Conditions: Pulmonary Sarcoidosis
Keywords: pulmonary sarcoidosis sarcoidosis canakinumab autoimmune diseases granulomas inflammation lung function testing immunosuppressive agents interleukin interleukin-1Beta [F-18]FDG-PET/CT respiratory pulmonary steroids corticosteroids lung diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess if ACZ885 will improve lung function in association with reduction of tissue inflammation in patients with chronic sarcoidosis.

Detailed description:

Arms:
arm 1: ACZ885 (300 mg/2 mL) will be administered subcutaneously to assigned study subjects once monthly for 6 months. arm 2: Placebo (0 mg/2 mL) will be administered subcutaneously to assigned study subjects once monthly for 6 months.

Interventions: intervention 1: ACZ885 intervention 2: Placebo
Intervention descriptions: intervention 1: ACZ885 will be administered subcutaneously to assigned study subjects once monthly for 6 months. intervention 2: Placebo will be administered subcutaneously to assigned study subjects once monthly for 6 months.

Protocol document:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
ACZ885
CACZ885X2205
A multiple-dose, subject-and investigator-blinded, 
placebo-controlled, parallel design study to assess the 
efficacy, safety, and tolerability of ACZ885 (canakinumab) 
in patients with pulmonary sarcoidosis
Document type:  
AmendedProtocolVersion
EUDRACT number:  
2016-001255-49
Version number:  
v01 (Clean)
Clinical Trial Phase:  
II
Release date:
12-Jun-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct.
Additional Manuals
Details for HRCT and [F-18]FDG-PET/CT imaging are described in the Parexel Imaging 
Investigator SOM.
Details on pulmonary function testing are described in the Biomedical Systems Centralized 
Spirometry, DLco, and Lung Volumes Procedure Manual.
For details on receipt, storage and handling of study medication please refer to the Pharmacy 
Manual.
For treatment assignment and randomization please refer to Cenduit Interactive Response 
Technology (IRT) Manual
Notification of serious adverse events
Refer to Section 9.2of the protocol for definitions and reporting requirements for Serious 
Adverse Events (within 24 hours after awareness of the SAE to the local Novartis Drug Safety 
and Epidemiology Department and notify the study lead).
Contact information is listed in the Site Operations Manual. 
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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................6
List of figures......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................12
Glossary of terms...............................................................................................................13
Protocol synopsis...............................................................................................................18
1 Introduction.......................................................................................................................21
1.1
Background............................................................................................................21
1.2
Nonclinical data.....................................................................................................24
1.2.1 
Teratogenicity and reproductive toxicity data.......................................24
1.3
Clinical data...........................................................................................................24
1.3.1 
Human safety and tolerability data.......................................................24
1.3.2 
Human pharmacokinetic data................................................................25
1.3.3 
Human pharmacodynamic data.............................................................25
1.4
Study purpose........................................................................................................25
2 Study objectives and endpoints.........................................................................................26
2.1
Primary objective...................................................................................................26
2.2
Secondary objectives.............................................................................................26
2.3
Exploratory objectives...........................................................................................29
3 Investigational plan...........................................................................................................30
3.1
Study design...........................................................................................................30
3.2
Rationale for study design.....................................................................................32
3.3 Rationale for dose/regimen, route of administration and duration of treatment....32
3.4 
Rationale for choice of comparator.......................................................................32
3.5
Rationale for choice ofbackground therapy..........................................................33
3.6
Purpose and timing of interim analyses/design adaptations..................................33
3.7
Risks and benefits..................................................................................................33
3.7.1 
Blood sample volumes..........................................................................34
4 Population..........................................................................................................................34
4.1
Inclusion criteria....................................................................................................35
4.2
Exclusion criteria...................................................................................................35
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5 Restrictions for Study Subjects.........................................................................................38
5.1
Contraception requirements...................................................................................38
5.2
Prohibited treatment...............................................................................................38
5.3
Dietary restrictions and smoking...........................................................................38
5.4
Other restrictions...................................................................................................38
6 Treatment...........................................................................................................................39
6.1
Study treatment......................................................................................................39
6.1.1 
Investigational treatment and control drugs..........................................39
6.1.2 
Additional study treatment....................................................................39
6.2
Treatment arms......................................................................................................39
6.3
Treatment assignment and randomization.............................................................39
6.4
Treatment blinding.................................................................................................40
6.5
Treating the subject................................................................................................41
6.6
Permitted dose adjustments and interruptions of study treatment.........................41
6.7
Emergency breaking of assigned treatment code..................................................42
6.8
Treatment exposure and compliance.....................................................................42
6.9
Recommended treatment of adverse events..........................................................42
6.10 Rescue medication.................................................................................................42
6.11 Concomitant treatment...........................................................................................43
7 Study completion and discontinuation..............................................................................44
7.1
Study completion and post-study treatment..........................................................44
7.2
Discontinuation of study treatment........................................................................44
7.3
Withdrawal of informed consent...........................................................................45
7.4
Lost to follow-up...................................................................................................
45
7.5
Study Stopping rules..............................................................................................45
7.6
Early study termination by the sponsor.................................................................46
8 Procedures and assessments..............................................................................................47
8.1
Assessment Schedule.............................................................................................47
8.2
Informed consent procedures.................................................................................50
8.3
Subject screening...................................................................................................50
8.4
Subject demographics/other baseline characteristics.............................................51
8.4.1 
Hepatitis screen, HIV screen, tuberculosis screen................................51
8.4.2  Alcohol test, drug screen, urine cotinine...............................................51
8.5
Efficacy/Pharmacodynamics.................................................................................51
8.5.1 
Clinical Outcome Assessments (COAs)...............................................51
8.5.2 
Imaging.................................................................................................53
8.5.3 
Six-minute walk test (6MWT)..............................................................54


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8.5.4 
Serum IL-1β..........................................................................................55
8.5.5 
Pulmonary function testing...................................................................55
8.6
Safety.....................................................................................................................57
8.6.1 
Physical examination............................................................................57
8.6.2 
Vital signs..............................................................................................57
8.6.3 
Height and weight.................................................................................57
8.6.4 
Laboratory evaluations..........................................................................57
8.6.5 
Electrocardiogram (ECG).....................................................................58
8.6.6 
Pregnancy and assessments of fertility.................................................58
8.6.7 
Immunogenicity (Anti-ACZ885 Antibodies)........................................58
8.6.8 
Local tolerability (subcutaneous injections).........................................59
8.7
Pharmacokinetics...................................................................................................59
8.8
Other assessments..................................................................................................60
8.8.1 
Exploratory biomarker assessments......................................................60
8.9
Use of residual biological samples........................................................................61
9 Safety monitoring..............................................................................................................62
9.1
Adverse events.......................................................................................................62
9.2
Serious adverse event reporting.............................................................................63
9.2.1 
Definition of SAE.................................................................................63
9.2.2 
SAE reporting........................................................................................64
9.3
Liver safety monitoring.........................................................................................65
9.4
Renal safety monitoring.........................................................................................66
9.5
Reporting Medication errors including misuse/abuse...........................................66
9.6
Pregnancy reporting...............................................................................................67
9.7
Early phase safety monitoring...............................................................................67
10 Data review and database management.............................................................................68
10.1 Site monitoring......................................................................................................68
10.2 Data collection.......................................................................................................68
10.3 Database management and quality control............................................................69
10.4 Data Monitoring Committee..................................................................................69
10.5 Adjudication Committee........................................................................................70
10.5.1
Infection Adjudication Committee........................................................70
10.5.2
Malignancy Adjudication Committee...................................................70
11 Data analysis......................................................................................................................70
11.1 Analysis sets..........................................................................................................70
11.2 Subject demographics and other baseline characteristics......................................70
11.3 Treatments.............................................................................................................70


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11.4 Analysis of the primary variable(s).......................................................................71
11.4.1
Variable(s).............................................................................................71
11.4.2
Statistical model, hypothesis, and method of analysis..........................71
11.4.3
Handling of missing values/censoring/discontinuations.......................71
11.4.4
Sensitivity analyses...............................................................................71
11.5 Analysis of secondary variable(s)..........................................................................72
11.5.1
Efficacy / Pharmacodynamics...............................................................72
11.5.2
Safety.....................................................................................................73
11.5.3
Pharmacokinetics..................................................................................73
11.5.4
Pharmacokinetic/pharmacodynamic interactions..................................74
11.5.5
Other assessments.................................................................................74
11.6 Analysis of exploratory variables..........................................................................74
11.6.1
Exploratory biomarkers.........................................................................74
11.7 Sample size calculation..........................................................................................74
11.8 Power for analysis of key secondary variables......................................................75
11.9 Interim analyses.....................................................................................................75
12 Ethical considerations........................................................................................................75
12.1 Regulatory and ethical compliance........................................................................75
12.2 Responsibilities of the investigator and IRB/IEC..................................................75
12.3 Publication of study protocol and results...............................................................76
13 Protocol adherence............................................................................................................76
13.1 Protocol Amendments...........................................................................................76
14 References.........................................................................................................................77
15 Appendix 1: Liver Event definitions and follow-up requirements....................................82
16 Appendix 2: Specific Renal alert criteria and actions.......................................................84
List of tables
Table 5-1  
Prohibited treatment..............................................................................38
Table 6-1  
Blinding levels......................................................................................41
Table 9-1  
Summary of reporting requirements for medication errors...................67
Table 15-1  
Liver Event definitions..........................................................................82
Table 15-2  
Actions required for Liver Events.........................................................82
Table 15-3  
Exclusion of underlying liver disease...................................................83
Table 16-1  
Specific Renal alert criteria and actions................................................84
Table 16-2  
Follow-up of renal events......................................................................85


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List of figures
Figure 1-1  
Immunohistochemistry staining of sarcoidosis lung biopsy tissue.......23
Figure 3-1  
Study Design scheme............................................................................30


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List of abbreviations
γ-GT
Gamma-glutamyl transferase
6MWT  
6-minute walk test
[F-18]FDG-PET
fluorine-18 fluorodeoxyglucose positron emission tomography
ADA
anti-drug antibodies
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA  
analysis of covariance
AST
aspartate aminotransferase
ATS/ERS  
American Thoracic Society/European Respiratory Society
AUC
area under the curve
BAL
bronchoalveolar lavage
BDR
bioanalytical data report
BTPS
Body temperature, ambient pressure, saturated with water vapor
BUN
blood urea nitrogen
CAPS
cryopyrin-associated periodic syndromes
CD-ROM  
compact disc –read only memory
CFR
Code of Federal Regulation
CK
creatinine kinase
cm
centimeters
CO2
carbon dioxide
CR
complete response
CRF
Case Report/Record Form (paper or electronic)
CRO
contract research organization
CT
computed tomography
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CTC
Common Toxicity Criteria
CV
coefficient of variation
CXR
chest X-ray
DLco 
diffusing capacity for carbonmonoxide
DAR
dose administration record
EC
ethics committee
ECG
electrocardiogram
EDC
electronic data capture
ELISA  
enzyme-linked immunosorbent assay
EOS
end of study visit
ePRO
electronic patient reported outcome
FCAS
familial cold autoinflammatory syndrome
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
FEF25-75
forced expiratory flow 25%-75% FEV1 forced expiratory volume in 1 
second
FEV3
forced expiratory volume in 3seconds
FVC
forced vital capacity
FVC%  
forced vital capacity (expressed as percent of normal expected value)
GCP
good clinical practice
h
hour
HBsAg  
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRCT
high resolution computed tomography
i.v.
intravenous
IAC
infection adjudication committee
IB
investigator
's brochure
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
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IL
interleukin
IN
Investigator Notification
IRB
institutional review board
IRT
interactive response technology
ITF
image transmittal form
IUD
intrauterine device
IUS
intrauterine system
kg
kilograms
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
MAC
malignancy adjudication committee
MedDRA  
medical dictionary for regulatory activities
mg
milligram(s)
ml
milliliter(s)
MMRC  
Modified Medical Research Council
MRI
Magnetic resonance imaging
MWS
Muckle Wells syndrome
PA
posteroanterior
PD
pharmacodynamic(s)
PET
positron emission tomography
PFT
pulmonary function test
PK
pharmacokinetic(s)
PR
partial response
PRO
patient reported outcome
RA
rheumatoid arthritis
RBC
red blood cell(s)
REB
research ethics board
ROI
region of interest
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RV
residual volume
s.c.
subcutaneous
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
sJIA
systemic juvenile idiopathic arthritis
SOM
site operations manual
SUSAR  
suspected unexpected serious adverse reaction
SUVmax  
maximum standardized uptake value
TB
tuberculosis
TBL
total bilirubin
TLC
total lung capacity
ULN
upper limit of normal
ULQ
upper limit of quantification
VA
alveolar volume
VD
dead space volume 
VT
tidal volume
WBC
white blood cell(s)
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Pharmacokinetic definitions and symbols
C   
The serum trough concentration during multiple dosing [mass / volume]
Cav  
The observed average serum concentration following drug administration
CL
The systemic (or total body) clearance from plasma (or serum or blood) following 
intravenous administration [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration following drug 
administration [mass / volume]
Vss
The volume of distribution at steady state following intravenous administration 
[volume]


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Glossary of terms
Control drug
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug.
Enrollment
Point/time of subject entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol).
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug” 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 other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage.
Medication 
number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Premature 
subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time 
all study drug administration is discontinued and no further assessments 
are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to 
a specific treatment arm assignment
Stage
Amajor subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
Study completion Point/time at which the subject came in for a final evaluation visit or 
when study drugwas discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature subject 
withdrawal.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of 
the required study procedures; includes investigational drug, active drug 
run-ins or background therapy.


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Subject
An individual who has consented to participate in this study. The term 
Subject may be used to describe either a healthy volunteer or a patient.
Subject number
A number assigned to each subject who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
subject in the study.
Variable
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints.


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Protocol synopsis
Protocol 
number
CACZ885X2205
Title
A multiple-dose, subject-and investigator-blinded, placebo-controlled, parallel 
design study to assess the efficacy, safety and tolerability of ACZ885 
(canakinumab) in patients with pulmonary sarcoidosis
Brief title
Study of efficacy, safety and tolerability of ACZ885 (canakinumab) in patients with 
pulmonary sarcoidosis
Sponsor and 
Clinical Phase
Novartis
Phase 2
Intervention 
type
Drug
Study type
Interventional 
Purpose and 
rationale
The purpose of this study is to assess if inhibition of IL-1β by ACZ885 will improve 
lung function in association with reduction of tissue inflammation in patients with 
chronic sarcoidosis.
Primary 
Objective
To compare the effect of ACZ885 versus placebo on the clinical disease activity of 
sarcoidosis patientsas measured by the change from baseline in the percent 
predicted forced vital capacity (FVC) at week 24
Secondary 
Objectives
To determine the effect of ACZ885 on decreasing the maximum standardized 
uptake value (SUVmax) ([F-18]FDG-PET) in nodules (nodal uptake regions) after 
12 weeks of treatment, compared to placebo.
To determine the effect of ACZ885 versus placebo on other parameters of 
pulmonary function testing in patients with sarcoidosis at 24 weeks compared to 
baseline.
To determine the effect of ACZ885 versus placebo on HRCT of patients with 
sarcoidosis at 24 weeks compared to initial HRCT scan as measured by side-by-
side comparison by blinded reviewers and HRCT scoring.
To determine the effect of ACZ885 versus placebo on the 6-minute walk test 
distance of patients with sarcoidosis at 12 and 24 weeks compared to baseline
To determine the effect of ACZ885 on additional [F-18]FDG-PET outcomes after 12 
weeks of treatment compared to placebo
To assess the safety and tolerability of ACZ885 in patients with sarcoidosis as 
measured by adverse events
Study design
This is a subject- and investigator-blinded, randomized, placebo-controlled, 
parallel-group, non-confirmatory study to assess the clinical efficacy of ACZ885 
administered subcutaneously (s.c.) every four weeks for a total of 24 weeks.


