Clinical trial NCT02961218
Conditions: Sickle Cell Anemia
Keywords: Sickle cell disease hemoglobinopathy pediatric
Sponsor: Novartis Pharmaceuticals
Start date: 2017-04-05; Completion date: 2020-04-27
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study assesses the efficacy, safety and tolerability of ACZ885 (canakinumab) in pediatric and young adult patients with sickle cell anemia (SCA).

Detailed description:
This was an ambulatory-based 24-week study followed by an additional 24-week open label phase. It was a subject- and investigator-blinded, randomized, placebo-controlled, parallel group, non-confirmatory study to assess the clinical efficacy of ACZ885 administered s.c. in six injections given 28 days apart (in each phase of the study).

Pediatric and young adult subjects diagnosed with sickle cell anemia (SCA) were planned to be randomized to either ACZ885 treatment or placebo treatment in a 1:1 ratio,.

For each subject, there was a maximum 28-day screening period that included recording of daily pain frequency and intensity by e-diary for at least 1 week. Subjects who met the eligibility criteria at screening underwent evaluation of baseline clinical and biomarker assessments prior to first dose administration.

On Day 1, monthly s.c. dosing with ACZ885 started at 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects. Subjects in the placebo treatment arm were injected with placebo in a like manner. All subjects returned to the study centers for safety checks on a monthly basis when they received treatment with either ACZ885 or placebo.

The final blinded dosing was given on Week 20, followed by blinded clinical assessments at Week 24. Subjects from both study arms were then offered optional, open label monthly dosing of ACZ885 for an additional 24 weeks (Weeks 24-48) with clinical outcome assessment.

Subjects returned for the end of study (EOS) visit at Week 56. For subjects who chose not to participate in the optional, open label portion of the study, or for those stopping treatment early for any other reason, an EOS visit occurred approximately 8 weeks after last dose received.

After enrollment of 49 subjects, Novartis decided to terminate the study early due to strategic reasons not related to safety and decided that no additional enrollment was needed in order to interpret the study objectives.

Arms: arm 1: Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects arm 2: Monthly doses of 300 mg (4 mg/kg for patients ≤ 40 kg) canakinumab s.c.
Interventions: intervention 1: ACZ885 intervention 2: Placebo
Intervention descriptions: intervention 1: Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects intervention 2: Monthly doses of placebo to match the administered dose of canakinumab s.c.

Protocol documents:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
ACZ885
Clinical Trial Protocol CACZ885X2206
A multiple-dose, subject- and investigator-blinded, 
placebo-controlled, parallel design study to assess the 
efficacy, safety and tolerability of ACZ885 (canakinumab) in 
pediatric and young adult patients with sickle cell anemia
Document type:
Amended Protocol Version
EUDRACT number:
2016-002101-19
Version number:
v05 (Clean)
Clinical Trial Phase:
II
Release date:
22-Mar-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not be part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below.  Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO& PS)
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual. 


Novartis
Confidential
Page 3
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms...............................................................................................................12
Protocol synopsis...............................................................................................................23
1
Introduction .......................................................................................................................27
1.1
Background............................................................................................................27
1.2
Nonclinical data.....................................................................................................30
1.2.1
Teratogenicity and reproductive toxicity data.......................................30
1.3
Clinical data...........................................................................................................30
1.3.1
Human safety and tolerability data .......................................................30
1.3.2
Human pharmacokinetic data................................................................32
1.3.3
Human pharmacodynamic data.............................................................32
1.4
Study purpose ........................................................................................................32
2
Study objectives and endpoints .........................................................................................33
2.1
Primary objective(s)...............................................................................................33
2.2
Secondary objective(s)...........................................................................................33
2.3
Exploratory objective(s) ........................................................................................34
3
Investigational plan ...........................................................................................................35
3.1
Study design...........................................................................................................35
3.2
Rationale of study design.......................................................................................36
3.3
Rationale for dose/regimen, route of administration and duration of treatment....38
3.4
Rationale for choice of comparator .......................................................................38
3.5
Rationale for choice of background therapy..........................................................38
3.6
Purpose and timing of interim analyses/design adaptations..................................39
3.7
Risks and benefits..................................................................................................39
Commercially Confidential Information


Novartis
Confidential
Page 4
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
3.7.1
Blood sample volumes..........................................................................40
4
Population..........................................................................................................................41
4.1
Inclusion criteria ....................................................................................................41
4.2
Exclusion criteria...................................................................................................42
5
Restrictions for Study Subjects .........................................................................................44
5.1
Contraception requirements...................................................................................44
5.2
Prohibited treatment...............................................................................................44
5.3
Dietary restrictions and smoking...........................................................................45
5.4
Other restrictions ...................................................................................................45
6
Treatment...........................................................................................................................45
6.1
Study treatment......................................................................................................45
6.1.1
Investigational treatment and control drugs..........................................45
6.1.2
Additional study treatment....................................................................45
6.2
Treatment arms......................................................................................................46
6.3
Treatment assignment and randomization.............................................................46
6.4
Treatment blinding.................................................................................................46
6.5
Treating the subject................................................................................................48
6.6
Permitted dose adjustments and interruptions of study treatment.........................48
6.7
Emergency breaking of assigned treatment code ..................................................48
6.8
Treatment exposure and compliance .....................................................................49
6.9
Recommended treatment of adverse events ..........................................................49
6.10
Rescue medication.................................................................................................49
6.11
Concomitant treatment...........................................................................................49
7
Study completion and discontinuation ..............................................................................50
7.1
Study completion and post-study treatment ..........................................................50
7.2
Discontinuation of study treatment........................................................................50
7.3
Withdrawal of informed consent ...........................................................................51
7.4
Lost to follow-up ...................................................................................................51
7.5
Study Stopping rules..............................................................................................52
7.6
Early study termination by the sponsor .................................................................52
8
Procedures and assessments ..............................................................................................53
8.1
Assessment schedule .............................................................................................53
8.2
Informed consent procedures.................................................................................56
8.3
Subject screening...................................................................................................56
8.4
Subject demographics/other baseline characteristics.............................................57
8.4.1
Alcohol Test and Drug Screen..............................................................57
8.4.2
Tuberculosis status................................................................................57


Novartis
Confidential
Page 5
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
8.4.3
HIV screen ............................................................................................57
8.4.4
Hepatitis screen.....................................................................................57
8.5
Efficacy / Pharmacodynamics ...............................................................................57
8.5.1
Clinical Outcome Assessments (COAs) ...............................................58
8.6
Safety.....................................................................................................................59
8.6.1
Blood pressure.......................................................................................59
8.6.2
Body height ...........................................................................................59
8.6.3
Body temperature..................................................................................59
8.6.4
Body weight ..........................................................................................59
8.6.5
Clinical Chemistry ................................................................................59
8.6.6
Hematology...........................................................................................59
8.6.7
Immunogenicity ....................................................................................59
8.6.8
Pulse rate...............................................................................................60
8.6.9
Urinalysis ..............................................................................................60
8.6.10
Pregnancy test .......................................................................................60
8.6.11
Physical examination ............................................................................60
8.7
Pharmacokinetics...................................................................................................60
8.8
Other assessments..................................................................................................61
8.9
Use of residual biological samples ........................................................................63
9
Safety monitoring..............................................................................................................63
9.1
Adverse events.......................................................................................................63
9.2
Serious adverse event reporting.............................................................................65
9.2.1
Definition of SAE .................................................................................65
9.2.2
SAE reporting........................................................................................66
9.3
Liver safety monitoring .........................................................................................67
9.4
Renal safety monitoring.........................................................................................68
9.5
Reporting Medication errors including misuse/abuse ...........................................68
9.6
Pregnancy reporting...............................................................................................69
9.7
Early phase safety monitoring ...............................................................................69
10 Data review and database management.............................................................................69
10.1
Site monitoring ......................................................................................................69
10.2
Data collection.......................................................................................................70
Commercially Confidential Information


