not clinically 


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significant." The physician making these assessments should date and initial each form. 
Values, which are considered clinically significant and/or study drug related will be noted on 
the respective Central Lab Assessment CRF page with reference to the date, study day, and 
hour if applicable. A copy of each laboratory report must be placed in the subject’s file. 
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis. Repeated evaluations are mandatory 
until normalization or until the change is no longer clinically relevant. In case of doubt, 
Novartis must be contacted. 
5.10.3.1 Hematology 
Haemoglobin, hematocrit, white blood cells (WBC) count with differential, red blood cells 
(RBC) count and platelet count will be evaluated at Visits 1,3,4,7,8,9,10, and 11  
 
5.10.3.2 Clinical chemistry 
Albumin, alkaline phosphatase, total bilirubin, indirect and direct reacting bilirubin, calcium, 
chloride, cholesterol, creatinine (with derivation of creatinine clearance value), CPK, γ-GT, 
glucose, LDH, inorganic phosphorus, α-amylase, potassium, total protein, SGOT, SGPT, 
sodium, triglycerides, urea/BUN and uric acid will be evaluated at Visits 1,3,4,7,8,9,10 and 11  
 
5.10.3.3 Urinalysis 
Urine sample will be obtained for semi-quantitative ‘dipstick’ measurements of specific 
gravity, pH value, protein, glucose, bilirubin, ketones, leukocytes, and blood at Screening and 
all subsequent visits. 
In case blood and/or leukocytes, and/or protein show traces/values in the ‘dipstick’ evaluation, 
a microscopic examination including RBC, WBC, and casts will be performed by the local 
laboratory. If casts are noted, the type is to be specified on the relevant local lab Assessment 
CRF (a note should be attached to the line referring to the urinalysis collection field). 
 
5.10.4 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed at Screening and End of Study Visit. 
The investigator will review the ECG, sign and date the tracing, and record any significant 
findings in the CRF. The CRF will contain the ventricular rate, PQ or PR interval, QRS 
duration, QT interval (uncorrected) and the overall interpretation (normal, clinically 
insignificant abnormality, clinically significant abnormalities which need to be specified 
further). 
Each ECG tracing should be labelled with the study number, patient initials, patient number, 
date, and kept in the source documents at the study site. 
Clinically significant abnormalities at Screening should also be recorded on the relevant 
medical history/Current medical conditions CRF page.  


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5.10.5 
Pregnancy and assessments of fertility 
Canakinumab should not be given to pregnant women. Female subjects of child-bearing 
potential must undergo pregnancy testing throughout the study and need to agree to an 
effective method of contraception during the entire study and for at least 3 months after study 
completion.  Serum test and/or urine test are mandatory for pregnancy at the screening 
visit for woman . Other assessments 
 
5.10.6 
   CSF Collection 
CSF analyses that were performed within 3  weeks before the study entry  could also be used. 
CSF cell count analysis will be performed in the local laboratory 
 
  
Each CSF sample will consist of 1 mL to be collected in a sterile polypropylene tube that 
contain no preservatives. After collection, the sample may be stored at 4°C. However, it must 
be processed to centrifugation within 1 hour of the lumbar puncture. Longer storage times at 
4°C must be documented accordingly in the source documents and CRF. 
 
 
 
 Sample tubes are centrifuged at 4000 x g for 10 minutes at 4°C to pellet cells and other 
insoluble material. The supernatant is then transferred to a new sterile polypropylene tube and 
gently mixed by inversion. Two (2) aliquots (0.5 mL) of the supernatant are dispensed to 0.5 
mL polypropylene cryovials.  This procedure limits oxidation effects by minimizing empty 
space in the cryovials. The 0.5 mL  cryovials containing the CSF aliquots as well as the 
polypropylene tubes containing the cell pellets are immediately placed on dry ice. 
 Once completely frozen, the tubes are transferred to a freezer for storage below -70°C until 
shipment to the central lab. The samples must be packed on sufficient dry ice for shipment to 
the central lab without thawing. Upon arrival at the central lab, CSF samples must be stored 
below -70°C. Any thawing of frozen samples must be avoided. 
 Sampling problems will be noted in the CRF as an attached note. 
 