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Population
The study will randomize approximately 38 patients with radiological evidence of 
parenchymallyinvolved,chronic pulmonary sarcoidosis of ≥1 year duration with 
persisting activity at baseline despite background therapy.
Inclusion 
criteria

Male and female subjects ages 18 to 80 years of age (inclusive)

Subjects must weigh at least 50 kg to participate in thestudy

Able to communicate well with the investigator, to understand and comply
with the requirements of the study

Disease duration of ≥1 year

Clinically active disease demonstrated either by a biopsy (any organ) or by
bronchoalveolarlavage (lymphocy
tosis >15%, CD4
+/CD8
+ratio >3.5,
CD103+CD4+/CD4
+ratio <0.2). Patients must also have all of the following
criteria:
o
Modified Medical Research Council (MMRC) dyspnea scale ≥ 1
o
Threshold FVC 50 -90% of predicted
o
Evidence of parenchymal lung involvement by HRCTat screening
or by historical radiological evidence
Exclusion 
criteria

Diagnosis of pulmonary hypertension requiring treatment

Current inhaled use of tobacco products(urine cotinine level > 500
nanograms/mL) at screening

History of bleeding disorder

Extra-pulmonary sarcoidosis as primary treatment indication (e.g., involving
brain, heart, eye and renal disease with significant hypercalcemia)

Any conditions or significant medical problems, which in the opinion of the
investigator, immuno-compromises the patient and/or places the patient at
unacceptable risk for immunomodulatory therapy, such as:
o
Absolute neutrophil count (ANC) < lower limit ofnormal (LLN)
(1,500/μl)
o
Platelets < LLN –75.0 x 109/L
o
Any active or recurrent bacterial, fungal (with exception of
onychomycosis) or viral infection
o
Presence of human immunodeficiency virus (HIV) infection, active
hepatitis B or hepatitis C infections based on screening lab result
o
Presence of active or latent tuberculosis (TB) Clinical evidence or
history of multiple sclerosis or other demyelinating diseases, or Felty’s
syndrome
Live vaccinations within 3 months prior toscreening
Current severe progressive or uncontrolled disease which in the judgment of the
clinical investigator renders the patient unsuitable for the trial
Two treatment armsin a ratio of 1:1: canakinumab (ACZ885)versus placebo-
controlled dose group


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Efficacy/PD 
assessments
Pulmonary function testing
[F-18]FDG-PET/CT
HRCT
Six-minute walk test (6MWT)
Serum IL-1β
Safety 
assessments
Physical examination, including vital signs and height/weight
Hematology, clinical chemistry, urinalysis
Local tolerability of subcutaneous(s.c.)injections of canakinumab/ACZ885
Electrocardiogram (ECG)
Other 
assessments
Data analysis
The primary variable for the assessment of efficacy will be the change from 
baseline in the percent predicted FVC. It will be analyzed using a Bayesian model 
for repeated measurements. The model will investigate effects for baseline by time 
interaction, treatment by time interaction and PET positivity (yes/no) prior to 
randomization. Uninformative priors will be utilized to obtain the posterior 
estimates. The posterior probability that ACZ885 is better than placebo in terms of 
change from baseline in percent predicted FVC at 24 weeks will be calculated. If it 
is at least 90%, it will be considered a sign of efficacy of ACZ885 increasing FVC 
after 24 weeks of treatment in this patient population.
Key words
Pulmonary sarcoidosis, [F-18]FDG-PET/CT, IL-1β, canakinumab
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1  
Introduction
1.1  
Background
Chronic sarcoidosis
Chronic sarcoidosis is a systemic disease characterized by development of granulomas, 
inflammation and accompanying fibrotic tissue reactions (Chen and Moller 2011). 
Althoughany organ can be affected, most common disease manifestations are found in lung, 
skin, and eye tissues. Chronic sarcoidosis is an orphan disease with an overall prevalence in 
US populations of 8/10,000. There exist ethnic differences in disease frequency and severity. 
Thedisease is more severe and frequent in African Americans than in those of 
NorthernEuropean descent (2.4% vs 0.85% lifetime risk) with risk of death up to 8%; 
(Swigrisetal2011).
There are no approved therapies for sarcoidosis. Corticosteroid use has long comprised the 
standard of care, with diverse and unapproved, secondaryimmunosuppressive usage 
(e.g.,methotrexate, azathioprine) as needed, all of which are accompanied by 
treatment-related,
severe adverse reactions
(Baughman 
and Nunes 
2012; 
Paramothayanetal2008). Clinical trials in sarcoidosis with biological therapies targeting the 
adaptive immune response have not met expectations. The typical clinical course for chronic, 
active sarcoidosis patients is characterized by progressive and debilitating declines in lung 
function, with the primary causes of morbidity and mortality including pulmonary 
hypertension and fibrosis (BaughmanandLower2011). Thus there is an unmet medical need 
in patients with chronic, active sarcoidosis for a disease modifying agent that induces 
resolution of granulomas and prevents deterioration or improves lung function.
The pathophysiology of sarcoidosis remains poorly understood but is suspected to be a host 
immunological response to an antigenic exposure. The role of T-lymphocytes in recognition 
of specific antigens and in theamplification of inflammatory responses has been well 
established. However, T-cell targeted therapeutics have not demonstrated substantial clinical 
benefits. Therefore, alternative therapeutic targets and disease mechanisms must be 
considered in this disease.
A role for IL-1βin sarcoidosis
IL-1β is a pro-inflammatory cytokine produced by a variety of cell types, particularly 
mononuclear phagocytes, in response to injury, infection and inflammation. In sarcoidosis, the 
IL-1β has been shown to be an important contributor to maintaining macrophage and Tcell 
alveolitis and epithelioid cell granuloma formation (Hunninghake1984). Epithelioidcells, the 
predominant cell type within sarcoid granulomas, have been shown to strongly express IL-1β 
(Devergneetal1992). In addition, 70-95% of bronchoalveolar lavage (BAL) macrophages 
from sarcoidosis patients demonstrate cytoplasmic staining of IL-1β (Chilosietal1988). 
Clinical relevance is suggested by studies showing that the degree of sarcoidosis inflammation 
measured by gallium scan and lymphocytic alveolitis correlates with spontaneous and 
stimulated IL-1β release by alveolar macrophages (Hunninghake1984; Steffenetal1993; 
Yamaguchietal1988; Barthetal1989). Finally,IL-1β is known to induce and enhance 


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granuloma formation in vitroand in vivo and to be involved in associated anergy 
(Kobayashietal1985; Kasaharaetal1989; Teraoetal1993). Thus, IL-1β represents a 
potential therapeutic target for sarcoidosis.
Therapeutic targeting of IL-1β and the inflammasome
ACZ885 (canakinumab) is a high affinity, fully human, monoclonal anti-human IL-1β 
antibody of the IgG1/κ isotype that is designed to bind to human IL-1β, blocking the 
interaction of this cytokine to its receptors, thus functionally neutralizing the bioactivity of 
this cytokine.
Canakinumab is currently marketed under the name Ilaris
® for treatment of adults and 
children aged 4 years and older that have a condition known as cryopyrin-associated periodic 
syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and 
Muckle-Wells syndrome (MWS). Ilaris
® is also approved for thesymptomatic treatment of 
acute gouty arthritis attacks and for the treatment of active systemic juvenile idiopathic 
arthritis (sJIA) in children 2 years of age and older. For further details please refer to the 
investigators’brochure (IB).
IL-1β is recognized as one of the principal pro-inflammatory cytokines in a variety of 
inflammatory conditions (Dinarelloetal2012), including those involving autoinflammation 
and the inflammasome.
The inflammasome is a multiprotein oligomer that is expressed in myeloid cells as a 
component of the innate immune system. Inflammasomes can be triggered by a variety of 
activators and processes, resulting in an inflammatory cascade that includes cleavage by 
caspase-1 of pro-IL-1β andpro-IL-18 into their active forms, along with triggering of other 
inflammatory processes. Over the last few years, there has been an increasing body of 
literature about the efficacy of targeting IL-1β in a wide spectrum of autoinflammatory 
conditions. Autoinflammatory disorders can be distinguished from autoimmune disorders by 
disease mechanisms involving innate immune regulation of cytokines and neutrophilic 
inflammation rather than adaptive immune responses involving antibodies and lymphocytes. 
Inflammasome-mediated diseases include rare orphan diseases classified together within the 
condition of hereditary periodic fevers. Another disease in which the inflammasome plays a 
key role is gouty arthritis. These conditions have in common either conditions or mutations 
that result in increased inflammasome activation, resulting in chronically recurring 
inflammation.
Sarcoidosis as an inflammasome-mediated disease
Using unbiased, molecular profiling approaches guided by pathway signatures from recent 
canakinumab trials in other diseases, we discovered unanticipated evidence for significant 
involvement of the inflammasome as a generator of IL-1β in sarcoidosis; a disease heretofore 
primarily regarded as driven largely by cell-mediated immune processes. Confirmatory
studies examining lung and skin lesional tissues or ex vivocells from patients with chronic 
sarcoidosis provided further evidence for inflammasome and IL-1β activation in diseased 
tissues. In the representative Figure 1-1below, serial sections from an untreated sarcoidosis 
patient with highly active, multi-organ disease demonstrate strong, co-localizing staining of 
pulmonary granulomas for macrophages 
(CD68+), activated inflammasome 


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(cleavedcaspase-1) and its downstream product IL-1β. Functional assays with ex vivoBAL 
cells from sarcoidosis patients and normal healthycontrols revealed elevated non-stimulated 
and stimulated IL-1β levels in sarcoidosis-derived specimens with correlations to disease 
activity. Finally, neutrophils, an important component of autoinflammatory disorders, also 
play a role in sarcoidosis pathophysiology. Neutrophil chemotaxis, phagocytosis and numbers 
in sarcoidosis patients have been shown to correlate to disease activity and prognosis 
(Ziegenhagenetal2003; Tutor-Uretaetal2006; Schmekeletal1985; Drentetal1999; 
Turner-Warwick etal1986). Additional indicators of neutrophil activity, such as IL-8 and 
esterase are also elevated in sarcoidosis patients with correlations to disease activity 
(Caretal1994; Lozaetal2011; Hindetal1988).
The above evidence supports that inflammasome activity is upregulated in sarcoidosis patients 
and may play a role in disease activity. Thus, IL-1β pathway interruption with canakinumab is 
anticipated to confer therapeutic benefit.
Figure 1-1  
Immunohistochemistry staining of sarcoidosis lung biopsy tissue
Representative staining in serial sections of biopsy tissue from a sarcoidosis patient with highly active 
disease in need of immune suppressive treatment. CD68 is a marker for macrophages. Cleaved 
caspase-1 is indicative ofinflammasome activation. Positive staining represented by the color brown.


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1.2  
Nonclinical data
1.3  
Clinical data
1.3.1 
Human safety and tolerability data
As of 30 June 2016, an estimated 10,900patients have received canakinumab treatment in 66 
Novartis-sponsored investigational clinical trials and 17investigator-initiated trials in a wide 
spectrum of IL-1β driven diseases such as CAPS, mild asthma, psoriasis, wet age-related 
macular degeneration, gouty arthritis, type 2 diabetes mellitus, rheumatoid arthritis (RA), and 
sJIA. Health authority approvals for Ilaris
® have been granted for CAPS, gouty arthritisand 
sJIA. The post-marketing cumulative patient exposure since the first launch of the product is 
estimated to be approximately 8,588patient treatment-years. The doses administered i.v. 
ranged from 0.3 mg/kg to 10 mg/kg or a fixed dose of 600 mg, and from 0.5 mg/kg to 
9mg/kg s.c. or fixed doses of 5 mg to 300 mg s.c.The frequency of dosing ranged from a 
single dose to weekly repeatedadministration. Every four weeks s.c. dosing of 4 mg/kg up to 
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300 mg is approved by the FDA in sJIA. Canakinumab has a long half-life, averaging 
approximately 4 weeks in man and has been well-tolerated by patients at all dose levels 
investigated. So far the duration of exposure to canakinumab is more than 4years for the first 
4 MWS patients enrolled in the CACZ885A2102 trial. Final and preliminary data from 
completed clinical studies demonstrate efficacy as well as good safety in patients with CAPS, 
sJIA,RA and gouty arthritis. The details of the SAEs and AEs of the completed studies and 
relevant details of the SAEs of the ongoing studies are summarized in the latest version of the 
IB. Adverse events in unblinded studies ranged from mild to moderate in severity and 
included upper respiratory tract infections, nasopharyngitis and otitis, headache, nausea, 
diarrhea, and asthenic conditions.
Immunogenicity has not proved to be a significant concern for canakinumab. Canakinumab 
studies across multiple indications and dosing regimens have demonstrated that the incidence 
of treatment-emergent ADA development remains very low, in the range of 0.3% to 2.9%. 
Furthermore, there have been no clinical consequences evident for these detected antibodies.
1.3.2  Human pharmacokinetic data
Canakinumab has the expected pharmacokinetics of an IgG1-type antibody with a low volume 
of distribution (VSS=6.0 L) and low clearance that is dependent on body weight (e.g., 
CL=0.174 L/day in a a CAPS patient of body weight 70 kg, 0.11 L/day ina SJIA patient of 
body weight 33 kg and 0.23 L/day in a gout patient of body weight 93 kg). Half-lives vary 
between 21 and 30 days. Within the dose range studied, the pharmacokinetics of canakinumab 
were linear. The systemic exposure parameters, AUC and Cmax, increase in proportion to 
dose overthe dose range of 0.30 to 10.0mg/kg given as i.v. infusion and from 150mg to 
300mg when administered as an s.c. injection. Theabsolute bioavailability of s.c. 
canakinumab is 70%. A mathematical model to characterize the binding kinetics of 
canakinumab to IL-1β has been created. The model successfully fits the patient data and 
allows estimation of canakinumab clearance and volumes of distribution, together with IL-1β 
rate of release and half-lives.
1.3.3 
Human pharmacodynamic data
Canakinumab binds to and inactivates IL-1β and blocks downstream events of IL-1β signaling, 
including IL-1β production, IL-1β pathway-related gene activation, elevation of acute phase 
proteins,
 and C-reactive protein (CRP), and mobilization of 
neutrophils and platelets from bone marrow.
Normally undetectable, serum IL-1β becomes detectable in humans when complexed with 
canakinumab. These IL-1β/canakinumab complexes are biologically inactive and have been 
utilized inall clinical studies as a surrogate PD marker because their increase reflects the 
reduction of free IL-1β levels caused by binding to canakinumab.
1.4  
Study purpose
This study is designed as a proof-of-concept study to assess if inhibition of IL-1β by 
canakinumab will improve lung function in association with attenuation of tissue 
inflammation in patients with chronic sarcoidosis, therefore allowing further development of 
the compound for treatment of this disease population.
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2  
Study objectives and endpoints
2.1  
Primary objective
Primary objective
Endpointsrelated to 
primary objective
To compare the effect of ACZ885 versus placebo on the
clinical disease activityof sarcoidosis patients as measured by
the change from baseline in the percent predicted forced vital
capacity (FVC) at week 24
Change from
baseline in percent
predicted FVC at
week 24
Rationale for Primary Outcome
FVC has been shown in sarcoidosis patients to correlate with mortality risk and is the most 
often used functional outcome in sarcoidosis studies, providing a benchmark for comparison 
against previously tested agents (Baughmanetal2012). Based on published results with 
corticosteroids, significant clinical responses by spirometry in sarcoidosis patients can be 
detected as early as 24 weeks, with maximum effect shown by 52 weeks 
(Baughmanetal2013).
2.2  
Secondary objectives
Secondary objectives
Endpointsrelated to 
secondary objectives
To determine the effect of ACZ885 on decreasing the
maximum standardized uptake value (SUVmax) [F-18]FDG-
PET in nodules (nodular uptake regions) after 12 weeks of
treatment, compared to placebo.
Percent change from
initial scan in [F-
18]FDG-PET SUVmax
at week 12
To determine the effect of ACZ885 versus placebo on other
parameters of pulmonary function testing (i.e., absolute
FVC, FEV1, FEV1/FVC, FEV3,FEF25-75, FEV3/FVC,
FEV6, TLC, RV, RV/TLC, DLco and post-bronchodilator
FEV1/reversibility) in patients with sarcoidosis at 24 weeks
compared to baseline
Lung function testing
results at 24 weeks
compared to baseline
To determine the effect of ACZ885 versus placebo on
HRCT of patients with sarcoidosis at 24 weeks compared to
initial HRCT scan as measured by side-by-side comparison
by blinded reviewers and HRCT scoring
HRCT results at 24
weeks compared to
HRCT initial scan
measured by blinded
reviewers and HRCT
scoring
To determine the effect of ACZ885 versus placebo on the 6-
minute walk test (6MWT) distance of patients with
sarcoidosis at 12 and 24 weeks compared to baseline
6MWT results at week
12 and 24 compared to
baseline