Novartis
Confidential
Page 6
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
10.3
Database management and quality control............................................................70
10.4
Data Monitoring Committee..................................................................................71
10.5
Adjudication Committee........................................................................................71
11 Data analysis......................................................................................................................72
11.1
Analysis sets ..........................................................................................................72
11.2
Subject demographics and other baseline characteristics......................................72
11.3
Treatments .............................................................................................................72
11.4
Analysis of the primary variable(s) .......................................................................73
11.4.1
Variable(s).............................................................................................73
11.4.2
Statistical model, hypothesis, and method of analysis..........................73
11.4.3
Handling of missing values/censoring/discontinuations.......................74
11.4.4
Sensitivity analyses ...............................................................................74
11.4.5
Supportive analyses...............................................................................74
11.5
Analysis of secondary variable(s)..........................................................................74
11.5.1
Efficacy / Pharmacodynamics...............................................................74
11.5.2
Inflammation and hemolysis biomarkers at Week 12...........................75
11.5.3
Absence from school/work ...................................................................75
11.5.4
Incidence of acute blood transfusion.....................................................75
11.5.5
Safety.....................................................................................................76
11.5.6
Pharmacokinetics ..................................................................................76
11.5.7
Pharmacokinetic / pharmacodynamic interactions................................76
11.5.8
Other assessments .................................................................................76
11.6
Analysis of exploratory variables ..........................................................................77
11.7
Sample size calculation..........................................................................................79
11.8
Power for analysis of key secondary variables......................................................80
11.9
Interim analyses.....................................................................................................80
12 Ethical considerations........................................................................................................81
12.1
Regulatory and ethical compliance........................................................................81
12.2
Responsibilities of the investigator and IRB/IEC..................................................81
12.3
Publication of study protocol and results...............................................................81
Commercially Confidential Information


Novartis
Confidential
Page 7
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
13 Protocol adherence ............................................................................................................81
13.1
Protocol Amendments ...........................................................................................82
14 References .........................................................................................................................83
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................87
16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................89
List of tables
Table 5-1
Prohibited treatment..............................................................................45
Table 6-1
Blinding levels ......................................................................................48
Table 9-1
Summary of reporting requirements for medication errors...................68
Table 11-1
Probability of meeting decision rules at IA1.........................................80
Table 15-1
Liver Event Definitions.........................................................................87
Table 15-2
Actions required for Liver Events.........................................................87
Table 15-3
Exclusion of underlying liver disease ...................................................88
Table 16-1
Specific Renal Alert Criteria and Actions.............................................89
Table 16-2
Follow-up of renal events......................................................................90
List of figures
Figure 3-1
Study design..........................................................................................35
Commercially Confidential Information


Novartis
Confidential
Page 8
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
List of abbreviations
γ-GT
gamma-glutamyl transferase
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
AUC
area under curve
BMI
Body Mass Index
BUN
blood urea nitrogen
CAPS
cyropyrin-associated periodic syndromes
CINCA
chronic infantile neurological, cutaneous, articular syndrome
CFR
Code of Federal Regulation
CK
creatinine kinase
CO2
carbon dioxide
COAR
Clinical Operations, Analytics & Regions
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CTC
Common Toxicity Criteria
CV
coefficient of variation
EDC
Electronic Data Capture
ELISA
enzyme-linked immunosorbent assay
EOS
End of study
EU
European Union
FCU
familial cold urticaria
FCAS
Familial Cold Autoinflammatory Syndrome
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLM
generalized linear model


Novartis
Confidential
Page 9
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
h
Hour
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
hs-CRP
high-sensitivity C-reactive protein
Hydroxyurea
Hydroxyurea/hydroxycarbamide
i.v.
intravenous
IAC
Infection Adjudication Committee
ICH
International 
Conference
on 
Harmonization 
of 
Technical 
Requirements for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IL
interleukin
IL-18BPa
interleukin-18 binding protein
IL-1RA
interleukin-1 receptor antagonist
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intention-to-treat
IUD
intrauterine device
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
LOCF
last observation carried forward
MAC
Malignancy Adjudication Committee
MAR
missing at random
MCID
Minimally clinical important difference
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMRM
Mixed-effect Model for Repeated Measures
MWS
Muckle Wells Syndrome
NOMID
neonatal-onset multisystem inflammatory disease
Commercially Confidential Information


Novartis
Confidential
Page 10
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
POC
Proof of concept
RBC
red blood cell(s)
s.c.
subcutaneous
SAE
serious adverse event
SCA
sickle cell anemia
sCR
serum creatinine
SD
standard deviation
sJIA
systemic juvenile idiopathic arthritis
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
tuberculosis
TBL
total bilirubin
TCD
Transcranial Doppler
TRAPS
TNF receptor-associated periodic syndrome
UK
United Kingdom
ULN
upper limit of normal
US
United States of America
VAS
visual analog scale
WBC
white blood cell(s)
WHO
World Health Organization
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 11
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Pharmacokinetic definitions and symbols
AUCinf
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to infinity [mass x time / volume]
Cav,ss
The average steady state plasma (or serum or blood) concentration during 
multiple dosing
CL
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time]
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or blood) 
following extravascular administration [volume / time]
CLr
The renal clearance from plasma (or serum or blood) [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]


Novartis
Confidential
Page 12
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which 
is used as a comparator to the investigational drug being tested in the 
trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up), which applies across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
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 Directive 
2001/20/EC and is synonymous with “investigational new drug” or 
“test substance”
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.
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Non-investigational 
medicinal 
Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.)
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.


Novartis
Confidential
Page 13
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Patient
An individual with the condition of interest
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
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major 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 drug was 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.
Study treatment
Any drug administered to the study participants as part of the required 
study procedures; includes investigational drug (s), control(s) or non-
investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 


Novartis
Confidential
Page 14
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject 
does not want to participate in the study any longer, and does not want 
any further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained 
biologic material


Novartis
Confidential
Page 15
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 16
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 17
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 18
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 19
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 20
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 21
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 22
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 23
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Protocol synopsis
Protocol number
CACZ885X2206
Title
A multiple-dose, subject- and investigator-blinded, placebo-controlled, parallel 
design study to assess the efficacy, safety and tolerability of ACZ885 
(canakinumab) in pediatric and young adult patients with sickle cell anemia.
Brief title
Study of efficacy, safety and tolerability of ACZ885 (canakinumab) in pediatric 
and young adult patients with sickle cell anemia.
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
This study is designed to assess if inhibition of IL-1β by canakinumab will reduce 
daily pain in association with attenuation of intravascular inflammation in pediatric
and young adult patients with sickle cell anemia, therefore allowing further 
development of the compound for treatment of this disease population.
A pediatric and young adult population (8-20 years of age) is chosen because the 
patients are more likely to be without significant accumulated, SCA-related 
co-morbidities and are most likely to benefit from the compound’s mechanism of 
action. Moreover, canakinumab has been widely studied in inflammatory diseases 
involving pediatric populations that encompass the age range proposed in this 
study, with an estimated 528 pediatric patients <1 to 17 years exposed to 
canakinumab treatment
in Novartis-sponsored interventional studies as of 
30 June 2017. Among the inflammatory diseases involving pediatric patients for 
which canakinumab has received health authority approvals include sJIA and 
CAPS for patients ≥2 years and ≥4 years, respectively.
The dose of canakinumab selected for the current proof-of-concept trial is 300 mg 
s.c. (4 mg/kg for patients ≤40 kg), monthly. This dosing regimen is predicted to
achieve and maintain suppression of the inflammation over time, allowing for
tissue repair and reductions in pain and crisis frequency.
Stratification is planned for patients at treatment randomization according to 
presence or absence of concurrent hydroxyurea use because this standard-of-
care therapy has potential therapeutic benefits against the disease, but its 
practical use in pediatric populations remains limited.
The rationale for the additional safety visit 8 weeks after the final clinical 
assessment at Week 48 is to monitor for any potential, late appearing AEs after 
having terminated treatment.
The opportunity for continued, open label treatment is provided in this study 
design to allow participants from the placebo-treated arm the option for receiving 
active treatment and for those in the active treatment group to continue on 
treatment, thus providing additional exposure data and evidence for sustained 
efficacy in this patient population in which canakinumab is envisaged as a long 
term treatment.