5.10.7 
Pharmacokinetics 
 
All blood samples will be taken by either direct venipuncture or an indwelling cannula  
inserted in a forearm vein. It is important to note that the volume of blood sampling will be 
adapted to the age of the child according to clinical practice at the investigator site. For each 
scheduled PK sample, 2 mL of blood will be drawn into a plain barrier tube to obtain 1 ml 
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 analysis. 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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Time points for canakinumab PK sample collection at Visits:  
 Day 0 (Visit 1) 
 Day 7 (Visit 2) 
 Day 30 (Visit 4); pre-dose 
 Day 60 (Visit 5); pre-dose 
 Day 90 (Visit 6) pre-dose 
 Day 180(Visit 9) pre-dose 
 Day 240(Visit 11) pre-dose 
 Day 360 (Visit 15) pre-dose 
 
5.10.7.1 
Analytical method(s) 
 
Analytes, media and methods: canakinumab in serum by competitive ELISA, limit of 
quantification (LOQ) at 100 ng/mL. 
Details of the analytical methods to assess canakinumab in serum will be described in the 
bioanalytical data report. 
 
5.10.7.2 
PK sample handling, labeling and shipment instructions 
 
5.10.7.2.1 
Sample labeling 
Serum tubes will be used to collect samples. 
 
The samples for the pharmacokinetic profile will be labeled as follows: 
PK 
Study Code: CACZ885NTR01 
Subject Number: 
Sample Number: 
Date / Study Day: 
 
Labels will be provided to the investigator with all label information preprinted on the label. 
The actual sample collection date and exact time will be entered on the PK Blood Collection 
Log CRF page.  Sampling problems will be noted on the PK Blood Collection Log CRF  
5.10.7.2.2 
Shipment of pharmacokinetic samples to Central Laboratory 
 
For each shipment, all pharmacokinetic samples are to be entered in the shipping log which 
can be found in the central laboratory manual. The original document will be retained at the 
site in the Investigator’s file, and a copy of the PK Samples Shipping Log page must be 
included with the package of PK samples shipped. 


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5.10.7.2.3 
Instructions for shipment of biological samples to Central 
Laboratory 
 
All pharmacokinetic specimens will be kept at ≤ -18°C until shipment.  
Samples have to be packed according to the ICAO/IATA-Packing-Instructions in an insulated 
box. To guarantee that the samples remain deep frozen during transport, use about 10 kg of 
dry ice per box which will keep the samples frozen during the whole duration of the transport 
(air freight). A copy of the shipping log can be found in the central laboratory manual and 
must be included with the shipment. All samples from the site should be shipped to the central 
laboratory. 
 
All PK/PD samples will be shipped to the following vendor: 
 
 
 
 
France 
phone 
 
fax
 
5.10.8 
Pharmacodynamic (PD) assessments 
 
Total IL-1β (sum of IL-1β free and bound to canakinumab) will be assessed. Please note if at 
a dosing visit, sample should be obtained pre-dose.  
5.10.8.1 
Blood collection 
 
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 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 analysis. 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 clinic  lab. 
 
Time points for Total IL-1β sample collection at Visits:  
 Day 0 (Visit 1) 
 Day 7 (Visit 2) 
 Day 30 (Visit 4); pre-dose 
 Day 60 (Visit 5); pre-dose 
 Day 90 (Visit 6); pre-dose 
 Day 180(Visit 9); pre-dose 
 Day 240(Visit 11); pre-dose 


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 Day 360 (Visit 15); pre-dose 
 
All PK/PD samples will be shipped to the following vendor: 
 
 
 
 
 
phone 
 
fax
 
5.10.8.2 
Analytical method(s) 
 
Total IL-1β will be analyzed in serum by means of a competitive ELISA assay, limit of 
quantification at 1.00 pg/mL. 
 
5.10.8.2.1 
Sample labeling 
 
Serum tubes will be used to collect samples. 
 
The samples for the pharmacodynamic profile will be labelled as follows: 
PD 
Study Code: CACZ885NTR01 
Subject Number: 
Sample Number: 
Date / Study Day: 
 
Labels will be provided to the investigator with all label information pre-printed on the label. 
The actual sample collection date and exact time will be entered on the PD Blood Collection 
CRF page. Sampling problems will be noted on the PD Blood Collection Log CRF (a note 
should be attached to the line referring the PD blood collection field). 
For each shipment, the same procedure described above has to be followed. 


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6 
Safety monitoring  
 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavourable 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. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfil 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. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information. 
 the severity grade 
 
 mild: usually transient in nature and generally not interfering with normal activities 
 moderate: sufficiently discomforting to interfere with normal activities 
 severe: prevents normal activities 
 its relationship to the investigational treatment (no/yes), or  
 


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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 adverse event (SAE)  
 action taken regarding investigational treatment  
 whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
 its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
 
Serious adverse events  
6.2.1 
Definition of SAE 
An SAE is any adverse event (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria  
 is fatal or life-threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for : 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent  
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); [study/investigational] (select) 
treatment dosage adjusted/temporarily interrupted; study drug(s) permanently discontinued; 
concomitant medication given; non-drug therapy given. The action taken to treat the adverse 
event should be recorded on the Adverse Event CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 