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Secondary objectives
Endpointsrelated to 
secondary objectives
To determine the effect of ACZ885 on additional [F-
18]FDG-PET outcomes (i.e., SUVmean, SUVpeak and
volume of the lesions) after 12 weeks of treatment compared
to placebo
Percent change from
initial scan in
additional [F-18]FDG
PET outcomes at week
12
To assess the safety and tolerability of ACZ885 in patients
with sarcoidosis as measured by adverse events (AEs)
Adverse events in
patients taking
ACZ885 compared to
placebo
Rationale for imaging with HRCT and FDG PET/CT in screening and/or 
secondary outcomes
High resolution computed tomography (HRCT) is used in this study for both screening and 
for clinical outcome measurements. Standard plain chest radiographic views are frequently 
used in the diagnostic and staging processes for sarcoidosis patients. However, the chest 
radiographic scores (Scadding stages 0-IV) have limited value in predicting severity of 
pulmonary involvement and are relatively insensitive as a disease marker in therapeutic trials. 
HRCT (without contrast agent) provides superior resolution of lung morphology when 
compared to chest radiography or even conventional CT. HRCT can detect parenchymal 
disease in patients with normal chest radiographs or demonstrate more extensive disease in 
patients having only focal abnormalities on chest radiographs (Batra1993; Drentetal2003). 
Typical HRCT features of sarcoid parenchymal abnormalities include nodular densities, 
patchy areas of ground glass opacities, irregular linear opacities, end-stage fibrosis and 
honeycomb appearance. The nodules found on HRCT have been shown to likely represent 
confluent interstitial granulomas. Signs of distortion on HRCT are consistent with the 
development of fibrosis. Sequential HRCTs have shown that nodules and patchy ground glass 
densities are reversible, whereas honeycombing and lung distortion suggest irreversible 
fibrosis. Moreover, HRCT abnormalities have been reported to correlate better than 
radiographic stage to pulmonary functional parameters and serum biomarkers. Of particular 
note, relationships have been noted between HRCT findings and BAL neutrophil numbers, a
marker of disease activity. HRCT correlations with other sarcoidosis disease activity markers 
have also been found, including BAL total cell count and serum levels of sIL-2R.
This study will use highly sensitive [F-18]FDG-PET/CT imaging to provide early evidence 
for effective decrease in IL-1β-driven inflammation on ACZ885 treatment. 
[F-18]FDG-PET/CT detects increased inflammation-associated metabolic activity in 
sarcoidosis with sensitivity of 90-100%, and decreases in [F-18]FDG-PET/CT at 24 weeks 
compared to baseline have been correlated with improvements in FVC over this time period 
(Keijsersetal2008; Milmanetal2012; Adamsetal2014) with evidence of improvement by 
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serial [F-18]FDG-PET detected in sarcoid patients reported as early as 1-2 months 
(Brudinetal1994; Braunetal2008; Imperialeetal2013). In addition, evidence suggests that 
low dose prednisone therapy does not appreciably alter [F-18]FDG-PET tracer uptake 
evaluated in a second, follow up scan while high dose (e.g., 40 mg/d) does result in PET 
signal reduction (Brudinetal1994). We postulate rapid reduction in inflammasome activity 
upon ACZ885 treatment, and a temporally associated decrease in [F-18]FDG-PET is expected 
by 12 weeks. However, detectable clinical signs of improvement in pulmonary function are 
anticipated to require additional time after cessation of tissue inflammation by the 
experimental treatment. Hence, the endpoint related to pulmonary function assessment occurs 
later at 24 weeks. In consideration of evidence suggesting that patients with FDG PET tracer 
uptake in parenchymal lung tissues have active disease more likely to improve with effective 
intervention versus no changes in patients with negative PET findings (Keijsersetal2011; 
Vorselaarsetal2015), patients in this study will undergo stratification at randomization based 
on baseline FDG PET/CT results. In addition, later analyses for this study will also stratify 
patients for the presence of lung parenchymal PET tracer uptake at baseline.
Rationale for other secondary outcomes
Full pulmonary function tests include spirometry (FVC, FEV1, FEV1/FVC, FEF25-75, 
FEV3/FVC, FEV6,lung volumes (TLC, RV, RV/TLC) and gas diffusion (DLco) to allow 
further characterization of the patients’ response to treatment. Emerging evidence suggests 
that sarcoidosis involves a component of small airways disease caused by constriction by peri-
bronchiolar granulomatous inflammation (Daviesetal2000). Therefore,the following 
spirometry measures: FEV3, FEV3/FVC, 1-(FEV3/FVC) will be performed to assess small 
airway disease. (Burgeletal2011). The Investigator needs to pay special attention to capture 
the FEV3 data (not always captured by traditional software; may be captured by saving the 
flow volume loop).
The 6MWT (including distance walked, changes in oxygenation, and Borg Questionnaire) is a 
practical and simple assessment of functional capacity, reflective of activities of daily living 
(Enright2003) that has beenincreasingly applied to assess various lung diseases, including 
interstitial lung diseases other than sarcoidosis where it has proved useful for both predicting
mortality and monitoring response to therapy. Its application in sarcoidosis studies has been 
more limited (Baughmanetal2007) and results should be interpreted in recognition of the 
multi-factorial nature of the disease (Baughman and Lower 2011).


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2.3  
Exploratory objectives
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3  
Investigational plan
3.1  
Study design
Figure 3-1  
Study Design scheme
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This is a 32-week, subject-and investigator-blinded, randomized, placebo-controlled, 
parallel-group, non-confirmatory study to assess the clinical efficacy of ACZ885 administered 
subcutaneously (s.c.) in 6 injections given 28 days apart (Figure 3-1). Thestudy will 
randomize approximately 38 patients (targeting 30 completers) with evidence of parenchymal 
involvement and histologically proven, chronic pulmonary sarcoidosis of ≥1 year duration 
with persisting activity at baseline despite background therapy as determined by clinical 
history, radiologicevidence (e.g.HRCT, MRI or chest x-ray), spirometry and MMRC 
dyspnea scale assessments. Randomization will be stratified by positive PET parenchymal 
tracer uptake (yes/no). Acceptable background therapy includes a stable regimen of 
prednisone ≤15 mg/day and/or no more than one immune suppressive agent 
(i.e.,methotrexate, azathioprine, leflunomide or hydroxychloroquine).
Re-screening of subjects may be allowed with the consultation of the Sponsor’s medical 
expert.
For each subject, there will be a maximum 40-day screening period. Screening is valid for 
40days from the time of the first screening assessment. [F-18]FDG-PET/CT scans obtained 
locally at the study site within 8 weeks of randomization will be acceptable for baseline 
assessment prior to receiving the first injection of ACZ885. However, any prior [F-18]FDG-
PET/CT imaging must also have been done without changes in treatment during the 
subsequent period leading up to study randomization.
Subjects who meet the eligibility criteria at screening will undergo evaluation of full baseline 
clinical and biomarker assessments prior to injection. Baseline assessments including safety 
laboratoryevaluations and pulmonary function tests will not be available prior to dosing and 
for those measures eligibility criteria will be determined based on the screening results. 
Enrolled subjects will be randomized at a 1:1 ratio to receive treatment with either ACZ885 or 
placebo. On Days1, 29, 57, 85, 113and 141patients will be administered s.c. dosing with 
ACZ885 at 300 mgor corresponding placebo treatment. All patients will return to the study 
center for safety and pharmacokinetic (PK) checks on an every four week basis at which time 
they will receive either study treatments depending on treatment arm. Additionally, patients 
will undergo clinical assessments that include pulmonary function tests with lung volumes, 
DLCO, 6MWT, and clinical outcome assessments as outlined in the AssessmentSchedule.
At week 12, a second [F-18]FDG-PET/CT will be obtained. In addition, functional clinical 
measures 
 will take place at this time point. Thefinal dosing will 
take place on week 20, followed by a visit on week 24
. Also included at the week 24 visit is the second HRCT 
assessment. Patients return for the end of study (EOS) visit at week 32.
A follow-up visit or phone call for SAEs must be performed 30 days following early 
discontinuation, or 8 weeks after last injection of study drug, whichever is later. 
Ifanaphylactic reactions occur after injection, two more immunogenicity samples (at the time 
of the event and 8 weeks later) need to be taken. Any patient who discontinues the study early 
will complete the Week 32, EOS visit. Patients discontinuing after week 12 will also undergo 
a second HRCT assessment at this visit, as assessedon a case-by-case basis by the Sponsor.
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3.2  
Rationale forstudy design
A randomized, placebo-controlled, subject and investigator blinded approach is used to 
eliminate potential bias in reporting safety and clinical efficacy data in this first exploratory 
study in sarcoidosis patients.
The patient exclusion criteria of background prednisone dosing >15 mg/day is justified
because chronic high dose steroids (e.g., 40 mg/day) have been reported to attenuate the 
[F-18]FDG-PET signal while low dose steroids do not have this effect (Brudinetal1994).
3.3  
Rationale for dose/regimen, route of administration and duration 
of treatment
The dose of ACZ885 (canakinumab) selected for the current proof-of-concept trial is 300mg 
s.c. every four weeks. This dose will ensure optimal tissue penetration for suppressing the
established granulomatous inflammation over time and allow for tissue repair and recovery of
organ functionality. The current label for canakinumab (Ilaris
®) indicates a standard starting
dosage of 2 or 4 mg/kg up to 150 mg s.c.every 8 weeks and allows for every 8 weeks dosing
up to 8mg/kg for CAPS patients ≤40 kg and up to 600mg s.c. for those patients >40kg if a
satisfactory clinical response has not been achieved 7 days after treatment start. Every4week
s.c. dosing up to 300 mg is indicated for patients with systemic juvenile idiopathic arthritis.
RA patients, a relatively comparable patient population to sarcoidosis in terms of age range
and inflammatory levels, have been treated with 300 mg s.c. up to 184 weeks
(studiesCACZ885A2201, E1 & E2) at every 2 weeks for the first 12 weeks and every
4weeks thereafter. This dosing regimen was well-tolerated, without dose-dependent
differences in AE incidence compared to every 4 weeksdosing of 150 mg s.c.
ACZ885 administered s.c. has an approximate bioavailability of 70% compared to i.v. 
administration. However, there are likely to be differential, organ-dependent tissue levels of 
ACZ885, with lung tissue penetration expected to be 10-15% of the systemic exposure 
(Wang etal2008, Shahetal2012, Shahetal2013). Analysis of a recent failed trial of the 
TNF-α inhibitor golimumab in chronic sarcoidosis patients suggested insufficient dosing may 
have been a factor (Judsonetal2014). Thus, higher dosing of ACZ885 is desired for initial 
clinical testing of IL-1β blockade, a novel therapeutic targetforthis disease process.
The duration of every 4-week dosing to week 20 is based on the expected time of 24weeks 
required for detecting functional improvement in the clinical outcome of change in percent of 
predicted FVC for this patient population.
In summary, in order to optimally assess the potential for ACZ885 in its first trial in 
sarcoidosis patients, an every 4-week dosing at 300 mg s.c. is justified to reach adequate 
circulating and tissue levels within the target organs for the anticipated duration required for a 
meaningful change in the lung inflammation and in the subsequent clinical outcomes.
3.4  
Rationale for choice of comparator
In this study, the placebo to ACZ885 will be used as comparator to provide objective evidence 
of potential AEs and other safety data as well as clinical efficacy generated from patients 
exposed toACZ885.