Novartis
Confidential
Page 24
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Primary 
Objective(s)
To determine the effect of canakinumab versus placebo on daily pain experienced 
by sickle cell anemia patients (Reduction of average daily pain VAS over the 
period of Week 8 to 12 as compared to baseline levels).
Secondary 
Objectives
-
To determine the duration of effects of canakinumab versus placebo on daily 
pain experienced by SCA patients (Reduction of average daily pain VAS over 
4-week intervals up to Week 24 as compared to baseline levels)
-
To determine the effect of canakinumab versus placebo on laboratory markers 
of inflammation (Week 12 versus baseline of: serum hsCRP, WBC count, 
Absolute counts of blood neutrophils, Absolute counts of blood monocytes).
-
To determine the effect of canakinumab versus placebo on laboratory and 
functional markers of hemolysis.
-
To determine the effect of canakinumab versus placebo on SCA-related days 
missed from school or work
-    To determine the effect of canakinumab versus placebo on reducing the need 
for acute blood transfusion
-
To assess the safety and tolerability of canakinumab in patients with SCA as 
measured by adverse events (AEs), including immunogenicity as indicated by 
the presence of anti-drug antibodies
-
To determine the PK of canakinumab in SCA patients
Study design
This study is an ambulatory-based study of 24 weeks duration followed by an 
additional 24-week open label phase and is subject- and investigator-blinded, 
randomized, placebo-controlled, parallel group, non-confirmatory to assess the 
clinical efficacy of canakinumab administered s.c. in 6 injections given 28 days 
apart (monthly injections). This study will randomize approximately 60 pediatric 
and young adult patients (targeting 48 completers) diagnosed with SCA who 
experience chronic or episodic pain, i.e., detectable average daily pain level over 
a 1-2 week screening period and ≥2 painful episodes in the past year of likely 
sickle cell etiology requiring analgesia and interfering with the patient’s normal 
daily routine.
Population
This study will recruit patients, 8 to 20 years of age (both inclusive) with SCA.
Key Inclusion 
criteria
-
Male and female subjects, 8-20 years of age (both inclusive) diagnosed with 
sickle cell anemia (HbSS) or sickle beta0 thalassemia (documented by family 
studies, or analysis of either hemoglobin or DNA).
-
Patient’s written informed consent from those ≥18 years of age must be 
obtained before any assessment is performed. Parent or legal guardian’s 
written informed consent and child’s assent, if appropriate, are required before 
any assessment is performed for patients < 18 years of age.
-
Detectable baseline of background or episodic pain measured by daily e-diary 
over 1 to 2 weeks during screening period as defined below: 
Average daily pain score ≥ 1 cm without analgesic use over a period of at least 
7 days and/or,
At least one episode of pain requiring analgesic use during a period of up to 
14 days.
-
History of ≥2 vaso-occlusive pain episodes in the past year, as defined as pain 
with no other, non-sickle cell identifiable cause that requires analgesia and 
interferes with the patient’s normal daily routine.


Novartis
Confidential
Page 25
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Key Exclusion 
criteria
-
History of known anaphylaxis or hypersensitivity to canakinumab or any
component thereof.
-
Ongoing or treatment within the past 3 months with red blood cell transfusion
therapy, or have evidence of iron overload requiring chelation therapy.
-
Transcranial Doppler ultrasound in the past year or at screening
demonstrating velocity in middle or anterior cerebral or internal carotid artery
≥200 cm/sec. Note, transcranial Doppler (TCD) assessment is only required in
patients for whom the trans-temporal acoustic window is sufficient for imaging
the cranial arteries.
-
Administration of any other blood products within 3 weeks prior of screening
visit.
Study treatment
The dose of canakinumab selected for the current proof-of-concept trial is 300 mg 
s.c. monthly (4 mg/kg for patients ≤40 kg),
Efficacy/PD 
assessments
-
Reduction of average daily pain VAS over the period of Week 8 to 12 as
compared to baseline levels
-
Reduction of average daily pain VAS over 4-week intervals up to Week 24 as
compared to baseline levels
-
Serum hsCRP, WBC count, absolute counts of blood neutrophils, absolute
counts of blood monocytes, hemoglobin concentration, reticulocyte count,
haptoglobin, LDH, bilirubin (total, direct and indirect),
.
Key safety 
assessments
-
Adverse events,
-
Other 
assessments
Data analysis
The post-baseline average daily pain VAS (visual analog scale) will be calculated 
for each dose from the start of the dose till the day before the next dose, i.e., in an 
averagely 4-week interval (e.g., Week 0-4, Week 4-8, etc., depending on the 
actual dosing days). The baseline average pain VAS will be calculated as the 
average of daily pain scores from screening up to pre-dosing over a period of at 
least 7 days. Reduction from baseline in the average daily pain VAS, i.e., baseline 
minus post-baseline, will be analyzed using a Bayesian model for repeated 
measures using Proc MCMC in SAS. The model includes baseline average daily 
pain score as a continuous covariate; treatment group, time and hydroxyurea use 
history (Yes/No) as fixed factors. Interactions of time by treatment group and time 
by baseline covariates will also be included in the model. Non-informative priors 
will be used for the fixed effects and weakly informative prior, for the covariance. 
Unstructured covariance structure will be used and other covariance structure will 
be investigated if there is convergence problem. Interaction of hydroxyurea use 
and treatment group will be explored via visualizations; if substantial interaction is 
suspected it will be further explored by including this interaction term in the whole 
model.
A comparison of canakinumab 300 mg s.c. versus placebo for the period of Week 
8-12 is of primary interest. Data up to Week 12 will be included in the primary
model. Bayesian posterior probabilities will be used to assess the following PoC
criteria as a guidance for decision making:
Prob (the reduction of average pain score over the period of Week 8-12 in 
canakinumab is greater than Placebo) > 90%, and
Prob (the reduction of average pain score over the period of Week 8-12 in 
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 26
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
canakinumab is greater than Placebo by 1) > 50%.
The target difference of 1 is chosen based on the literature search on the 
Minimally Clinical Important Difference (MCID) in pain studies.
Data up to Week 24 will also be analyzed with the same model specifications 
when there are at least about 50% completers at Week 24 and also upon the 
study completion. Pain data in the open label when available will also be 
summarized, visualized and explored in appropriate statistical models, to evaluate 
the maintenance of the efficacy in patients randomized to canakinumab group 
and/or improvements in patients randomized in placebo group.
Patients who have missed two consecutive dosing or more in the blinded 
treatment period or have other protocol deviations severely affecting the 
evaluation of efficacy will be excluded in the primary efficacy analysis for the 
blinded period. This is the primary PD analysis set.
Key words
ACZ885, canakinumab, adolescent, sickle cell anemia
Commercially Confidential Information