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necessary) of any changes in severity, the suspected relationship to the investigational 
treatment , 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. 
6.2.2 
SAE reporting  
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days  following the last administration of study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after the 30 days 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 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs) complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after 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 
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 


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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 Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 
Local Novartis Turkey Drug Safety Department will report all suspected unexpected serious 
adverse reactions (SUSARs) to Ministry of Health as per The Regulation on Clinical Trials 
and  Guidance on the collection, verification and submission of Adverse Event/Reaction 
Reports Occurring During Clinical Trials of Medicinal Products and Biological Products 
 
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 a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the [investigational/study treatment] (select) 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
 
Prospective suicidality assessment  
The Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior using a semi-structured interview to probe 
patient responses, has to be administered at each visit, including unscheduled ones.  
If at any assessment after screening and/or baseline the score is 4 or above on the Suicidal 
Ideation item or any “yes” on the Suicidal Behavior item, the patient must be referred to a 
health care professional for further assessment and/or treatment. The decision on whether the 
study treatment should be discontinued is to be taken by the health care professional to whom 
the patient is referred to.  
7 
Data review and database management  
 
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, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that investigational 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. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 


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information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
 
Data collection 
Designated investigator staff must enter the information required by the protocol onto the 
Novartis CRFs that are printed on 3 part, non-carbon-required paper. Field monitors will 
review the CRFs for completeness and accuracy and instruct site personnel to make any 
required corrections or additions. CRO working on behalf of Novartis by field monitors or by 
the investigational site, with one copy being retained at the investigational site. Once the 
CRFs are received by  CRO working on behalf of Novartis, their receipt is recorded, the 
original copy is placed in Central Files, and the non-carbon-required copy is forwarded to the 
responsible Data Management staff for processing. 
 
Database management and quality control 
 
Data from the CRFs are entered into the study database by CRO using double data entry. 
Verification is performed manually by a separate member of the Data Management staff by 
comparing the Case Report Form to the data entered into the database. 
Data from the CRFs are entered into the study database by  Data Management staff using 
double data entry and by referring to the scanned image of the CRF 
Data from the CRFs are entered into the study database by Contract Research Organization 
(CRO) staff following their own internal standard operating procedures that have been 
reviewed and approved by Novartis. 
Subsequently, the entered data are systematically checked by Data Management staff, using 
error messages printed from validation programs and database listings. Other errors or 
omissions are entered on Data Query Forms, which are returned to the investigational site for 
resolution. The signed original and resolved Data Query Forms are kept with the CRFs at the 
investigator site, and a copy is sent to Novartis so the resolutions can be entered into the 
database. Quality control audits of all key safety and efficacy data in the database are made 
prior to locking the database. 
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. 


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Laboratory samples will be processed by institute  and the results will be sent electronically to 
Investigator. 
ECG readings will be processed by investigators and  results will be recorded . 
 
Data Monitoring Committee 
Not required. 
 
Adjudication Committee 
Not required. 
8 
Data analysis 
 
Analysis sets 
Investigators will enter the information required by the protocol into the Novartis Case Report 
Forms (CRFs). Non-obvious errors or omissions will be entered on Data Query Forms, which 
will be returned to the investigational site for resolution. 
The data from all centers will be pooled and summarized with respect to demographic and 
baseline characteristics and efficacy and safety observations. 
 
 Data will be presented for the complete intent-to-treat 
population (all subjects having taken at least one dose of study medication) as well as the per-
protocol population (all subjects who completed the study without major protocol deviations).  
Safety data will be evaluated for the safety population (all subjects having taken at least one 
dose and who have at least one post-baseline assessment). 
Data summaries will be presented. 
 
This trial is an exploratory study, and it is not powered for a statistical analysis. The statistical 
analyses of the measurements will be performed when possible, and these analysis will be 
done by the investigators and an independent Contract Research Organization.  
 
 
Patient demographics and other baseline characteristics 
 
Demographic and baseline characteristics will be summarized descriptively for the safety 
population. Continuous variables will be summarized by mean, standard deviation, median,  
minimum, maximum, and number of subjects with non-missing data. Categorical variables 
will be summarized by absolute frequencies and percentages.  
 
Treatments 
 
The exposure to study drug (number of injections) and duration of exposure (days) will be 
summarized and listed. 
 


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Analysis of the primary variable(s) 
8.4.1 
Variable(s) 
Percentage of complete responders. 
Symptoms measured by VAS.  
Percentage of patients achieved appropriate steroid tapering. 
Changes of general disease activity measured by BDCAF. 
8.4.2 
Statistical model, hypothesis, and method of analysis 
To claim the efficacy of canakinumab on the resolution of attacks, at least 50% response will 
be aimed in at least 50% of the patients. 
All parameters will be compared with baseline values. Complete / Partial / Non responders 
definitons  can be seen in efficacy assessment section.  
 