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3.5  
Rationale for choice of background therapy
Patients will continue on stable background therapy as established prior to study entry, 
thereby justifying potential treatment with placebo. Subjects will be maintained on their 
pre-existing stable medical regimen for treatment of preexisting medical conditions, including 
sarcoidosis.
3.6  
Purpose and timing of interim analyses/design adaptations
3.7  
Risks and benefits
ACZ885 has not been previously administered with therapeutic intent to patients with active, 
chronic sarcoidosis. Therefore, no statement can be made at this time on the actual clinical 
benefits of ACZ885 in this patient population. However, given the mechanism of action of 
ACZ885 and the relevant inflammatory pathways involving IL-1β as discussed in the 
background (Section 1.1), there is a reasonable expectation that a therapeutic response can be 
achieved with the compound in sarcoidosis.
Overall, the development program with ACZ885 has demonstrated a good safety and 
tolerability profile as evidenced by a low number of study discontinuations for AEs, 
predominantly mild injection site reactions and no specific target organ toxicity. The AEs 
profile is characterized by non-specific gastrointestinal and central nervous system events, and 
infections predominantly of the upper respiratory tract, in some instances serious, with all 
infections responding to standard therapy.
The available toxicology, efficacy, safety, tolerability, lack of detectable immunogenicity and 
efficacy data in MWS, RA, sJIA and gouty arthritis, further support the clinical development 
of canakinumab in diseases in which IL-1β is likely to have a predominant role. 
However,since preventing IL-1β receptor signaling may alter immunologic responsiveness in 
unanticipated ways, patients receiving ACZ885 will be closely monitored for clinical and 
laboratory indicators of immune suppression and immune dysregulation, such as infection 
including opportunistic infections (recognizing that blocking IL-1β may mask feverand blunt 
the inflammatory response to infection), blood cells count abnormalities 
(includingneutropenia), and development of malignancies, autoimmune manifestations and 
hypersensitivity reactions.
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The total radiation whole body effective dose in this protocol will be less than 25mSv; 
14mSv from HRCT scanning and 11 mSv from [F-18]FDG-PET/CT scans, including 
attenuation correction scans. In largerpatients, a higher injected [F-18]FDG activity may be 
required but the total radiation exposure in these patients will not exceed 30 mSv. 
Thisamount of radiation is considered to be a moderate risk, categoryIII (ICRP62) and is 
balanced against the substantial societal benefit gained from the trial.If patients have a 
historical [F-18]FDG-PET/CT scan that can be used as baseline scan, thenonly the follow up 
scan will be conducted as part of the clinical protocol.
As part of the spirometry assessment at Visits 101 and 107, a single dose of short-acting 
bronchodilators (SABA) salbutamol/albuterol will be administered. For more information 
please refer to product information (SmPC/USPI).
Women of child bearing potential should be informed that taking the study drug 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 subject will not reliably comply, they should not 
be entered in the study.
There may be unknown risks of ACZ885 which may be serious and unforeseen.
3.7.1 
Blood sample volumes
A maximum of 350 mL of blood is planned to be collected over a period of approximately 
38weeks, from each subject as part of the study. Additional samples for monitoring of any 
safety findings would be in addition to this. This is not considered to be a risk for this 
population.
Timings of blood sample collection are outlined in the Assessment Schedule,Section8.2.
A summary blood log is provided in the Site Operations Manual, together with instructions 
for all sample collection, processing, storage and shipment information.
See Section 8.9regarding the potential use of residual samples.
4  
Population
This study will recruit patients with chronic active pulmonary sarcoidosis as defined by 
disease duration ≥1 year with evidence of persistent or progressive parenchymal changes as 
characterized by radiological evidence. A total of approximately 38 patients will be 
randomized to participate in the study. The sample size will be re-estimated at the interim 
analysis and number of randomizedpatients may be increased up to a maximum of 90.
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria.


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Subject selection is to be established by checking through all inclusion/exclusion criteria at 
screening and first baseline prior to the first injection. Safety laboratory evaluations and 
pulmonary function tests taken at first baseline will not be available prior to first injection, 
and screening values should be used for inclusion in the study. A relevant record 
(e.g.,checklist) of the eligibility criteria must be stored with the source documentation at the 
study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
4.1  
Inclusion criteria
Pulmonary sarcoidosis patients eligible for inclusion in this study must fulfill allof the 
following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female subjects ages 18 to 80 years of age (both inclusive)
3. Subjects must weigh at least 50 kg to participate in the study
4. Able to communicate well with the investigator and to understand and comply with the
requirements of the study.
5. Disease duration of ≥1 year
6. Clinically active diseasedemonstrated eitherby a biopsy (any organ) or by
bronchoalveolar lavage(lymphocytosis >15%, CD4
+/CD8
+ratio >3.5,
CD103+CD4+/CD4
+ratio <0.2)(Heron et al 2008). Patientsmust also haveall of the
following criteria:
MMRC dyspnea scale ≥1
Threshold FVC 50 -90% of predicted (Pellegrinoetal2005, Vorselaarsetal2015)
Evidence of parenchymal lung involvement by HRCTat screening or by historical
radiological evidence(e.g. CT, MRIor x-ray)
4.2  
Exclusion criteria
Pulmonary sarcoidosis patients fulfilling any of the following criteria are noteligible for 
inclusion in this study:
1. History of known hypersensitivity to canakinumab
2. Current inhaled use of tobacco products(urine cotinine level >500 nanograms/mL)at
screening
3. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of
enrollment, or until the expected PD effect has returned to baseline, whichever is longer,
or longer if required by local regulations
4. Previous exposure to concomitant treatment according to the following criteria:
a.Prednisone >15 mg/day or changes in prednisone dose in the 8 weeks prior to screening
b.More than one immune-modulator (i.e., methotrexate, azathioprine, leflunomide,
hydroxychloroquine) or changes in their dosing levels within 12 weeks of
randomization. Refer toSection 5.2, 
'Prohibited treatments
' for additional details
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5. Prior treatment with any biologic drug targeting the immune system within 180 days of
randomization or history of any previous use of rituximab
6. Diagnosis of pulmonary hypertension requiring treatment
7. History of bleeding disorder
8. Extra-pulmonary sarcoidosis as primary treatment indication (e.g., involving brain, heart,
eye and renal disease with significant hypercalcemia)
9. Any conditions or significant medical problems which in the opinion of the investigator
immune-compromise the patient and/or places the patient at unacceptable risk for
immunomodulatory therapy, such as:
Absolute neutrophil count (ANC) <LLN (1,500/μl)
Thrombocytopenia CTCAE v4.03 Grade 1: Platelets <LLN (75.0 x 10
9/L)
Any active or recurrent bacterial, fungal (with exception of onychomycosis) or viral
infection
Presence of human immunodeficiency virus (HIV) infection, active hepatitis B or
hepatitis C infectionsbased on screening lab results
Presence of active or latent tuberculosis (TB). If historical Tb result is available, Tb
status needs to be confirmed pre-randomization as determined by screening laboratory
measurements.
Clinical evidence or history of multiple sclerosis or other demyelinating diseases, or
Felty’s syndrome
10.Live vaccinations within 3 months prior to screening
11.Current severe progressive or uncontrolled disease, which in the judgment of the clinical
investigator renders the patient unsuitable for the trial
12.Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor
tolerability or lack of access to veins)
13.Donation or loss of blood (amount depending on age and weight, 10-20% or more of
volume, within 8 weeks prior to first dosing, or longer if required by local regulation
14.History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin), treated or untreated, within the past 5 years, regardless of whether there is
evidence oflocal recurrence or metastases
15.Contraindications to FDG-PET scan investigations, such as severe claustrophobia or
uncontrolled diabetes
16.Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed bya positive hCG
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17.Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using basic methods of contraception during dosing of
investigational drug. Basic contraception methods include:
Total abstinencefrom heterosexual intercourse (when this is in line with the preferred
and usual lifestyle of the subject). Periodic abstinence (e.g.,calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods
of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least 6weeks before taking
investigational drug. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to screening). For female subjects on the
study, the vasectomized male partner should be the sole partner for that subject.
Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal
suppository
Use of oral, injected or implanted hormonal methods of contraception or other forms
of hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception or placement of
an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should be stable on the same pill for a 
minimum of 3 months before taking study drug
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g.,age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.
18.History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such
abuse as indicated by the laboratory assays
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.


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5  
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the following restrictions:
5.1  
Contraception requirements
Please refer to exclusion criteria (Section 4.2) for details of contraception requirements for the 
study.
5.2  
Prohibited treatment
Use of the treatments displayed in the table below are NOT allowed during the screening 
period or after the start of study treatment due the concern for increased potential 
immunosuppressant-related conditions. These are prohibitedfor the duration of the study until 
30 days after the last study visit.
Table 5-1  
Prohibited treatment
Medication
Action to be taken
Biologic drugs targeting the systemic immune system (e.g., 
TNF-α blockers, anakinra, rituximab, abatacept, tocilizumab)
Discontinue study drug
Live vaccines (within 90 days of study drug dosing) 
Discontinue study treatment; if live vaccines 
are given after screening but prior to study drug 
administration, the subject may be enrolled 
after 90 days have passed since vaccine 
administration if the subject continues to meet 
eligibility criteria upon re-screening
Systemic immune suppressive drugs, except for the following: 
prednisone ≤15 mg/d and/or no more than one of the following 
cytotoxic drugs: methotrexate, azathioprine, leflunomide or 
hydroxychloroquine, provided dosing of these listed 
medications has remained unchanged ina 12week period prior 
to randomization and remains unchanged throughout study 
period
Any acute dosing of immune suppressive drugs 
may require discontinuation of study treatment 
and participation and will have to beevaluated 
with Sponsor on a case-by case basis
5.3  
Dietary restrictions and smoking
There are no specific dietary restrictions except for those required when preparing for PET 
scanning. Subjects are not allowed to participate in the trial if they smoke.
5.4  
Other restrictions
On study days when spirometry will be performed, patients should refrain from the following:
Using of bronchodilators for at least 6 hours for short-acting β-2 agonist and at least 48
hours for long-acting β-2 agonist prior to spirometry testing
Drinking alcohol for 4 hours prior to spirometry testing
Participating in strenuous activity for 30 min prior to spirometry testing
Wearing clothes that substantially restrict full chest and abdominal expansion
Eating a large meal within 2 hours of testing


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On study days when [F-18]FDG-PET/CT scan is performed, patients should:
Refrain from alcohol consumption and vigorous sports activities 24 hours prior to the
measurement
Be well-hydrated and fasted 4 hours prior to administration of radiotracer
Have a blood glucose level below 11 mmol/L (200 mg/dL)
6  
Treatment
6.1  
Study treatment
Details on the storage and management of study medication, randomization and instructions 
for prescribing and taking study treatment are outlined in Section 3 of the Site Operations 
Manual.
6.1.1 
Investigational treatment and control drugs
The investigational drug, ACZ885 (canakinumab) 150 mg/ 1mL and matching placebo liquid 
in vials will be prepared by Novartis and supplied to the Investigator as blinded subject packs.
6.1.2 
Additional study treatment
[F-18]fluorodeoxyglucose ([F-18]FDG) PET tracerwill be produced under GMP.
[F-18]FDG PET has approved New Drug Application in the US and marketing authorities
in the EU for certain indications. [F-18]FDG will be sourced locally.
Salbutamol/Albuterol will be used during the spirometry testing and will be sourced
locally.
6.2  
Treatment arms
Subjects will be assigned to one of the following two treatment arms in a ratio of 1:1. 
Studytreatments are defined as:
Doses of 300 mg ACZ885 s.c. every four weeks
Doses of placebo to match the 300 mg ACZ885 s.c. every four weeks
6.3  
Treatment assignment and randomization
All eligible subjects will be randomized via Interactive Response Technology (IRT) to one of 
the treatment arms. The investigator or his/her delegate will contact the IRT after confirming 
that the subject fulfills all the inclusion/exclusion criteria. Subjects will undergo stratification 
based on baseline [F-18] FDG-PET/CT results. The IRT will assign a randomization number 
to the subject, which will be used to link the subject to a treatment arm and will specify a 
unique medication number for the first package of investigational treatment to be dispensed to 
the subject. The randomization number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
Asubject randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of treatment arms to randomization numbers.Once a 


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patient is deemed eligible for enrollment into the study and ready for dosing, the next lowest 
available randomization number will be assigned. These randomization numbers are linked to 
the different treatment arms, which in turn are linked to medication numbers. A separate 
medication list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of medication 
numbers to packs containing the investigational drug.
6.4  
Treatment blinding
This is a subject-and investigator-blindedstudy; subjects, investigator staff, and persons 
performing the assessments will remain blind to the identity of study treatments according to 
the specifications provided in Table 6-1.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, taste and odor.
Randomization data are kept strictly confidential, and are accessible only to authorized 
personnel, until unblinding of the trial as described in the blinding table (Table 6-1). 
Theclinical team may communicate unblinded interim analysisresults (e.g., information 
needed for planning/modifying another study) to relevant Novartis teams for information, 
consulting and/or decision purposes. 
No further dissemination of interim results should occur, in particular not with individuals 
involvedin treating the study's subjects or assessing clinical data (e.g.,ECGs, images, 
symptoms) obtained in the study.
Unblinding will occur in the case of patient emergencies (see Section 6.7), at the time of 
interim analysis and at the conclusion of the study.
Site staff
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (seeSection 6.7).
Sponsor staff
The following unblinded sponsor roles are required for this study:
Unblinded sample analyst(s) (PK/PD/IG)
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-1. For example, unblinded summaries and 
unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g.,biomarker 
expert) are allowed to access treatment assignment information for the purpose of conducting 
interim analyses.


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Table 6-1  
Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim 
Analysis & 
dose escalation
Subjects/Patients
B
B
UI
B
Site staff
B
B
UI
B
Unblinded site staff (see text for 
details) 
NA
NA
NA
NA
Drug Supply and Randomization 
Office
UI
UI
UI
UI
Unblinded sponsor staff (see text 
for details)
UI
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
UI
Independent committees used for 
assessing interim results
NA
NA
NA
NA
All other sponsor staff not 
identified above
B
B
UI
UI
B Remains blinded
NA Not applicable
UI Allowed to be unblinded on individual patient level
6.5  
Treating the subject
ACZ885 will be administered to the subject via the following route of administration (s.c.
injection)at the investigational site. See the Site Operations Manual for further details.
Sponsor qualified medical personnel will be readily available to advise on trial-related 
medical questions or problems.
6.6  
Permitted dose adjustments and interruptions of study treatment
Scheduled dosing of study drug may be delayed by up to 5 days if subjects present with 
conditions that require withholding of study drug, e.g., evidence for active infection 
(treatedor untreated) or acute abdominal pain. Outside of this 5-day window, the dose will be 
considered missed. These changes must be recorded on the Dosage Administration Record 
CRF. The 5-day window for those subjects requiring study drug to be withheld until 
resolution isin addition to the defined +/-5 day visit window, therefore subjects can be no 
more than 10 days outside of the scheduled visit. Subjects must maintain at least 21 days 
between visits.
Subjects who are unable to generate the requisite number of reproducible spirometry 
maneuvers at baseline will be allowed an additional 5 days beyond the 40-day screening 
period, if necessary, for repeat spirometry prior to dosing. All other baseline measures should 
be repeated at the same visit asthe first dose administration.
Subjects are able to miss no more than one dose administration. All missed dose 
administrations must be discussed with the Sponsor to determine if the subject should be 
discontinued from further study treatment.