Novartis
Confidential
Page 27
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
1
Introduction
1.1
Background
Sickle cell anemia (SCA)
SCA is a life-long disease with high morbidity and mortality. This inherited disease is the 
most common hemoglobinopathy and is caused by a single amino acid change in the β-globin 
chain that results in structurally abnormal hemoglobin S, or by compound heterozygosity for 
hemoglobin S and another β-globin chain abnormality, typically hemoglobin C or 
β-thalassemia. These mutations lead to abnormally shaped sickle cell erythrocytes with 
reduced membrane elasticity with increased propensity for lysis and adherence. Heterozygous 
individuals carrying one copy of the mutation (sickle cell trait) usually have no overt disease, 
but those homozygous for the mutation can experience disease severity and potential 
complications to varying extents, dependent on the proportion of red blood cells affected, 
other, coexisting conditions such as G6PD deficiency or thalassemia, and exposure to 
environmental factors such as infection, dehydration and acidosis that favor sickling.
There are an estimated 312,000 people homozygous for hemoglobin S (hemoglobin SS, 
HbSS) born each year throughout the world (Saraf et al 2014). Global distributions of 
newborns with the disease are 60% in sub-Saharan Africa, 20% in Arab-Indian regions, 7% 
in the Americas and 5% in Eurasia. There are about 20-25 million individuals world-wide 
who have homozygous sickle cell disease, including 12 -15 million in sub-Saharan Africa, 
5-10 million in India and about 3 million scattered about elsewhere in the world. Due to the 
similar historical distribution patterns of malaria and of hemoglobin S, it has been proposed 
that protection from malaria provided a heterozygote advantage for these mutations in 
selected populations. Subsequent migration patterns have distributed sickle cell genes into 
regions not endemic for malaria.  About 8% of African Americans carry the sickle gene and 
100,000 live with SCA. However, they are responsible for >70,000 annual hospitalizations 
(Kauf et al 2009). Among SCA patients the median age at death is 42 years in Western society 
and half that age in less developed countries.
Clinical manifestations of the disease include chronic inflammation, acute and chronic pain, 
fatigue and chronic hemolytic anemia with recurrent vaso-occlusive crises. Thus, patients 
experience chronic signs and symptoms of their disease throughout life, punctuated by 
episodic crises, together resulting over time in severe end-organ damage and early mortality. 
Children and adults with SCA have an overall reduced quality of life. Chronic fatigue also 
plays a role in reduced quality of life in SCA patients and is associated with acute care visits 
for pain as well as school absences and missed caregiver workdays (Dampier et al 2010, 
Panepinto et al 2014). Other known complications of the disease include stroke, osteonecrosis,
nephropathy, pulmonary disease, retinopathy, priapism and reduced cognition. The spleen is 
frequently affected early in life due to repeated infarctions, leading to increased susceptibility 
to infections by encapsulated organisms.


Novartis
Confidential
Page 28
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Treatment options for SCA are quite limited, with hydration, analgesia and antibiotics used 
for management of acute SCA crises. Hydroxyurea (ribonucleotide reductase inhibitor), first 
synthesized in 1869, is approved in the US and in the EU for SCA and is used to reduce 
frequency of crises by increasing the proportion of fetal hemoglobin over the mutated sickle 
form. However, hydroxyurea remains underutilized by SCA patients and their physicians due 
to uncertainties regarding associated toxicities. This cytostatic drug has a wide range of 
potential AEs that include bone marrow toxicity and potential increased leukemia risks and 
thus requires close monitoring. L-glutamine (Endari™) is approved in the US to reduce the 
acute complications of SCA in adult and pediatric patients 5 years and older. Another SCA 
therapy is frequent blood transfusions to reduce the proportion of sickle-prone RBCs in 
circulation. The only known potential cure for SCA is bone marrow transplantation which has 
proven effective in children but its potential long term toxicities limit use to only the most 
severely affected patients. Therefore, alternative therapeutic targets and disease mechanisms 
should be considered in this disease.
Evidence for chronic intravascular inflammation in sickle cell disease
Due to increased hemolysis of the abnormal, sickled red blood cells, SCA patients have 
constitutively high levels of circulating hemoglobin/heme that exhausts the body’s protective 
scavenger capacity, driving acute on chronic inflammation under sterile or infectious 
conditions. High levels of C-reactive protein (CRP) and other inflammation mediators such as 
IL-1β, IL-6, IL-17, IL-18 and TNF-α are common in SCA. Increased levels of IL-1β and 
IL-18 trigger endothelial cell activation, upregulation of adhesion molecules and neutrophil 
activation (Dinarello 1999; Morel et al 2001; Gerdes et al 2002). Acute crises arise from 
increased adhesive interactions between sickled RBCs and leukocytes with endothelial cells, 
triggered by stressors such as dehydration or otherwise mild viral infections, causing vascular 
obstruction and tissue ischemia. A vicious, positive feedback cycle of inflammation ensues, 
resulting in marked pain and end organ damage.
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 and pro-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.


Novartis
Confidential
Page 29
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Sickle cell anemia as an inflammasome-mediated disease
Recent literature evidence has identified SCA to have a strong inflammasome-driven 
component via high rates of constitutive intravascular hemolysis that overwhelm the 
scavenger capacity of the body for heme and free iron, resulting in chronic activation of 
endothelial cells and vascular inflammation. In mouse models, heme induces IL-1β 
production and neutrophil migration dependent on caspase-1 cleavage, thus demonstrating 
inflammasome activation (Dutra et al 2014). In the same report, the hemolysis-induced 
lethality in an animal model was greatly reduced in Nlrp3-, Asc- and caspase-1-deficient mice, 
indicating inflammasome involvement. Transgenic SCA animal models largely recapitulate 
human pathophysiology, with subclinical inflammation and increased neutrophil counts as 
well as elevated soluble vascular adhesion molecules (Cain et al 2012). Anti-IL-1β antibody 
treatment in another transgenic SCA mouse model markedly ameliorated intravascular flow 
impedance induced by hypoxia (Kaul and Gram 2011).
Therapeutic targeting of IL-1β in sickle cell disease
IL-1β is recognized as one of the principal pro-inflammatory cytokines in a variety of 
inflammatory conditions, including those involving autoinflammation and the inflammasome 
(Church et al 2008). This cytokine is produced by a variety of cell types, particularly 
mononuclear phagocytes, in response to injury, infection and inflammation.
ACZ885 (canakinumab) is a high affinity, fully human, monoclonal anti-human interleukin-
1β (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 registered in more than 70 countries worldwide under the name 
Ilaris®. Depending on countries, Ilaris is approved for treatment of adults and children aged 
2 years and older that have a condition known as cryopyrin-associated periodic syndromes 
(CAPS), including familial cold autoinflammatory syndrome (FCAS) / Familial Cold 
Urticaria (FCU), Muckle-Wells syndrome (MWS) and Neonatal-Onset Multisystem 
Inflammatory Disease (NOMID) / Chronic Infantile Neurological, Cutaneous, Articular 
Syndrome (CINCA). Additional monogenetic periodic fever syndromes for which Ilaris® has 
received approvals include tumor necrosis factor receptor-associated periodic syndrome 
(TRAPS), colchicine-resistant/intolerant familial Mediterranean fever (crFMF) and hyper-
Immunoglobulin D Syndrome with periodic fever syndrome (HIDS)/ Mevalovate Kinase 
Deficiency (MKD) (Rigante 2016). Ilaris® is also approved for the treatment of active 
systemic juvenile idiopathic arthritis (sJIA) in children 2 years of age and older and in Europe 
for the symptomatic treatment of acute gouty arthritis attacks. For further details please refer 
to the Investigators Brochure (IB).
The above evidence supports that inflammasome activity is constitutively upregulated in 
sickle cell anemia patients and may play a role in disease activity. Thus, IL-1β pathway 
interruption with canakinumab is anticipated to confer therapeutic benefit.