Analysis of secondary variables 
8.5.1 
Efficacy variables  
Kaplan-Meier estimates will be presented for time to relapse. 
Continuous endpoints (steroid tapering, VAS scores, BDCAF scores) will be summarized by 
mean, standard deviation, median, median, interquartile range, minimum and maximum.  
Differences between pre-treatment and post-treatment values will be analysed by the non-
parametric Wilcoxon signed rank test at the 0.05 level of significance.  
Correlations between the different parameters will be explored by Spearman’s rank 
correlation coefficient.  
 
Categorical variables will be summarized by absolute frequencies and percentages. 
8.5.2 
Safety variables  
The assessment of safety will be based mainly on the frequency of adverse events, which 
includes all serious adverse events. Adverse events will be summarized by the number and 
percentage of subjects having any adverse event, having an adverse event in each body system 
and having each individual adverse event. Any other information collected (e.g. severity or 
relatedness to study medication) will be listed as appropriate. 
Newly occurring notable laboratory values and newly occurring vital sign abnoramilites will 
be tabulated. Listings with abnormalities flagged will be provided 
8.5.3 
Pharmacokinetics 
 
A mixed effects modeling approach will be taken in order to analyze the complete PK data 
from the study. Quality of individual fits to the dataset will be assessed and if the fits are 
apparently unbiased, the model derived population pharmacokinetic model parameter mean 
and inter-individual variance-covariance matrices of parameters such as CL (clearance), V 


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(apparent volume of distribution), ka (first-order absorption rate constant) and 
withinindividual variance will be estimated. In addition, posthoc estimates of the same 
parameters, i.e. CL, and V will be reported for each individual. 
 
Interim analyses 
There will be statistical analysis at Day 30 , Day 90, Day 180 and Day 360. 
 
Sample size calculation 
Because of exploratory nature of the study, 10 patients will provide information. 
9 
Ethical considerations 
 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and with the ethical principles laid down in the Declaration of Helsinki. 
 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents.  
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the HA/EC, and a copy of 
the approved version must be provided to the Novartis monitor after HA/EC approval. 
 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 


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Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted HA Ethics Committee before study start. A signed and dated statement 
that the protocol and informed consent have been approved by the HA/EC must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, HA/ECs, 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. 
 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
10 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants.  Under no circumstances should an investigator collect additional data 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
 
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 HA/EC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations.  
 
 


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11 
References  
1- Vitale et al ,Dermatology. 2014;228(3):211-4 
2- Cantarini et al ,Clin Exp Rheumatol. 2012 May-Jun;30(3 Suppl 72):S115 
3- Ugurlu et al ,Ann Rheum Dis. 2012 Sep;71(9):1589-91 
4- Caso et al , Mediators Inflamm. 2014;2014:107421 
5- Kalra et al ,J Neurol. 2014 Sep;261(9):1662-76 
12 
Names and addresses 
Novartis personnel: 
 
 
Statistician:  
Addresses and telephone/fax numbers: 
Novartis CPO: Novartis Ürünleri İlaç Sektörü 
Rüzgarlıbahçe Mah Suryapı Akel İş merkezi 
No 6 Kavacık Beykoz İstanbul Turkey 
Tel: 
 
 
Site for AE/SAE reporting: 
E-mail : drug_safety.turkey@novartis.com 
Fax: 
 
 
Novartis Ürünleri İlaç Sektörü 
Rüzgarlıbahçe Mah Suryapı Akel İş merkezi 
No 6 Kavacık Beykoz İstanbul Turkey 
Tel: 
 
 
Clinical laboratory: 
 
 Turkey 
Central  Lab 
 
 
 
France 
phone 
 
fax
 
 


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13 
Appendix 1: Blood collection Log 
The volume of blood to be collected for lab parameters that will be analyzed by the central 
laboratory can be found in the central laboratory manual. The blood collection logs for PK/PD 
 samples are shown in Table 13-1. 
Table 13-1 
Blood Collection Log for PK/PD 
 Samples 
 
Day 
Pharmacokinetics 
Pharmacodynamic 
Analyte/purpose 
Canakinumab 
Total IL-1β 
  
PK 
Collection 
No. 
Sample 
No. 
mL 
Number 
mL 
Day 0 
1 
1 
2 
101 
3 
Day 7 
2 
2 
2 
102 
3 
Day 30 
3 
3 
2 
103 
3 
Day 60 
4 
4 
2 
104 
3 
Day 90 
5 
5 
2 
105 
3 
Day 180  
6 
6 
2 
106 
3 
Day 240  
7 
7 
2 
107 
3 
Day 360  
8 
8 
2 
108 
3