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6.7  
Emergency breaking of assigned treatment code
Emergency treatment code breaks must only be undertaken when it is required to in order to 
treat the subject safely. Most often, study treatment discontinuation and knowledgeof the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. 
When the investigator contacts the system to break a treatment code for a subject, he/she must 
provide the requested subject identifying information and confirm the necessity to break the 
treatment code for the subject. The investigator will then receive details of the investigational 
drug treatment for the specified subject anda fax or email confirming this information. 
Thesystem will automatically inform the study monitor for the site and the study team that 
the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT in case of emergency. The investigator will need to provide:
protocol number
study drug name (if available)
subject number
The investigator must provide oral and written information to inform the subject how to 
contact his/herbackup in cases of emergency when he/she is unavailable to ensure that un-
blinding can be performed at any timeand instructions for contacting the local Novartis CPO 
(or any entity to which it has delegated responsibility for emergency code breaks) to the 
subject in case an emergency treatment code break is required at a time when the investigator 
and backup are unavailable.
6.8  
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with ACZ885, as detailed in Section 8.7.
6.9  
Recommended treatment of adverse events
There is no treatment that can reverse the activity of ACZ885. Given that ACZ885 is an IgG1 
isotype monoclonal antibody, plasmapheresis may be of value in removing ACZ885 from the 
body. Potential adverse events should therefore be treated symptomatically at the discretion of 
the Investigator. Medication used to treat AEs must be recorded on the concomitant 
medications/significant non-drug therapies eCRF.
6.10 
Rescue medication
In the context of this study, rescue medications are defined as those medications used acutely 
to directly manage medical signs or symptoms related to the subject’s underlying sarcoidosis. 
Addition or alteration of immunosuppressant or corticosteroid therapy for or by a patient 
during the study are not allowed and may require his or her termination from study 
participation. If a patient is withdrawn from the study, the Week 32 EOS visit should be 
completed.


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Non-sarcoidosis flares (bronchitis)
Patients with sarcoidosis may experience episodes of bronchitis that do not indicate worsening 
of their disease. Production of yellow-green sputum is a characteristic of bronchitis. 
Treatment details are at the discretion of the investigating physician. First line treatment is 
typically with antibiotics. Unresponsive patients may require the addition of a short course of 
corticosteroids. This may result in the patient being withdrawn from the trial (SeeTable 5-1) 
in which case the Week 32 EOS visit should be completed.
Acute pulmonary exacerbations of sarcoidosis (APES)
APES are defined as acute worsening of pulmonary signs and symptoms in patients with 
known sarcoidosis not explained by another cause, combined with a decline in spirometry 
(≥10% decrease from previous baseline FVC and/or FEV1, present for at least one month 
(Panselinas and Judson 2012). Patients’ signs and symptoms ofAPES typically respond 
tocorticosteroids. This may result in the patient being withdrawn from the trial 
(SeeTable5-1) in which case the Week 32 EOS visit should be completed.
Use of rescue medication must be recorded on the concomitant medications/significant 
nondrug therapies CRF.
6.11 
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
Common potential concomitant medications in this study population are anticipated to include 
topical corticosteroids or systemic corticosteroids at ≤15 mg/d prednisone or equivalent, 
and/or up to one of the following systemic immune-modulating drugs: methotrexate, 
azathioprine, leflunomide or hydroxychloroquine.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study must 
be recorded on the concomitant medications/significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.


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7  
Study completion and discontinuation
7.1  
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. Study completion is defined as when the last 
subject completes their EOS visit, and any repeat assessments associated with this visit have 
been documented and followed-up appropriately by the Investigator, or in the event of an 
early study termination decision, the date of that decision.
A follow-up visit or phone call for SAEs must be performed 30 days following early 
discontinuation, or 8 weeks after last injection of study drug, whichever is later.  Thephone 
call for SAEsis kept as source documentation. All SAEs reported during this time period 
must be reported as described inSection9.2and the Site Operations Manual. Documentation 
of attempts to contact the subject should be recorded in the source documentation.
7.2  
Discontinuation of study treatment
Individual subject withdrawal
Subjects may voluntarily discontinue from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.
Any patient who discontinues the study early will complete the Week 32 EOS visit. Forthose 
patients discontinuing after Week 12, the volumetric and HRCT exam should also be included 
as assessed on a case-by-case basis by the Sponsor.
If a subject discontinuation occurs for any reason, the Investigator must make every effort to 
determine the primary reason for a subject’s discontinuation from the studyand record this 
information on the CRF.
The investigator should discontinue study treatment for a given subject or discontinue the 
subject from study if, on balance, he/she believes that continuation would be detrimental to 
the subject’s well-being.
If a liver or renal event occurs, follow guidelines outlined in Appendix1and Appendix2
regarding discontinuation of study treatment.
Study treatment must be permanently discontinued under the following circumstances:
Subject withdraws consent
Pregnancy
Severe allergic reaction or anaphylaxis following administration of the study drug
Non-compliance as defined by missing more than one dose administration
Emergence of the following adverse events:
Serious infections combined with neutropenia CTCAE v4.03 grades ≥1 (ANC<1.5x
109/L)
Confirmed diagnosis of latent or active TB
Onset of any malignancy


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Any of the following laboratory abnormalitiesconfirmed to be sustained by repeat
assessment within7 days after initial lab assessment:
Neutropenia CTCAE v4.03 grades ≥2
Thrombocytopenia CTCAE v4.03 grade 4
Use of prohibited treatment as per Table5-1.
Any other protocol deviation that results in a significant risk to the patient’s safety
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently 
for any reason.
Subjects who discontinue study treatment should NOT automatically be considered 
withdrawn from the study. See Section 8for the required assessments of these subjects after 
discontinuation of study treatment.
7.3  
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore anddoes not want any further visits or assessments anddoes not want any further 
study-related contact anddoes not allow analysis of already obtained biologic material.
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the subject 
are not allowed unless safety findings require communicating or follow-up.
7.4  
Lost to follow-up
For 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 subject, e.g., dates of telephone calls, registered 
letters, etc. A subject should not be considered lost to follow-up until his/her scheduled end of 
study visit would have occurred.
7.5  
Study Stopping rules
All subjects will undergo regular monitoring at scheduled visits for safety and tolerability, 
including adverse events, throughout the duration of the study. If significant risk to the study 
subjects is identified, the study may be put on hold or terminated based on a full safety review.
The study will be stopped if any of the following criteria are met, and no further dosing 
pending a full safety review:
An overt change in the rate of incidence of expected drug-related serious adverse events
such as infections, opportunistic infections, hypersensitivity, white blood cell (WBC) or
platelet count decreases as compared to the rates described in the current version of the IB.


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New unexpected serious adverse events considered related to canakinumab in more than
3individuals on active therapy.
7.6  
Early study termination by the sponsor
The investigator must contact the IRT to register the subject’s discontinuation from the study 
and/or investigational treatment. The study can be terminated by Novartis at any time for 
medical or ethical reasons, and/or in accordance with the respective contractual terms. 
Shouldthis be necessary, the subject should be seen as soon as possible and treated as a 
prematurely withdrawn subject as described in Section 7. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the subject’s interests. The investigator will be responsible for informing 
institutional review boards (IRBs) and/or ethic committees (ECs) of the early termination of 
the trial.




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1Visit structure given for internal programming purpose only
2A window of ±5 days is allowed for the treatment visits, but the interval between 2 doses must be at least 21 days
3All patients who discontinue early must complete the EOS Visit. For those discontinuing after week 12, the volumetric and HRCT exam shouldalso be included as 
assessed on a case-by-case basis by the Sponsor
4Limited to females of childbearing age. Serum testing is done at screening and urine test is done predose at Day 1 and at theEOS
5If the dipstick result is positive for protein, nitrite, leukocytes and/or blood, the sample should be sent for microscopic analysis of WBC, red blood cell count (RBC) and 
casts
6Vital signs taken after resting in a sitting position for at least 3 minutes
7For subjects at baseline who are unable to generate reproducible spirometry maneuvers, an additional 5 days beyond the 40 day screening window will be allowed for 
the subjects to return for repeat spirometry.
8Oxygen saturation %, pulse rate, and Borg Questionnaire score will be recorded before the test.Oxygen saturation %, pulse rate, Borg Questionnaire score, and 
distance walked will be recorded at the end of the test. 6MWT should occur after ECGs have been completed. Pulse rate should be taken after sitting for at least 3 
minutes. 
9The screening HRCT should be completed as the last assessment for eligibility criteria. If patients have evidence ofparenchymal involvement of disease from historical
radiological evidence (e.g. CT, MRI or x-ray), then baseline HRCT can be performed at same time as the [F-18]FDG-PET/CT. At each timepoint, two scans will be 
collected: 1 HRCT scan and 1 lower dose volumetric CT scan. 
10The [F-18]FDG-PET/CT requires a blood glucose level below 11 mmol/L. The measurement is performed by finger prick at site the same day [F-18]FDG-PET/CT is 
performed
11For baseline, [F-18]FDG-PET/CT results obtained within 8 weeks of randomization will be accepted. The [F-18]FDG-PET/CT at baseline should always be conducted 
after all other assessments are done and patient found eligible unless a previous result was usedor sponsor agreementwas obtained. It should not be done post-
randomization. 
12All assessments for a given visit should be completed before study drug is administered
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8.2  
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. If the subject is capable 
of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document.
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 documentedin the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
8.3  
Subject screening
In general, it is permissible to re-screen a subject; however, each case must be discussed and 
agreed with the Sponsor’s medical lead on a case-by-case basis.
Patient re-screening will be allowed in the study in the event of a delay in treatment, e.g., in 
the event of a washout period of more than 28 days. However, the screening HRCT cannot be 
repeated and re-screening may not occur if planned dosing will not take place within 8weeks 
of these screening imaging assessments.
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8.4  
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data to be collected on all subjects include: 
date of birth, age, sex, race, predominant ethnicity.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses,and not symptoms,will be recorded.
The following should be recorded on the respective CRF page:
Relevant medical history/current medical conditions
Prior and current medications / significant non-drug therapies
Response to treatment withprevious drug therapies (e.g., corticosteroids, methotrexate,
azathioprine, TNF-α blockers)
8.4.1 
Hepatitis screen, HIV screen, tuberculosis screen
All subjects will be screened for HIV, hepatitis B and C, and tuberculosis. See the Site
Operations Manual for details.
8.4.2 
Alcohol test, drug screen, urine cotinine
All subjects will be screened for substances of abuse and cotinine. See the SiteOperations 
Manual for details.
8.5  
Efficacy/Pharmacodynamics
Pharmacodynamic assessments are specified below, with the methods for assessment and 
recording specified in the Study Operations Manual. Assessments will be performed/samples 
collected at the timepointsdefined in the Assessment Schedule.
In order to better define the PD profile, the timing of the sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol.
8.5.1 
Clinical Outcome Assessments (COAs)
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8.5.2 
Imaging 
Details for HRCT and [F-18]FDG-PET/CT imaging are described in the Parexel Imaging 
Investigator SOM.
To avoid unnecessary radiation,all screening activities except imaging needs to be completed 
prior to HRCT scan for eligibility. Evaluation by HRCT for eligibility must be completed 
prior to the patient undergoing baseline [F-18]FDG-PET/CT. Patients with historical 
radiologic evidence of parenchymal disease involvement (either HRCT or historical chest x-
ray) can be used for eligibility, allowing the HRCT baseline assessment to be performed along 
with [F-18]FDG-PET/CTon same visit day without waiting for HRCT screening result.
8.5.2.1 [F-18] FDG-PET/CT
In this study, [F-18]FDG-PET/CT imaging will provide early evidence for anti-inflammatory 
effects of IL-1β blockade by ACZ885on the sarcoidosis process. [F-18]FDG-PET/CT has 
been shown to detect lung parenchymal involvement at any chest x-ray (CXR) stage, 
including therapy-resistant disease, and can also provide information on extra-pulmonary 
disease. Lung fluorodeoxyglucose (FDG)uptake in sarcoidosis has been shown by PET 
imaging to correlate with important sarcoidosis BAL biomarkers, including percentage 
neutrophils and CD4:CD8 ratio. In two previous sarcoidosis trials, the [F18]FDG-PET/CT 
endpoint was shown to be decreased by 53-55% on treatment (Keijsersetal2008; 
Milmanetal2012). Improvements in FVC over a 24 week period have been correlated with 
decreases in [F-18]FDG-PET/CT compared to baseline, with evidence of improvement by 
serial [F-18]FDG-PET/CT detected in sarcoid patients reported as early as 1-2 months 
(Brudinetal1994; Braunetal2008; Imperialeetal2013). Furthermore, [F-18]FDG-PET/CT 
imaging was able to predict subsequent decreases in FVC and DLco 
(Sobic-Saranovicetal2013;Vorselaarsetal2015).
Inthis study, all patients will undergo whole-body head to mid-thigh [F-18]FDG-PET/CT 
imaging on a state-of-the-art, 3D PET/CT scanner with a reconstructed resolution of ≤5mm. 
Subjects with glucose levels above 11 mmol/L (200 mg/dL) should have their scan delayed or 
be rescheduled as appropriate. The blood glucose level measured prior to the radiotracer 
administration should be recorded in the image transmittal form (ITF). Subjects will have the 
radiotracer administered through an i.v. line, whereafter theywill be positioned comfortably 
in a supine position to rest for 60 min, while the radiotracer distributes through the body. 
Nearthe end of this 60 min rest, subjects will be asked to void their bladder prior to the 
scanning procedure.A whole body low-dose attenuation CT will be acquired with a whole 
body effective dose of 1.5 mSv. Maximum injected radioactivity dose 200 MBq will result in 
a whole body effective dose of 4 mSv (ICRP2008). Higher[F-18]FDG activities may be 
required in large or obese patients to ensure sufficient imaging quality,but it will not exceed 
350 MBq. One further imaging scan will be performed at week 12 according to the schedule 
on enrolled patients with results quantitatively compared to baseline findings using 
centralizedquantitative reading. Detailedinformation will be provided in the Parexel Imaging 
Investigator SOM. Totalinjected activity and body weight will be recorded and used to 
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compute standardized uptake values. The total dose for all PET/CT scanning (excluding 
HRCT) in this protocol will be maximally 11mSv,or 16mSv in larger or obese patients 
requiring a higher[F-18]FDG injected dose.
8.5.2.2 Volumetric CT and HRCT
HRCT will be utilized in this study for assessing therapeutic response at Week 24.
At the time points specified in the schedule, an HRCT scan of the lung without contrast agent 
will be acquired at full inspiration according to parameters as listed in a separate imaging 
acquisition manual. In addition to the lung assessment by HRCT,
andrequire an additional,full 
expiratory low-dose CT. Thus, subjects will undergo a total of 2HRCT scans and two lower 
dose volumetric CT scans.
With 4 CT scans planned for subjects during this study, the total whole body effective dose 
per subject from the CT scanning (excluding [F 18]FDG-PET/CT) will be maximally 14mSv. 
In all subjects, the baseline and follow-up HRCT scan should be performed where possible on 
the same scanner, although scans on the PET/CT scanner may be used if they are determined 
to be comparable with follow-up scans on a different scanner.
8.5.3 
Six-minute walk test (6MWT)
The 6-minute walk test (6MWT) is a simple, economical and reproducible test that measures 
how many meters a person can walk in 6 minutes. Repeated measurement of the 6MWT over 
time has been used in studying numerous musculoskeletal, pulmonary, and cardiovascular 
conditions and is a validated outcome in investigational drug trials.
Patients will be instructed by the test administrator using a script and established testing 
protocol. The testing should be conducted on an individual basis (patient and testers) with no 
additional audience or support other than that of the trained personnel conducting the test. If a 
walking aid is required at baseline, patients will be asked to use the least assistive walking aid 
that in their opinion will enable them to complete the 6MWT safely. Patients should be 
encouraged to usethe same walking aid when performing all tests throughout the study.
A change in walking aid to perform the test is permitted if required for safety reasons 
(e.g.,deterioration of balance). The testing should occur at approximately the same time of the 
day as the baseline assessment to prevent any possible diurnal variations. The same test 
administrator should perform all repeat tests on a patient whenever possible to reduce 
technician-related differences in test performance.
In circumstances where the test is interrupted for reasons other than patient fatigue the test 
may be repeated once, preferably on the same day (with a minimum 60 minute rest period). 
Ifre-testing on the same day is not possible, the test may be repeated as soon as possible, but 
within 2-3 days of the original attempt.
Patients resting values of oxygen saturation (%), heart rate (bpm), and Borg Questionnaire 
score will be recorded before the test. Oxygen saturation (%), heart rate (bpm),distance 
walked (meters), and Borg Questionnaire scorewill be recorded at the end of the 6MWT. 
Requirement of rescue medications, including supplemental oxygen therapy, and any adverse 
events occurring during the 6MWT will be recorded. If a patient is on chronic oxygen therapy, 
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supplemental oxygen will be allowed during the 6MWT; however, the same level/rate of 
supplemental oxygen should be maintained through the initial 6MWT and all subsequent trials. 
Complete details of course set-up, test administration, equipment and recording into the eCRF 
are described in the Site OperationsManual.
8.5.4 
Serum IL-1β
8.5.5 
Pulmonary function testing
For details on pulmonary function testing please refer to below sections and the Biomedical 
Systems Centralized Spirometry, DLco and Lung Volumes Procedure Manual.
8.5.5.1 Diffusing Capacity (DL
CO)
Diffusion capacity for carbon monoxide (DL
CO) will be determined according to ATS 
guidelines (MacIntyreetal2005). Measurements will include DL
COand alveolar volume (V
A). 
DLCO is determined by measuring the uptake of carbon monoxide from the lung over a 
breath-holding period. VA represents an estimate of lung gas volume into which CO is 
distributed and then transferred across the alveolar capillary membrane making it critical in 
the measurement of DLCO. VA is typically measured simultaneously with CO uptake by 
calculating the dilution of an inert tracer gas (e.g.,argon, methane, or helium). In normal 
subjects, the sum of VAand VD(dead space volume)closely matches the total lung capacity 
(TLC) determinedby plethysmography. However, in cases of poor gas mixing in patients with 
obstructed airways, tracer gas dilution is markedly reduced leading to VA values that are 
significantly less than those expected based on actual total thoracic gas volumes. Additional 
information for obtaining DL
COis provided in the Pulmonary Function Tests Manual.
8.5.5.2 Lung Volumes
A body plethysmograph will be used to measure Functional Residual Capacity (FRC), 
Inspiratory Capacity (IC), Total Lung Capacity (TLC), and Residual Volume (RV). 
Allplethysmography evaluations should follow the recommendations of the ATS/ERS Task 
force: Standardization of the measurement of lung volumes (Wanger etal2005). Additional 
information for conduct of plethysmography will be provided in the Biomedical Systems 
Centralized Spirometry, DLco and Lung Volumes Procedure Manual.
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8.5.5.3 Spirometry
Spirometry testing will be performed according to the American Thoracic Society guidelines 
(Milleretal2005a; Milleretal2005b) at screening to assess patients’ eligibility for the study 
and as detailed in the assessment schedule. Eligibility criteria are based on FVC in percent of 
predicted, stratified by gender, age, height, and race (Pellegrinoetal2005).
The spirometry equipment used during the trial must meet or exceed the minimal ATS/ERS 
recommendations for diagnostic spirometry equipment as defined in the guidelines
(Milleretal2005b).
The same spirometry equipment should be used for all assessments performed by a subject. 
Alimited number of staff, as designated by the investigator, will evaluate all patients at all 
visits throughout the entire trial. Where possible the same technician should perform all 
maneuvers for an individual subject. All staff conducting the spirometry tests must have 
received appropriate training, which must be documented.
Results from FVC, FEV1,FEV3and FEV6tests are highly dependent on effort and 
cooperation from the subject. Thus, throughout the maneuver, enthusiastic coaching of the 
subject is required.
All clinic visits will start in the morning. The following spirometry measurements will be 
taken: forced vital capacity (FVC); absolute and FVC% (forced vital capacity, expressed as a 
percentage of the normal expected value) and forced expiratory volume in one second (FEV1). 
Additional spirometry data to be captured include FEF25-75, FEV1/FVC, FEV3/FVCand 
FEV6.
For all clinic spirometry assessments, three acceptable maneuvers should be performed for 
each time-point. All spirometry maneuvers should be performed in sitting position whilst 
wearing nose clips. The FEV1and FVC values recorded in the CRF must be the highest 
values measured irrespective of whether or not they occur on the same curve. Alldisplaceable 
volumes will be reported in liters (L) at the following conditions: normal body temperature 
(37° C), ambient pressure, saturated with water vapor (BTPS).
Additional information for conduct of spirometry evaluations is provided in the Biomedical 
Systems Centralized Spirometry, DLco and Lung Volumes Procedure Manual.
8.5.5.4 Spirometry Reversibility Test
Two spirometry evaluations will be performed at Visit 101 and Visit 107, the first prior to use 
of salbutamol/albuterol, the second performed after intake of salbutamol/albuterol. Theinitial 
spirometry assessment will be performed after a wash-out period of at least 6hours fora 
short-acting β-2 agonist and at least 48 hours for a long acting β-2 agonist. After the initial 
spirometry assessment salbutamol/albuterol is administered, and the second spirometry 
assessment is performed within 30 min of administration. Investigators should follow the
reversibility procedures citedin the ATS/ERS guidelines above with regard to bronchodilator 
use. The primary spirometry readout will be the post-bronchodilator FVC.
Reversibility (%) will be calculated as follows:
(FEV1 (post bronchodilator) –FEV1 (pre-bronchodilator) x 100)/FEV1 (pre-bronchodilator)