Novartis
Confidential
Page 30
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
1.2
Nonclinical data
1.2.1
Teratogenicity and reproductive toxicity data
1.3
Clinical data
1.3.1
Human safety and tolerability data
As of 30 June 2017, an estimated 10,939 patients, of which 528 pediatric patients aged <1 to 
17 years, have received canakinumab treatment in 74 Novartis-sponsored investigational 
clinical trials and 16 third party, investigator-initiated trials in a wide spectrum of diseases
where IL-1β plays a role, such as cryopyrin-associated periodic syndromes (CAPS), mild 
asthma, psoriasis, wet age-related macular degeneration (AMD), gouty arthritis, type 2 
diabetes mellitus, atherosclerosis, rheumatoid arthritis (RA), and systemic juvenile idiopathic 
arthritis (sJIA). Health authority approvals for Ilaris have been granted for monogenetic 
periodic fever syndromes, including CAPS, TRAPS hyper-Immunoglobulin D Syndrome with 
periodic fever syndrome (HIDS)/ Mevalovate Kinase Deficiency (MKD), colchicine-
resistant/intolerant familial Mediterranean syndrome (crFMF), gout and sJIA. The post-
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 31
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
marketing cumulative patient exposure since the first launch of the product is estimated to be 
approximately 15,260 patient treatment-years as of 30 June 2017 year. 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 9 mg/kg s.c. or fixed doses of 5 mg to 300 mg s.c. ACZ885 has a long half-life 
averaging approximately 4 weeks in man and monthly s.c. dosing of 4 mg/kg up to 300 mg is 
approved by the FDA and EMA for sJIA. The frequency of dosing ranged from a single dose 
to quarterly repeated administration. Pediatric patients and those patients with a severe CAPS 
phenotype may require higher than usual doses to attain full clinical response, and current 
labeling for canakinumab allows for dose escalation up to a maximum of 8 mg/kg for patients 
≤40 kg and to 600 mg for patients >40 kg. Patients with systemic juvenile idiopathic arthritis 
(SJIA) also tend to require higher dosing of canakinumab for adequate response. These 
indications encompass a relatively comparable patient population to the ACZ885X2206 
patient population in terms of age range and inflammatory levels. In registration and post-
registration studies for canakinumab in this indication, there were no differences observed in 
the incidence of overall AEs across the different dosing groups, including those receiving 
either 150 mg or 300 mg s.c. monthly.
Studies in adult RA patients have been treated with 300 mg s.c. up to 184 weeks (studies 
CACZ885A2201, -E1 and -E2) at every 2 weeks for the first 12 weeks and every 4 weeks 
thereafter. The 300 mg dosing regimen was well-tolerated, without dose-dependent 
differences in AE incidence compared to every 4 weeks s.c. dosing of 150 mg.
Overall, the development program with ACZ885 has demonstrated a good safety and 
tolerability profile as evidenced by 1) a low number of study discontinuations for AEs, 
predominantly mild injection site reactions, and 2) no specific target organ toxicity. The AE 
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 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 include upper respiratory tract infections, nasopharyngitis and otitis, headache, 
nausea, diarrhea, and asthenic conditions. So far the maximum median duration of exposure to 
canakinumab is more than 4 years for the first 4 MWS patients enrolled in the 
CACZ885A2102 trial.
Similar to patients with monogenetic periodic fever syndromes, patients suffering from sickle 
cell anemia also have chronic inflammation and elevated serum levels of C-reactive protein 
and IL-1β (Akohoue et al 2007; Qari et al 2012) with recurrent periodic crises involving 
further, elevations of inflammation and serum CRP (Mohammed et al 2010;
Kanavaki et al 2012). In a recently completed, large clinical trial involving pediatric and 
adult patients with periodic fever syndromes (CACZ885N2301), insufficient or non-response 
to initial canakinumab dosing at 150 mg resulted in further dose escalation to 300 mg/month 
in 16% of patients with crFMF, 32% of patients with HIDS and 36% of patient with TRAPS. 
In those patients, canakinumab dosed at 300 mg s.c. monthly was shown to bind additional 
IL-1β along with increased responder rates over rates observed with monthly s.c. dosing at 
150 mg (i.e., crFMF +9.7%, HIDS +21.6%, TRAPS +27.3%). Similar improvements with 
increased monthly dosing of 300 mg versus 150 mg were also seen in secondary outcomes 
(i.e., physician global assessment of disease activity, serum reductions of acute phase 


Novartis
Confidential
Page 32
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
reactants). Thus, these results suggest that canakinumab dosing at 300 mg binds additional 
target and is more clinically effective than 150 mg dosing in patients with more severe 
inflammation.
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. The serum clearance (CL) of canakinumab 
varied according to body weight (e.g., CL=0.174 L/day in a CAPS patient of body weight 
70 kg, 0.11 L/day in a 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 over the dose range of 0.30 to 10.0 mg/kg 
given as i.v. infusion and from 150 mg to 300 mg when administered as an s.c. injection. 
The absolute bioavailability of s.c. canakinumab is 70%. After accounting for body weight 
differences, no clinically significant differences in the pharmacokinetic properties of 
canakinumab were observed between CAPS, SJIA and gouty arthritis patients. 
Furthermore, with body weight-based dosing, canakinumab administered in pediatric 
indications (e.g., CAPS and SJIA) was observed to be similar in various age subgroups. 
For instance, in SJIA patients, exposure parameters corrected for body weight (such as AUC 
and Cmax) were comparable across age groups from 2 to <20 years following subcutaneous 
administration of canakinumab 4 mg/kg every 4 weeks. 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, such as serum amyloid A (SAA) 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 in all 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 to assess if inhibition of IL-1β by canakinumab will reduce daily pain 
in association with attenuation of intravascular inflammation in pediatric and young adult 
patients with sickle cell anemia, therefore allowing further development of the compound for 
treatment of this disease population.


Novartis
Confidential
Page 33
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
2
Study objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To determine the effect of ACZ885 versus
placebo on daily pain experienced by
sickle cell anemia patients

Reduction of average daily pain VAS
over the period of Week 8 to 12 as
compared to baseline levels
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To determine the duration of effects of
canakinumab versus placebo on daily pain
experienced by SCA patients

Reduction of average daily pain VAS
over 4-week intervals up to Week 24 as
compared to baseline levels

To determine the effect of canakinumab
versus placebo on laboratory markers of
inflammation

Week 12 versus baseline of:

Serum hs-CRP

WBC count

Absolute counts of blood neutrophils

Absolute counts of blood monocytes

To determine the effect of canakinumab
versus placebo on laboratory and
functional markers of hemolysis

Week 12 versus baseline of:

Hemoglobin concentration

Reticulocyte count

Haptoglobin

LDH

Bilirubin (total, direct and indirect)

Oxygen percent saturation (SaO2)

To determine the effect of canakinumab
versus placebo on SCA-related days
missed from school or work

Number of days absent from school or
work due to pain as recorded by daily e-
diary

To determine the effect of canakinumab
versus placebo on reducing the need for
acute blood transfusion

The rate of SCA-related acute
transfusion

To assess the safety, including
immunogenicity, and tolerability of
canakinumab in patients with SCA as
measured by adverse events (AEs)

Adverse events in patients taking
ACZ885 compared to placebo up to a
total of 56 weeks treatment.

To determine the PK of ACZ885 in SCA
patients

Serial serum PK determinations in
patients with SCA


Novartis
Confidential
Page 34
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
2.3
Exploratory objective(s)
Commercially Confidential Information


Novartis
Confidential
Page 35
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
3
Investigational plan
3.1
Study design
This study (Figure 3-1) is an ambulatory-based study of 24 weeks duration followed by an 
additional 24-week open label phase and is subject- and investigator-blinded, randomized, 
placebo-controlled, parallel group, non-confirmatory to assess the clinical efficacy of 
canakinumab administered s.c. in 6 injections given 28 days apart. This study will randomize 
approximately 60 pediatric and young adult patients (targeting 48 completers of 8 to 20 years 
old) diagnosed with SCA who experience chronic or episodic pain, i.e., detectable average 
daily pain level over a 1-2 week screening period and at least 2 painful episodes in the past 
year of likely sickle cell etiology requiring analgesia and interfering with the patient’s normal 
daily routine.
Figure 3-1
Study design
Acceptable prior established background therapy includes hydroxyurea and supportive 
antibiotic and analgesic medications. Patients will be randomized to either ACZ885 treatment 
or placebo treatment in a 1:1 ratio, with treatment stratification based on concurrent 
hydroxyurea therapy (yes/no).
Subjects who are prematurely withdrawn from the study for reasons other than safety or lack 
of efficacy will be replaced on a case-by-case basis. Re-screening of subjects may be allowed 
under the guidance of the Sponsor’s medical expert.
For each subject, there will be a maximum 28-day screening period that will include recording 
of daily pain frequency and intensity by e-diary for at least 1 week.
Commercially Confidential Information


Novartis
Confidential
Page 36
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Subjects who meet the eligibility criteria at screening will undergo evaluation of full baseline 
clinical and biomarker assessments prior to first dose administration. The screening daily pain 
results will be used to derive the baseline value for this primary endpoint of average daily pain. 
All safety evaluations must be available prior to dosing and results must demonstrate all 
eligibility criteria are met. Enrolled subjects will be randomized at a 1:1 ratio to receive 
treatment with either canakinumab or placebo with stratification based on concurrent 
hydroxyurea therapy. On Day 1, monthly s.c. dosing with canakinumab will begin at 4 mg/kg 
for patients weighing ≤ 40 kg and 300 mg for all other patients. Patients in the placebo 
treatment arm will be injected in a like manner with placebo. All patients will return to the 
study centers for safety checks on a monthly basis when they will receive treatment with 
either canakinumab or placebo. Additionally, patients will undergo clinical and laboratory 
evaluations as outlined in the Assessment Schedule every 28 days. The final blinded dosing 
will take place on Week 20, followed by blinded clinical assessments at Week 24. Patients 
from both study arms are then offered optional, open label monthly dosing of ACZ885 for an 
additional 24 weeks (Weeks 24-48), with clinical outcomes again assessed according to the 
Assessment schedule.  Patients return for the end of study (EOS) visit at Week 56. For 
patients who choose not to participate in the optional, open label portion of the study, or for 
patients stopping treatment early for any other reason, an EOS visit will occur approximately 
8 weeks after last dose received.
The EOS for an individual patient is defined as the EOS visit described above, which will 
occur approximately 8 weeks after last dose received. The global EOS is defined as the EOS 
visit of the last patient in the trial performing the EOS. 
A follow-up visit or phone call for SAEs must be performed 8 weeks following 
end-of-treatment visit or early discontinuation, or 8 weeks after last injection of study drug, 
whichever is later. If anaphylactic reactions occur after injection, two more immunogenicity 
samples (at the time of the event and 8 weeks later) need to be taken.
3.2
Rationale of study 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 SCA patients.
A pediatric and young adult population is chosen because those patients are more likely to be 
without significant accumulated, SCA-related co-morbidities and are most likely to benefit 
from the compound’s mechanism of action. Moreover, canakinumab has been widely studied 
in inflammatory diseases involving pediatric populations that encompass the age range 
proposed in this study, with an estimated 528 pediatric patients <1 to 17 years exposed to 
Commercially Confidential Information


Novartis
Confidential
Page 37
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
canakinumab treatment as of 30 June 2017. Inflammatory diseases involving pediatric patients 
for which canakinumab has received health authority approvals include sJIA and CAPS for 
patients ≥2 years and ≥4 years, respectively. Because levels of inflammation tend to increase 
during the course of childhood in SCA patients, this initial, early phase study will focus on 
pediatric and young adult patients of ages 8-20 years to increase the likelihood of detecting 
beneficial effects with an anti-inflammatory intervention.
Stratification is planned for patients at treatment randomization according to presence or 
absence of concurrent hydroxyurea use because this standard-of-care therapy has potential 
therapeutic benefits against the disease, but its practical use in pediatric populations remains 
limited.
High-sensitivity C-reactive protein (hs-CRP) is a marker that directly correlates with long 
term morbidity (van Beers et al 2015) and is part of this study's inclusion criteria. The hs-CRP 
threshold value of ≥1.0 mg/L used in this study's inclusion criteria is based on evidence from 
the literature that the 25-75 percentile value range of hs-CRP across a large, cross-sectional 
African American adolescent population aged 10-15 years is 0.1-1.2 mg/L (Ford et al 2003). 
In contrast, the 25-75 percentile value range of hs-CRP in children with HbSS/HbSβ0thal 
ranged from 1.02-5.3 mg/L (Krishnan et al 2010). Importantly, the sickle cell variant HbSC in 
this study had lower hs-CRP values of 0.3-1.2 mg/L, with correspondingly reduced severity of 
anemia and other clinical manifestations of the disease. In a second report 
(Akohoue et al 2007) serum CRP values of the majority of HbAA adolescents (89%) were 
either <0.5 mg/L or not detectable, while in the steady-state HbSS adolescents, 34% had CRP 
levels ranging between 1-5 mg/L and >50% had CRP concentrations averaging 15.6 mg/L 
(5.7-52.6). Thus, the use of hs-CRP ≥1.0 mg/L in this study's inclusion criteria will ensure that 
enrolled patients have a minimal threshold of inflammation, an important therapeutic target of 
canakinumab.
The rationale for the additional safety visit 8 weeks after the final clinical assessment at 
Week 48 is to monitor for any potential, late appearing AEs after having terminated treatment. 
More information may be found in the Investigator’s Brochure.
The opportunity for continued, open label treatment is provided in this study design to allow 
participants from the placebo-treated arm the option for receiving active treatment and for 
those in the active treatment group to continue on treatment, thus providing additional 
exposure data and evidence for sustained efficacy in this patient population in which 
canakinumab is envisaged as a long term treatment.