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8.6  
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Scheduledetailing when each assessment is 
to be performed.
8.6.1 
Physical examination
See the Site Operations Manual for details.
8.6.2 
Vital signs
Blood pressure (BP)
Pulse
Body temperature(same method of measurement should be used throughout study)
8.6.3 
Height and weight
Height
Body weight
8.6.4 
Laboratory evaluations
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening and/or at the initial baseline, the assessment 
may be repeated once prior to randomization. If the repeat value remains outside of 
protocol-specified ranges, the subject is excluded from the study.
In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range for the laboratory at screening and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the investigator and shall 
be based, in part, upon the nature and degree of the observed abnormality. Theassessment 
may be repeated once prior to randomization.
In all cases, the investigator must document in the source documents the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the subject to continue in the study.
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differentials 
(e.g.,neutrophils, basophils, eosinophils, monocytes, lymphocytes) and platelet count will be 
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Clinical chemistry
Albumin, alkaline phosphatase (ALP), total bilirubin, bicarbonate/CO2, calcium, cholesterol, 
chloride, creatinine, CK, γ-GT, glucose, LDH, inorganic phosphorus, lipase, amylase, 
magnesium, potassium, total protein, AST, ALT, sodium, triglycerides, urea/BUN and uric 
acid.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.
Urinalysis
A semi-quantitative "dipstick" evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes and blood.
Microscopy, WBC, RBC and casts will also be assessed in case of an abnormal dipstick test.
8.6.5 
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
Site Operations Manual.
PR interval, QRS duration, heart rate, RR, QT, QTc
The Fridericia QT correction formula (QTcF) calculated with the RR interval expressed in 
seconds should be used for clinical decisions.
Clinically significant abnormalities should be recorded on the relevant medical history/current 
medical conditions CRF page prior to informed consent signature and on the Adverse Events 
page thereafter. Clinically significant findings must be discussed with the Sponsor.
8.6.6 
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. Seethe 
Assessment Schedulefor timing of the protocol required pregnancy testing; additional 
pregnancy testing may be performed to meet local requirements. A positive urine pregnancy 
test requires immediate interruption of study treatment until serum β-hCG is performed and 
found to be negative.
If additional pregnancy testing is needed per local requirements, those additional results will 
be kept as source documentation only.
8.6.7 
Immunogenicity (Anti-ACZ885 Antibodies)
To assess potential immunogenicity, serum samples for determination of anti-ACZ885 
antibodies (ADA) will be collected during the study (see Assessment Schedule).
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing, and shipment.
In the case of an anaphylactic reaction occurring after injection, a sample will be taken at the 
time of the event and 8 weeks later. An immunogenicity positive subject at the end of the 
study will be followed up for three months.


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Immunogenicity analytical method
An ELISA based method will be used forthe detection of potential ADA formation.
Thedetailed method description to assess immunogenicity will be described in the 
bioanalytical raw data of the study and in the respective Bioanalytical Data Report (BDR).
8.6.8 
Local tolerability (subcutaneous injections)
Local tolerability at the sites of s.c. injections will be evaluated by the investigator. Anylocal 
reactions should be observed until they have disappeared. An assessment of severity (i.e., 
none, mild, moderate, severe) of the following signs and symptoms: pain, redness, swelling, 
induration, hemorrhage and itch, and the exact location of any local reaction will be recorded 
in the eCRF.
8.7  
Pharmacokinetics
PK samples will be collected at the timepoints defined in the Assessment Scheduleaccording 
to the instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing and shipment. See Section 8.9regarding the potential use of residual 
samples.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol.
Pharmacokinetic parameters
Concentrations will be expressed in mass per volume units. Missing values or those below the 
limit of quantification will be indicated in the data listings and treated as zero in data 
presentations and calculations.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
A previously utilized and validated mixed effects modeling approach may be used to 
characterize the exposure-related PK parameters (i.e., AUC and CL) of canakinumab. 
Theseresults may be reported in a separate report from the final CACZ885X2205 clinical 
study report.
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8.8  
Other assessments
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8.9  
Use of residual biological samples
Residual blood and lesional biopsy samples may be used for another protocol-specified 
endpoint.
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9  
Safety monitoring
9.1  
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign including abnormal laboratory findings, symptom ordisease) in a subject or 
clinical investigation subject after providing written informed consentfor participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section9.5for 
an overview of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
they induce clinical signs or symptoms,
they are considered clinically significant,
they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverseevents. Alert ranges for liver-and kidney-related events are 
included in Appendix 1and Appendix 2, respectively.
Pre-existing medical conditions/diseases (i.e., Medical History(ies)) are considered AEs if 
they worsen after providing written informed consent.
Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1.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
2.Its relationship to study treatment
3.Its duration (start and end dates) or if the event is ongoing an outcome of not recovered/not
resolved must be reported.
4.Whether it constitutes a SAE (see Section 9.2for definition of SAE) and which seriousness
criteria have been met
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All adverse events must be treated appropriately. Treatment may include one or more of the 
following:
no action taken (e.g.,further observation only)
investigational treatment dosage increased/reduced
investigational treatment interrupted/withdrawn
concomitant medication or non-drug therapy given
hospitalization/prolonged hospitalization (see Section 9.2for definition of SAE)
6.Its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the IB.  Once an adverse event is detected, it must be followed until its resolution or 
until it is judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
9.2  
Seriousadverse event reporting
9.2.1 
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:
is fatal or life-threatening
results in persistent or significant disability/incapacity
constitutes a congenital anomaly/birth defect
requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:
routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition, includingplanned imaging procedures.
elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent form
treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of an SAE given above and not resulting in hospital admission
social reasons and respite care in the absence of any deterioration in the subject’s
general condition
is medically significant, e.g., defined as an event that jeopardizes the patient or may
require medical or surgical intervention to prevent one of the outcomes listed above.


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All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life-threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology (DS&E) as per Section 9.2.2.
9.2.2 
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment.
Note: SAEs reported by subjects deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the Site 
Operations Manual.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previouslyreported 
one must be reported separately as a new event.
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
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If the SAE is not previously documented in the IBor package insert (new occurrence) and is 
thought to be related to the study treatment,a Drug Safety and Epidemiology Department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an IN to inform all investigators involved in any study 
with the same study treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committeesin accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis. Note: SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information.
9.3  
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Appendix 1for complete definitions of liver events.
Follow-upof liver events
Every liver event defined in Appendix 1should be followed up by the investigator or 
designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Appendix 1.
Repeating liver chemistry tests (ALT, AST, TBL, ALP and γGT) to confirm elevation
within 48-72 hours
These liver chemistry repeats should always be performed using the central laboratory, with 
the results provided via the standard electronic transfer.  If results will not be available from 
the central laboratory within 24 hours, then the repeats can also be performed at a local 
laboratory to monitor the safety of the subject. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should 
have results reported in the CRF.
If the initial elevation is confirmed, close observation of the subject will be initiated,
including consideration of treatment interruption if deemed appropriate.
Discontinuation of the investigational drug refer to Section 7.2(Discontinuation of study
treatment), if appropriate
Hospitalization of the subject if appropriate
Causality assessment of the liver event
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Repeating liver chemistry tests two or three times weekly. Testing should include ALT,
AST, ALP, PT/INR, and γGT. If total bilirubin is elevated > 2 x ULN, fractionation into
direct and indirect bilirubin is required. To rule out muscular origin of transaminase
elevations, CPK should be measured along with liver chemistry tests. Frequency of
re-testing can decrease to once a week or less if abnormalities stabilize or the study drug
has been discontinued and the subject is asymptomatic. Re-testing should be continued up
to resolution.
Obtaining a more detailed history of symptoms and prior or concurrent diseases.
Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and
special diets.
Exclusion of underlying liver disease, as specified in Table 15-3.
Imaging such as abdominal US, CT or MRI, as appropriate
Obtaining a history of exposure to environmental chemical agents.
Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
9.4  
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix2.
9.5  
Reporting Medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF.  Study treatment errors are only to be 
reported to Novartis Drug Safety and Epidemiology department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the AE CRF irrespective of the 
misuse/abuse being associated with an AE/SAE. In addition, all instances of misuse or abuse 
must be reported to Novartis Drug Safety and Epidemiology. As such, instances of misuse or 
abuse are alsoto be reported using the SAE form/CRF. Table 9-1summarizes the reporting 
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Table 9-1  
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose
Administration (DAR) CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse  
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1andSection 9.2, respectively.
9.6  
Pregnancy reporting
To ensure patient safety, each pregnancy in a subject on study drug 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. The study drug must be discontinued, though the subject may stay in 
the study, if she wishes to do so. All assessments that are considered as a risk during 
pregnancy must not be performed. The subject may continue all other protocol assessments.
Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatments.
Any SAE experienced during pregnancy and unrelated to the pregnancy must be reported on 
an SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
9.7  
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. 
Suchevaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.