Novartis
Confidential
Page 38
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
3.4
Rationale for choice of comparator
3.5
Rationale for choice of background therapy
Not applicable.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 39
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
3.6
Purpose and timing of interim analyses/design adaptations
3.7
Risks and benefits
Canakinumab has not been previously administered with therapeutic intent to patients with 
sickle cell anemia. Therefore, no statement can be made at this time on the actual clinical 
benefits of canakinumab in this patient population. However, given the mechanism of action 
of canakinumab 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 patients with sickle cell anemia.
Sickle cell anemia patients are at increased risk for infection, in part due to functional 
hyposplenism or from undergoing splenectomy (Booth et al 2010). This increased infection 
risk is primarily confined to very young children with the disease and is a major cause of early 
mortality from the disease. The main pathogen of concern is S. pneumoniae, and risk for 
invasive 
streptococcal 
disease 
in 
SCA 
patients 
drops 
markedly 
with 
age. 
Preventative measures are considered the key strategy in management of SCA infection risks. 
Optimal management of asplenic individuals includes life-long penicillin prophylaxis and 
keeping vaccinations up-to-date. Additional preventative measures include meticulous 
attention to hand washing, cooking food thoroughly, keeping perishable foodstuffs 
refrigerated, and avoiding contamination. Monitoring for early detection of infections is also 
important, with a low threshold for use of antibiotics.
Commercially Confidential Information


Novartis
Confidential
Page 40
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Hydroxyurea, approved for SCA in the EU and US, is a mutagenic chemotherapy drug 
associated with bone marrow toxicity that requires close monitoring of blood counts and early 
recognition and treatment of infections. Thus there is precedence for the application of an 
immune suppressive treatment in this patient population.
Overall, the development program with canakinumab 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 and urinary tract infections, in some 
instances serious, with all infections responding to standard therapy. Patients may also 
experience reduction in leukocyte counts and thus will require close monitoring of their 
counts, in particular when receiving concomitant treatment with hydroxyurea. Treatment with 
canakinumab has a theoretically increased risk for opportunistic infections such as 
M. tuberculosis, but the actual frequency remains unknown.
The available toxicology, efficacy, safety, tolerability, overall low incidence of 
immunogenicity (as represented by the presence of treatment-emergent anti-drug antibodies) 
and preliminary 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 
fever and blunt the inflammatory response to infection), blood cells count abnormalities 
(including neutropenia), and development of malignancies, autoimmune manifestations and 
hypersensitivity reactions.
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 and up to 3 months after the last dose. 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 canakinumab which may be serious and/or unforeseen.
3.7.1
Blood sample volumes
A maximum of 189 mL of blood is planned to be collected over a period of 12 months, 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, Section 8.1.
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 8.9 regarding the potential use of residual samples.


Novartis
Confidential
Page 41
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
4
Population
This study will recruit patients ages 8 to 20 years of age (both inclusive) with SCA, including 
hemoglobin SS and hemoglobin S-β0 thalassemia, as determined by family studies, 
hemoglobin or DNA analyses. A total of approximately 60 patients will be randomized to 
participate in the study. Re-evaluation of the sample size based on the variability observed on 
the primary endpoint and the discontinuation rate may be performed when the study 
approaches the first IA and the total enrollment will be capped at 90 (Section 11.7).
The investigator must ensure that all subjects being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order for the study population to be representative of all eligible subjects.
Subject selection is to be established by checking through all inclusion/exclusion criteria at 
screening and first baseline prior to the first injection. 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.
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.
4.1
Inclusion criteria
SCA patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Male and female subjects ages 8-20 years of age (both inclusive) diagnosed with sickle 
cell anemia (HbSS) or sickle beta0 thalassemia (documented by family studies, or analysis 
of either hemoglobin or DNA).
2. Patient’s written informed consent from those ≥18 years of age must be obtained before 
any assessment is performed. Parent or legal guardian’s written informed consent and 
child’s assent, if appropriate, are required before any assessment is performed for patients 
< 18 years of age.
3. Detectable baseline of background or episodic pain measured by daily e-diary over 1 to 
2 weeks during screening period as defined below: 
- Average daily pain score ≥ 1 cm without analgesic use over a period of at least 7 days 
and/or,
- At least one episode of pain requiring analgesic use during a period of up to 14 days.
4. History of ≥2 vaso-occlusive pain episodes in the past year, as defined as pain with no 
other, non-sickle cell identifiable cause that requires analgesia and interferes with the
patient’s normal daily routine.
5. Patients on hydroxyurea therapy need stable dosing >60 days prior to screening without 
signs of hematological toxicity and intention to remain on hydroxyurea therapy throughout 
the initial 6-month treatment period.
6. Screening hsCRP level ≥ 1.0 mg/L.
7. Full immunization status according to local guidelines against pneumococcus.
8. Able to communicate well with the investigator and to understand and comply with the 
requirements of the study.


Novartis
Confidential
Page 42
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
4.2
Exclusion criteria
SCA patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. History of anaphylactic reaction or known hypersensitivity to canakinumab, or any 
component thereof.
2. Past history of invasive serious pneumococcal disease, including sepsis, bacteremia, 
and/or meningitis. 
3. Ongoing or treatment within the past 3 months prior to screening with red blood cell 
transfusion therapy, or have evidence of iron overload requiring chelation therapy.
4. Administration of any other blood products within 3 weeks prior screening visit.
5. Uncontrolled liver disease or renal insufficiency, as defined by the following:
elevated alanine aminotransferase (ALT) ≥ 3x ULN (if ALT at screening is >3x but 
<5x ULN, a re-test will be allowed. If ALT at re-test is <3x ULN and confirmed at 
another re-test, the patient will be eligible for participation). Chronic kidney disease as per 
NKF stages ≥4: eGFR ≤29 mL/min/1.73 m2.
6. Clinically significant, abnormal vital sign data as judged by the investigator and verified 
with repeated testing. 
7. 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.
8. Prior treatment with any biologic drug targeting the immune system within 180 days of 
randomization.
9. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such 
abuse as indicated by the laboratory assays.
10. 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, but not limited to:
a.
Absolute neutrophil count (ANC) <1,500/μl
b. Thrombocytopenia CTCAE v4.03 Grade 1: platelets <LLN (<100.0 x 109/L)
c. Any active or recurrent bacterial, fungal (with exception of onychomycosis) or viral 
infection
d. Presence of human immunodeficiency virus (HIV) infection, active hepatitis B or 
hepatitis C infections based on screening lab results
e. Presence of active or latent tuberculosis (TB) or exposure risk established during 
screening such as, but not exclusively to:
Close contact (e.g., share the same air space in a household or other enclosed 
environment for a prolonged period such as days or weeks, but not minutes or hours), 
with a person with active pulmonary TB disease within the last year, or


Novartis
Confidential
Page 43
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Evidence of TB infection (active or latent) determined by positive QuantiFERON test 
or positive purified protein derivative (PPD) test (≥5 mm induration) at screening or 
within 2 months prior to screening visit, according to national guidelines. If presence 
of TB infection is established then treatment for TB as per national guidelines must 
have been completed prior to randomization and definitive cure has been demonstrated. 
In the absence of national guidelines, the following has been demonstrated: TB has 
been treated adequately by antibiotics, definitive cure can be demonstrated and risk 
factors resulting in TB exposure and contracting have been removed.
11. Live vaccinations within 3 months prior to study drug dosing.
12. Current severe progressive or uncontrolled disease, which in the judgment of the clinical 
investigator renders the patient unsuitable for the trial.
13. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins).
14. 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.
15. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases.
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 by a positive hCG 
laboratory test.
17. Transcranial Doppler ultrasound in the past year or at screening in patients with an 
accessible transtemporal window, demonstrating velocity in middle or anterior cerebral or 
internal carotid artery ≥200 cm/sec.
18. Female of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
the investigational treatment and for up to three months after the last dose. Where basic 
contraception is sufficient for this study, abstinence should be encouraged in a pediatric 
population and if appropriate for sexually mature adolescents and young adult, barrier 
methods should be advised and/or hormonal methods can be prescribed after careful 
evaluation by a physician.
Basic contraception methods include:

Total abstinence from 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 six weeks 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.


Novartis
Confidential
Page 44
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206

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 have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Females within the age range of this study are considered not of child bearing potential if 
they 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.
No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients.
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) for details of contraception requirements for the study.
5.2
Prohibited treatment
Use of the treatments displayed in the table below are NOT allowed after the start of study 
treatment due to the concern for either increased potential immunosuppressant-related 
conditions or for potential impact on efficacy assessments . These are prohibited for the 
duration of the study until 90 days after discontinuation of study drug.