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10  
Data review and database management
10.1 
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
Duringthe study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject 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 study 
drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospitalor clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject
's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
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 eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed.
10.2 
Data collection
Designated investigator staff willenter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21CFRPart11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. 
Afterdatabase lock, the Investigator will receive copies of the subject data for archiving at the 
investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment scheduleand can be recorded directly on the CRFs. All other data captured for 
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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10.3 
Database management and quality control
The CRO,working on behalf of Novartis,reviewsthe data entered into the eCRFs by 
investigational staff for completeness and accuracy and instructsthe site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to the CRO working on behalf of Novartis who will make the correction to 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. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Imaging-related data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data in reference to dispensing of study drug(s) to the subject and 
all IRT recorded dosage changes will be tracked using Interactive Response Technology 
(IRT). The system will be supplied by a vendor, who will also manage the database. 
Thedatabase will be sent electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
COAR Analytics NIBR Franchise Head and the relevant NIBR TA Head.
DNA samples (optional):
To maximize confidentiality, all samples and the information associated with these samples 
will be double-coded to preventthe exposure of the subject’s identity. This double-coding 
process allows Novartis to go back and destroy the sample at the subject’s request.  
Inaddition, sample information is stored in one secured database while genetic data is stored 
in an independent, secured database.
10.4 
Data Monitoring Committee
Not required.
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10.5 
Adjudication Committee
10.5.1
Infection Adjudication Committee
An independent Infection Adjudication Committee (IAC) has been formed on a program level 
and will review pertinent data from this trial.
The mission of the IAC is to independently and blindly review, evaluate and categorize 
reports of serious infection events across all potential indications and therapeutic areas in the 
canakinumab development program.
The members and procedures of the IAC are detailed in the IAC Charter.
10.5.2
Malignancy Adjudication Committee
An independent Malignancy Adjudication Committee (MAC) has been formed on a program 
level and will review pertinent data from this trial.
The mission of the MAC is to independently and blindly review, evaluate and categorize 
reports of malignancy events across all potential indications and therapeutic areas in the 
canakinumab development program.
The members and procedures of the MAC are detailed in the MAC Charter.
11  
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carriedout independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1 
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include allsubjects that received any study drug.
The PK analysis set will include all subjects with available PK data and no protocol 
deviations with relevant impact on PK data.
The PD analysis set will include all subjects that received any study drug and that have no 
protocol deviations with relevant impact on PD data.
11.2 
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, and any 
other relevant information will be listed by treatment group and subject.
11.3 
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.


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11.4 
Analysis of the primary variable(s)
The primary aim of the study is to compare the effect of ACZ885 versus placebo on the 
clinical disease activity of sarcoidosis patients as measured by the change from baseline in the 
percent predicted FVC at week 24.
11.4.1
Variable(s)
The primary variable will be the change from baseline inpercent predicted FVC after 
24weeks of treatment.
11.4.2
Statistical model, hypothesis, and method of analysis
The change from baseline in percent predicted FVC will be analyzed using a Bayesian model 
for repeated measurements. The model will investigate effects for treatment by time (included 
as a class variable) interaction, baseline by time interaction and PET positivity (yes/no) prior 
to randomization. Uninformative priors will be utilized to obtain the posterior estimates.
The posterior probability that ACZ885 is better than placebo in terms of change from baseline 
in percent predicted FVC at 24 weeks will be calculated. If it is at least 90%, it will be 
considered a sign of efficacy of ACZ885 in increasing FVC after 24 weeks of treatment in this 
patient population.
At the interim analysis, the posterior probability that ACZ885 is worse than placebo in terms 
of change from baseline in percent predicted FVC at week 12 will be calculated. If it is at 
least 60%, the study may be stopped for futility.
11.4.3
Handling of missing values/censoring/discontinuations
The primary analysis will consider patients with partial data (for instance without a 24 week 
assessment but with at least one post baseline assessment available). Estimates of the missing 
values will be derived by the model thatare valid under the missing at random (MAR) 
assumption.
11.4.4
Sensitivity analyses
Not applicable.


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11.5 
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
11.5.1.1[F-18]
The [F-18]FDG-PET/CT imaging data will be analyzed to identify the max standardized 
uptake values in the following categories:
A maximum of 5 focal nodal uptake regions (mediastinal, hilar)
A maximum of 5focal regions of uptake in lung parenchyma
A maximum of 5 extra-thoracic focal uptake regions on the whole body scan
[F-18]FDG-PET/CT mean
A region of lung parenchyma, unaffected by focal lesion uptake
The mean of the SUVmax (resp. SUVmean) for each category will be taken to obtain one 
SUVmax value (resp. SUVmean) per patient / time point / category.
The mean percent change from baseline in SUVmax in the nodules after 12weeks of 
treatment will be analyzed using ANCOVA with baseline SUVmax as a covariate and 
treatment and PET positivity (yes/no) as factors.
The same analysis as for the percent change from baseline in SUVmax in the nodules will be 
performed for the percent change from baseline in SUVmax in the lung parenchyma and the 
extra-thoracic regions, where available. It will also be repeated for SUVmean in the 
parenchyma.
The percentage of patients with at least 50% reduction of SUVmax in nodules will be 
analyzed via logistic regression with baseline SUVmax as a covariate and treatment and PET 
positivity (yes/no) as factors.
Also the change in the individual lung nodules will be examined, using a discretized scale of 
complete response (CR), partial response (PR), stable disease (SD) and progressive disease 
(PD) as in the oncology European Organization for Research and Treatment of Cancer criteria 
for [F-18]FDG-PET/CT. The proportion of individual responders and non-responders will be 
determined, based on PET. Patients who discontinue for lack of efficacy will be treated as a 
separate category in this summary.
The correlation between changes from initial FDG-PET scan in SUVmax and changes from 
baseline in FVC, FEV1, COAs, 6MWT distance will be assessed with graphical methods.
11.5.1.2High resolution computed tomography (HRCT)
Change in HRCT scoring from initial scan to 24 weeks will be analyzed, using a regression 
model with baseline HRCT score as a covariate and treatment and PET positivity (yes/no) as 
factors. The HRCT scans will be evaluated using an HRCT scoring system quantifying 
various features such as: BVB: thickening or irregularity of the bronchovascular bundle; PC: 
parenchymal consolidation (including ground-glass opacifications); ND: intraparenchymal 
nodules; LS: septal and nonseptal lines; PL: focal pleural thickening; LN: enlargement of the 
mediastinal lymph nodes. The score for the lung will be determined using a scoring system 
similar to previous published literature (Obersteinetal1997; Orsetal2013).


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In addition, HRCT results will be evaluated for worsening, improvement, or stable outcome 
by 2 blinded assessors in side-by-side comparison. Results will be summarized in a shift table.
11.5.1.3Other secondary variables
Data from other pulmonary function tests and 6MWT will be listed and summarized. 
Graphical representations of the pulmonary function test endpoints over time will be 
presented.
11.5.2
Safety
11.5.2.1Vital signs
All vital signs data will be listed by treatment, subject, and visit and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit.
11.5.2.2ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit.
11.5.2.3Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
11.5.2.4Adverse events
All information obtained on adverse events will be displayed by treatment and subject. 
Thenumber and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.
11.5.3
Pharmacokinetics
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11.5.4
Pharmacokinetic/pharmacodynamic interactions
The relationship between PK and efficacy/PD parameters may be investigated using graphical 
methods and simple regression models.
11.5.5
Other assessments
Not applicable.
11.6 
Analysis of exploratory variables
Statistical analysis for exploratory variables will be described in the statistical analysis plan.
11.6.1
Exploratory biomarkers
11.7 
Sample size calculation
The sample size is determined by calculations with respect to the Bayesian analyses
(Fischetal 2014)(based on uninformative priors) of the change from baseline in thepercent 
predicted FVC after 24weeks oftreatment. With 15 patients per group providing data at week 
24 and assuming a standard deviation of 9% (Judsonetal2014), there is approximately 80% 
power to meet the efficacy criterion, if the true effect of ACZ885 over placebo is 7%. 
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Underthe same assumption for the standard deviation, there is l0% probability of meeting the 
efficacy criterion if the true treatment difference is 0%(type I error rate).
11.8 
Power for analysis of key secondary variables
Not applicable.
11.9 
Interim analyses
12  
Ethical considerations
12.1 
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2 
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
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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, NovartisQuality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatoryfor the clinical study report.
12.3 
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
13  
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safetyof subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented.
13.1 
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9(Safety Monitoring) must be followed and the Study Lead 
informed.


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14  
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production by alveolar macrophages and peripheral blood monocytes from patients with 
sarcoidosis. Int Arch Allergy Immunol; 102:242-248.
Tutor-Ureta P, Citores MJ, Castejon R, et al (2006) Prognostic value of neutrophils and NK 
cells in bronchoalveolar lavage of sarcoidosis. CytometryPt B (Clin Cytometry); 
70B:416-422.
Vorselaars ADM, Crommelin HA, Deneer VHM, et al (2015) Effectiveness of infliximab in 
refractory FDG PET-positive sarcoidosis. Eur Resp J; 46:175-85.
Wang W, Wang EQ, Balthasar JP (2008) Monoclonal antibody pharmacokinetics and 
pharmacodynamics. Clin Pharmacol Ther; 84:548-558.
Wanger J, Clausen JL, Coates A, et al (2005) Series “ATS/ERS Task Force: Standardisation 
of lung function testing” Standardisation of the measurement of lung volumes. Eur Respir J; 
26:511-522.
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Protocol No. CACZ885X2205
Yamaguchi E, Okazaki N, Tsuneta Y, et al (1988) Interleukins in pulmonary sarcoidosis. Am 
Rev Respir Dis; 138:645-651.
Ziegenhagen MW, Rothe ME, Schlaak M, et al (2003) Bronchoalveolar and serological 
parameters reflecting the severity of sarcoidosis. Eur Respir J; 21:407-413.
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15  
Appendix 1: Liver Event definitions and follow-up 
requirements
Table 15-1  
Liver Event definitions
Definition
Thresholds
Potential Hy’s law cases
ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase
in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy
ALT or AST > 3 × ULN and INR > 1.5 (in the absence of
anticoagulation)
ALT or AST elevation 
accompanied by symptoms
ALT or AST > 3 × ULN accompanied by (general) malaise,
fatigue, abdominal pain, nausea, or vomiting, or rash, or
eosinophilia
Isolated ALT or AST elevation ALT or AST > 8 × ULN
5 x ULN < ALT/AST ≤8 x ULN
3 x ULN < ALT/AST ≤5 x ULN
Isolated ALP elevation
ALP > 2 × ULN (in the absence of known bone pathology)
Others
Any clinical event of jaundice (or equivalent term)
Any adverse event potentially indicative of liver toxicity
Table 15-2  
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case
Discontinue the study treatment immediately
Hospitalize, if clinically appropriate
Establish causality
Complete CRFs per liver event guidance
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 
× ULN
If confirmed, consider interruption or discontinuation
of study drug
If elevation persists for more than 2 weeks,
discontinue the study drug
Establish causality
Complete CRFs per liver event guidance
IsolatedALT or AST elevation > 3 to 
≤5× ULN (patient is asymptomatic)
Monitor liver chemistry tests two or three times weekly


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Criteria
Actions required
Isolated ALP elevation
Repeat liver chemistry tests within 48-72 hours
If elevationis confirmed, measure fractionated ALP; if
>50% is of liver origin, establish hepatic causality
Complete CRFs per liver event guidance
Any AE potentially indicative of liver 
toxicity
Consider study treatment interruption or
discontinuation
Hospitalize ifclinically appropriate
Complete CRFs per liver event guidance
Table 15-3  
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E
IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV RNA,
IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV 
infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
Ethanol history, gGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis
Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy
Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic
venous occlusion. Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease
Caeruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1-antitrypsin 
deficiency
Alpha-1-antitrypsin


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16  
Appendix 2: Specific Renal alert criteria and actions
Table 16-1  
Specific Renal alert criteria and actions
Criteria
Action required
Serum creatinine (sCr) increase
25 –49% compared to baseline
Consider causes and possible interventions
Follow up within 2-5 days
Serum creatinine increase >50%
Consider causes and possible interventions
Repeat assessment within 24-48h if possible
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or ≥ 
3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol
Consider causes and possible interventions
Assess serum albumin & serum protein
Repeat assessment to confirm
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset glucosuria on urine dipstick (unless 
related to concomitant treatment, diabetes)
Assess & document:
Blood glucose (fasting)
Serum creatinine
Urine albumin-creatinine ratio
New hematuria on dipstick
Assess & document:
Urine sediment microscopy
Assess sCr and urine albumin-creatinine ratio
Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation
Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy,it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)


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Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:
Blood pressure assessment (after 5 min rest, with an appropriate cuff size)
Signs and symptoms such as fever, headache, shortness of breath, back orabdominal pain,
dysuria, hematuria, dependent or periorbital edema
Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic
failure, contrast media or other known nephrotoxin administration, or other potential
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2  
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case Report 
Form (CRF) or via electronic data load. Review and 
record possible contributing factors to the renal event 
(co-medications, other co-morbid conditions) and 
additional diagnosticprocedures (MRI etc) in the 
CRF.
Urine dipstick and sediment microscopy
Blood pressure and body weight
Serum creatinine, electrolytes (sodium,
potassium, phosphate, calcium),
bicarbonate and uric acid
Urine output
Monitor subject regularly (frequency at investigator’s 
discretion) until:
Event resolution: (sCr within 10% of
baseline or protein-creatinine ratio within
50% of baseline)
or
Event stabilization: sCr level with ±10%
variability over last 6 months or protein-
creatinine ratio stabilization at a new level
with ±50% variability over last 6 months.
*Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive
metric for integrated kidney function that requires excellent tubular function. A high urinary osmolality
in the setting of an increase in sCr will point toward a “pre
-renal” cause rather than tubular toxicity.

SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
ACZ885
CACZ885X2205
A multiple-dose, subject- and investigator-blinded, 
placebo-controlled, parallel design study to assess the 
efficacy, safety, and tolerability of ACZ885 (canakinumamb) 
in patients with pulmonary sarcoidosis
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Amendment 4
Release date:
16-May -2019
Number of pages:
22
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May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Protected Personal Data


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Table of contents
Table of contents .................................................................................................................5
List of tables ........................................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Scope of document ..................................................................................................7
1.2
Study reference documentation ...............................................................................7
1.3
Study objectives.......................................................................................................7
1.3.1. Primary objective(s).......................................................................................7
1.3.2. Secondary objective(s)...................................................................................7
1.3.3. Exploratory objective(s) ................................................................................8
1.4
Study design and treatment....................................................................................10
2
First interpretable results (FIR) .........................................................................................10
3
Interim analyses.................................................................................................................11
4
Statistical methods: Analysis sets......................................................................................12
5
Statistical methods for Pharmacokinetic (PK) parameters................................................13
5.1
Variables................................................................................................................13
5.2
Descriptive analyses ..............................................................................................13
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................13
6.1
Primary objective...................................................................................................14
6.1.1
Variables ...............................................................................................14
6.1.2
Descriptive analyses..............................................................................14
6.1.3
Statistical model, assumptions and hypotheses.....................................14
6.1.4
Supportive analyses...............................................................................15
6.1.5
Sensitivity analyses ...............................................................................15
6.2
Secondary objectives .............................................................................................15
6.2.1
Variables ...............................................................................................15
6.2.2
Descriptive analyses..............................................................................17
6.2.3
Statistical model, assumptions and hypotheses.....................................17
6.3
Exploratory objectives...........................................................................................18
6.3.1
Variables ...............................................................................................18
6.3.2
Descriptive analyses..............................................................................18
7
Statistical methods for safety and tolerability data............................................................19
7.1.1
Variables ...............................................................................................19
7.1.2
Descriptive analyses..............................................................................19
7.1.3
Graphical presentation ..........................................................................20
8
Statistical methods for Biomarker data .............................................................................20
9
Reference list.....................................................................................................................22


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List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................12


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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CACZ885X2205”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
Tables, Figures, Listings (TFL) details the presentation of the data, including shells of summary 
tables, figures and listings, and Programming Datasets Specification (PDS) contains 
programming specifications e.g. for derived variables and derived datasets, to support the 
creation of CSR outputs.
1.2
Study reference documentation
Final study protocol is available at the time of finalization of Statistical Analysis Plan.
1.3
Study objectives
1.3.1. Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives

To compare the effect of ACZ885 versus
placebo on the clinical disease activity of
sarcoidosis patients as measured by the
change from baseline in the percent
predicted forced vital capacity (FVC) at
week 24

Change from baseline in percent
predicted FVC at week 24.
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To determine the effect of ACZ885 on
decreasing the maximum standardized
uptake value (SUVmax) [F-
18]FDGPET in nodules (nodular uptake
regions) after 12 weeks of treatment,
compared to placebo

Percent change from initial scan in [F-
18]FDG-PET SUVmax at week 12

To determine the effect of ACZ885
versus placebo on other parameters of
pulmonary function testing (i.e.,
absolute FVC, FEV1, FEV1/FVC,
FEV3, FEV6, FEF25-75, FEV3/FVC,
1- (FEV3/FVC), TLC, RV, RV/TLC,
DLco and postbronchodilator
FEV1/reversibility) in patients with

Lung function testing results at 24
weeks compared to baseline


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sarcoidosis at 24 weeks compared to 
baseline

To determine the effect of ACZ885
versus placebo on HRCT of patients
with sarcoidosis at 24 weeks compared
to initial HRCT scan as measured by
side-by-side comparison by blinded
reviewers and HRCT scoring

HRCT results at 24 weeks compared to
HRCT initial scan measured by blinded
reviewers and HRCT scoring

To determine the effect of ACZ885
versus placebo on the 6-minute walk test
(6MWT) distance of patients with
sarcoidosis at 12 and 24 weeks
compared to baseline

6MWT results at week 12 and 24
compared to baseline

To determine the effect of ACZ885 on
additional [F-18]FDG-PET outcomes
(i.e., SUVmean, SUVpeak and volume
of the lesions) after 12 weeks of
treatment compared to placebo

Percent change from initial scan in
additional [F-18]FDG PET outcomes at
week 12

To assess the safety and tolerability of
ACZ885 in patients with sarcoidosis as
measured by adverse events (AEs)

Adverse events in patients taking
ACZ885 compared to placebo
1.3.3. Exploratory objective(s)
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1.4
Study design and treatment
This is a subject- and investigator-blinded, randomized, placebo-controlled, parallel group, non-
confirmatory study to assess the clinical efficacy of ACZ885 administered subcutaneously (s.c.) 
every four weeks for a total of 24 weeks.
The study will randomize approximately 38 patients with evidence of parenchymal involvement 
determined by HRCT and histologically proven, chronic pulmonary sarcoidosis of ≥1 year 
duration with persisting activity at baseline despite background therapy.
Figure 1-1: Study design scheme
2
First interpretable results (FIR)
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3
Interim analyses 
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4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. In 
case(s) of miss-stratification, the real stratum will be used in the analysis.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with available PK data and no protocol deviations 
with relevant impact on PK data.
The PD analysis set will include all subjects that received any study drug and that have no 
protocol deviations with relevant impact on PD data.
For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety) analysis in case of these 
PDs: 
Exclude subject completely 
from all (safety) analysis 
sets
INCL01
Deviation from inclusion criteria: Written 
informed consent was not obtained before 
any study assessment was performed 
Yes
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
INCL01
Deviation from inclusion criteria: Written 
informed consent was not obtained before any 
study assessment was performed 
Yes
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Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
INCL01
Deviation from inclusion criteria: Written 
informed consent was not obtained before any 
study assessment was performed 
Yes
Subjects are excluded from PD analysis after the PD date in 
case of these PDs:
Exclude subject from PD 
analysis set after the date of 
the event
COMD01
Prohibited medication used
Yes
Subjects are excluded from PK and PD analysis in case of these 
PDs:
Exclude subject from PK 
and PD analysis sets
INCL01
Deviation from inclusion criteria: Written 
informed consent was not obtained before any 
study assessment was performed 
Yes
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
5.1
Variables 
The following pharmacokinetic parameter will be determined: ACZ885 serum concentration. 
5.2
Descriptive analyses
ACZ885 serum concentration data will be listed by subject and visit/sampling time point. 
6
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the PD analysis set will be included in the PD data analysis.
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6.1
Primary objective
To compare the effect of ACZ885 versus placebo on the clinical disease activity of sarcoidosis 
patients as measured by the change from baseline in the percent predicted forced vital capacity 
(FVC) at week 24.
6.1.1
Variables 
The primary variable will be the change from baseline in percent predicted FVC after 24 weeks 
of treatment. The FVC is measured at screening, day 1, week 4, week 8, week 12, week 16, 
week 20 and week 24. Baseline is defined as day 1. At the visits (day 1 and week 24) where 
pre- and post-bronchodilation assessments are done, the pre-bronchodilation values are used.
6.1.2
Descriptive analyses
The raw percent predicted FVC values will be listed by treatment, subject and visit/time and 
descriptive statistics of both the raw and change in percent predicted FVC will be provided by 
treatment and visit/time. Summary statistics will include arithmetic mean, SD, CV (arithmetic), 
median, minimum and maximum. 
Graphical methods will be employed to show mean (SD) figures for change in percent predicted 
FVC. 
6.1.3
Statistical model, assumptions and hypotheses
The change from baseline in percent predicted FVC will be analyzed using a Bayesian model 
for repeated measurements. The model will investigate effects for treatment by time (included 
as a class variable) interaction, baseline by time interaction. Uninformative priors will be 
utilized to obtain the posterior estimates.
The posterior probability that ACZ885 is better than placebo in terms of change from baseline
in percent predicted FVC at 24 weeks will be derived. If it is at least 90%, it will be considered 
a sign of efficacy of ACZ885 in increasing FVC after 24 weeks of treatment in this patient 
population.
The primary analysis will include all available information in terms of measurements at all 
times. If missing measurements are missing at random, an analysis of the available data provides 
consistent estimates of model parameters. Alternative assumptions may be explored to 
investigate the robustness of the results under plausible non-missing at random situations.
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6.1.3.1
Graphical presentation of results
Model estimated means with 90% credibility intervals will be used to present the results over 
time.
6.1.4
Supportive analyses
6.1.5
Sensitivity analyses
A sensitivity analysis will be performed on the primary endpoint adding PET positivity 
(yes/not) prior to randomization a factor. The same analysis as defined in Section 6.1.3 will be 
performed, and adding PET positivity as a covariate in the model.
A further sensitivity analysis may be performed using an LOCF imputation for missing values. 
The main purpose of this analysis will be the investigation of potential bias, caused by subjects 
excluded from the analysis due to prohibited concomitant medication use (as concomitant 
medication increase is primarily due to poor response). However, the analysis will not be 
restricted to these subjects. A summary of prohibited medication incidence (as defined by the 
Protocol Deviations database), will be produced which will present the number of subjects with 
COMD01 deviations and time to first COMD01 deviation by treatment group, this summary 
will serve to decide whether the LOCF analysis will be performed. 
6.2
Secondary objectives
6.2.1
Variables 
Secondary variables for this study are: 

[F-18]FDG-PET/CT

HRCT

Pulmonary function tests: Change from baseline in absolute and % predicted FVC,
FEV1, FEF25-75, FEV1/FVC, FEV3, FEV3/FVC, FEV6, TLC, RV, RV/TLC, DLCO,
and post-bronchodilator FEV1/reversibility and other parameters as needed

6MWT outcomes: Change from baseline in distance, oxygen saturation, hearth rate and
Borg Questionnaire score
For the pulmonary function test parameters the direction of benefit is as follows

an increase in values is beneficial: absolute and % predicted FVC, FEV1, FEF25-75,
FEV1/FVC, FEV3, FEV6, FEV3/FVC, DLCO

a decrease in values is beneficial: RV, TCL, RV/TCL.
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[F-18]FDG-PET/CT 
The [F-18]FDG-PET/CT imaging data will be analyzed to identify the max standardized uptake 
values in the following categories:

A maximum of 5 focal nodal uptake regions (mediastinal, hilar)

A maximum of 5 focal regions of uptake in lung parenchyma

A maximum of 5 extra-thoracic focal uptake regions on the whole body scan [F-
18]FDG-PET/CT mean

Reference regions
o
Lung parenchyma, unaffected by focal lesion uptake
o
Ascending aorta blood pool
The mean of the SUVmax values (resp. SUVmean) for each category will be taken to obtain 
one SUVmax value (resp. SUVmean) per patient / time point / category. The percent change 
from initial scan mean SUVmax values (resp. SUVmean) will be used for all analysis.
Also the change in the individual lung nodules will be examined, using a discretized scale of 
complete response (CR), partial response (PR), stable disease (SD) and progressive disease 
(PD) as in the oncology European Organization for Research and Treatment of Cancer criteria 
for [F-18]FDG-PET/CT (Young et al, 1999). 
High resolution computed tomography
The HRCT scans will be evaluated using the following HRCT scoring systems:

Parameters provided by Paraxel*:

total parameter score

total sarcoidosis score

and HRCT results evaluated for worsening, improvement, or stable outcome by
independent reviewer(s)

Parameters provided by MedQIA read-out:

Key: Percentage air trapping in the whole lung

Secondary: Percentage air trapping at the lobar level (i.e. by location)
and HRCT results evaluated for worsening, improvement, or stable outcome by two 
independent assessors consolidated into one reading by MedQIA.Change in HRCT total score
from initial scan will be used for analysis.


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Details on the derivations of these scores are provided in the study’s independent imaging 
charter and they will be included in the source database.
*Where multiple reviewers have assessed the Paraxel HRCT, the worse results will be selected
for categorical summaries and the mean will be used for the continuous.
6.2.2
Descriptive analyses
All secondary variables will be listed by treatment, subject and visit/time. Descriptive statistics 
will be provided by treatment and visit/time for all continuous variables. Summary statistics 
will include arithmetic mean, SD, CV (arithmetic), median, minimum and maximum. Graphical 
methods will be employed to show mean (SD) figures for raw or derived value (such as change 
from baseline or percent change from baseline) for each endpoint. 
Incidences of patients with complete response (CR), partial response (PR), stable disease (SD) 
and progressive disease (PD) will be summarized by treatment group over time, patients who 
discontinue for lack of efficacy will be treated as a separate category in this summary. The best 
response by subject will also be summarized by treatment group; CR is the best possible 
response and will supersede any previous response of PR or SD. PR will supersede SD. If a 
subject has a response of PD this is the only best response they can have.
The correlation between changes from initial FDG-PET scan in SUVmax and changes from 
baseline in FVC, FEV1, PROs, 6MWT distance will be assessed with scatterplot grids. As we 
may not be able to assume normality of the data, Kendall’s tau-b coefficients and its 
corresponding p-values will be displayed to assess correlation.
Summary stats by PET positivity will be provided for the analyses on:

PET data

HRCT total scores

6MWT

FEV1,FEV3,FEV6 (L as well as % of predicted)
Data on new lesions from [F-18]FDG-PET/CT will be only listed.
6.2.3
Statistical model, assumptions and hypotheses
[F-18]FDG-PET/CT 
The mean percent change from baseline in SUVmax in the nodules at week 12 will be analyzed 
using ANCOVA with baseline SUVmax as a covariate and treatment  as factor.
The same analysis as for the percent change from baseline in mean SUVmax in the nodules will 
be performed for the percent change from baseline in SUVmax in the lung parenchyma and the 
extra-thoracic regions, where available, at week 12. It will also be repeated for SUVmean in the 
parenchyma.


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The percentage of patients with at least 50% reduction of SUVmax in nodules will be analyzed 
via logistic regression with baseline SUVmax as a covariate and treatment and PET positivity 
(yes/no) prior to randomization as factors.
The same sensitivity and subgroup analyses as the primary may also be performed, if deemed 
necessary.
High resolution computed tomography
Change in total HRCT score and total parameter scores from initial scan to 24 weeks will be 
analyzed, using an ANCOVA model with baseline HRCT score as a covariate and treatment at 
screening as factors. 
The same sensitivity and subgroup analyses as the primary may also be performed, if deemed 
necessary.
Key Pulmonary function tests (FEV1, FEV3 and FEV6)
FEV1, FEV3 and FEV6 (both in liters and percent as units) will be analyzed using the same 
analysis as defined in Section 6.1.3 but under a frequentist approach (no prior will be applied). 
The same sensitivity and subgroup analyses as the primary may also be performed, if deemed 
necessary. 
6.3
Exploratory objectives
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7
Statistical methods for safety and tolerability data
All subjects within the safety analysis set will be included in the safety data analysis.
7.1.1
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, immunogenicity, as well as subject demographics, baseline 
characteristics (including but not limited to PET disease assessment and MMRC dyspnea scale), 
and treatment information.
7.1.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and subject.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. Summary statistics will be provided by treatment and 
visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject. The 
number and percentage of subjects with adverse events will be tabulated by body system and 
preferred term with a breakdown by treatment. A subject with multiple adverse events within a 
body system is only counted once towards the total of this body system and treatment.


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Immunogenicity
All immunogenicity results will be listed by subject and visit/time.
7.1.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Statistical methods for Biomarker data
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9
Reference list
Young H, Baum R, Cremerius U, et al (1999) Measurement of clinical and subclinical tumour 
response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 
EORTC recommendations. Eur J Cancer; 35:1773-1782.