Novartis
Confidential
Page 45
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Table 5-1
Prohibited treatment
Medication
Action to be taken
Biologic drugs targeting the 
systemic immune system (e.g., 
TNFα 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 rescreening
Systemic immune suppressive 
drugs, except for hydroxyurea 
maintained within a stable dosing 
regimen of >60 days prior screening
Discontinue study treatment if these medications are taken for 
more than 3 days. Maintain hydroxyurea at a stable dosing 
regimen throughout trial
Scheduled regular blood 
transfusion therapy
Discontinue from study
5.3
Dietary restrictions and smoking
There are no specific dietary restrictions.
5.4
Other restrictions
Not applicable.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational treatment and control drugs
The investigational drug, ACZ885 (canakinumab) 150 mg and matching placebo liquid vials 
will be prepared by Novartis and supplied to the Investigator as open labeled pack medication.
6.1.1.1
Bio-batch retention samples
Not applicable for this study.
6.1.2
Additional study treatment
No additional study treatment beyond investigational drug and control drug are included in 
this trial.


Novartis
Confidential
Page 46
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
6.2
Treatment arms
Subjects will be assigned to one of the following two treatment arms in a ratio of 1:1.
Study treatments are defined as:
During the blinded period: 

Monthly doses of 300 mg (4 mg/kg for patients ≤ 40 kg) canakinumab s.c.

Monthly doses of placebo to match the administered dose of canakinumab s.c.
During the open label period: 

Monthly doses of 300 mg (4 mg/kg for patients ≤ 40 kg) canakinumab s.c.
6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual subjects by way of a randomization 
number. As stratification is planned for patients at treatment randomization according to 
presence or absence of concurrent hydroxyurea use, two randomization lists will be prepared: 
5101-5190 for stratum 1 (presence of hydroxyurea use); 6101-6190 for stratum 2 (absence of 
hydroxyurea use). There is no minimal or maximal number to which either stratum is 
expected to reach. A longer randomization list is chosen here as the sample size may be 
increased at re-evaluation when the study approaches the first interim analysis (Section 11.7).
The randomization number is only used to identify which treatment the subjects have been 
randomized to receive. The Subject number assigned to a subject at screening remains the 
unique identifier for the subject throughout the study.  For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM.
Subjects enrolled will use sequential subject numbering. There will be no replacement in this 
study, as a dropout rate of 20% is already taken into consideration in the sample size 
estimation.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. The randomization numbers will be generated using the following 
procedure to ensure that treatment assignment is unbiased and concealed from subjects and 
investigator staff. A randomization list will be produced by or under the responsibility of 
Novartis Drug Supply Management using a validated system that automates the random 
assignment of treatment arms to randomization numbers in the specified ratio.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
randomization of subjects.
6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects and investigators will remain 
blinded to study treatment throughout the study, except where indicated below.
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, and odor.


Novartis
Confidential
Page 47
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study:
The unblinded site pharmacist or dedicated unblinded site personnel will assign the treatment 
according to the randomization list. Unblinded site personnel will only be involved in the 
treatment preparation for administration.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Sponsor staff
The following unblinded sponsor roles are required for this study:
Unblinded sample analyst(s) (PK blood)
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.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project at 
the time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.


Novartis
Confidential
Page 48
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Following final database lock all roles may be considered unblinded.
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
Pharmacist and unblinded site staff
UI
UI
UI
UI
Drug Supply and Randomization 
Office
UI
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
UI
All other sponsor staff not identified 
above
B
B
UI
UI
B Remains blinded
UI Allowed to be unblinded at individual patient level
6.5
Treating the subject
ACZ885 will be administered to the subject at the study site via subcutaneous injection, 
followed by a minimum, post-dose monitoring period of 15 minutes to monitor for evidence 
of hypersensitivity reaction to the IMP (e.g., altered vital signs, rash, headache).
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 (treated 
or 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.
6.7
Emergency breaking of assigned treatment code
Emergency unblinding must only be undertaken when it is essential to treat the subject safely 
and efficaciously. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. A complete set of emergency code break cards will be provided to the investigator 
site(s) and a complete set will be available at Novartis. All code break cards must be retained 
until the end of the study and returned to Novartis. They must be stored in a secure place but 
be accessible to the investigator 24 hours per day in case of emergency. The investigator will 
receive a blinded code break card for each subject, with the details of study treatment covered 
by a removable, scratch-off cover. In an emergency, the scratch-off cover can be removed to 
determine the treatment. The scratch-off covers are not to be removed for any reason other 
than an emergency. When the investigator removes the scratch-off cover he/she must note the 


Novartis
Confidential
Page 49
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
date, time, and reason for removing it and retain this information with the case report form 
documentation. The unblinded treatment code must not be recorded on the CRF.
The investigator must also immediately inform the study monitor 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 code break cards at any time in case of emergency.   The investigator will 
need to provide: 

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject 
and, if applicable, whether the subject can continue into the next trial phase.
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 sickle cell 
disease. Patients may receive hydration and analgesics for chronic or episodic pain with 
recording of analgesic type and dosing information in daily diary. Patients are allowed to 
receive acute blood transfusions during the study; such intervention must be captured in the 
CRF.
6.11
Concomitant treatment
Subjects will be maintained on their pre-existing stable medical regimen for treatment of 
preexisting medical conditions, including sickle cell anemia. Common potential concomitant 
medications in this study population are anticipated to include analgesics and stable 
hydroxyurea therapy, defined as an hydroxyurea dosing regimen that remains fixed except for 


Novartis
Confidential
Page 50
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
any adjustments according to hematologic parameters or other standard of care clinical 
monitoring.
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 section of the 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.
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. The study will complete when the last subject 
completes their Study Completion visit, and any repeat assessments associated with this visit 
have been documented and followed-up appropriately by the Investigator.
7.2
Discontinuation of study treatment
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 EOS visit, about 8 weeks after 
the last dosing visit.
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 study and 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.
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

Emergence of the following adverse events:

Serious infections combined with neutropenia CTC grades ≥1 (ANC <1.5 x 109/L)

Confirmed diagnosis of active TB

Onset of any malignancy

Any of the following laboratory abnormalities:

Neutropenia CTCAE v4.03 Grades ≥3: neutrophils <1.0 x 109/L

Thrombocytopenia CTCAE v4.03 Grade 3: platelets <50.0 x 109/L


Novartis
Confidential
Page 51
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206

Use of prohibited treatment as per Table 5-1.

Any other protocol deviation that results in a significant risk to the patient’s safety
The appropriate personnel from the site and Novartis will assess whether 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. 
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because 
they fail to appear for study visits without stating an intention to withdraw), the investigator 
should show "due diligence" by documenting in the source documents steps taken to contact 
the subject, e.g., dates of telephone calls, registered letters, etc.
Subjects who are withdrawn from the study before Week 24 for reasons other than safety or 
lack of efficacy will be replaced on a case-by-case basis.
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 from the study is defined as when a subject:

Does not want to participate in the study anymore and

Does not want any further visits or assessments and

Does not want any further study related contacts and

Does not allow analysis of already obtained biologic material.
In this situation, the investigator must make every effort (e.g., telephone, e-mail, letter) to 
determine the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the 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 discontinue or 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 cannot be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.


Novartis
Confidential
Page 52
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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 can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient's interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee of the early termination of this trial. In addition, the study will be paused if any of 
the following criteria are met, and no further dosing pending a full safety review:

The observed proportion of patients having canakinumab-related serious adverse events 
such as infections, opportunistic infections, hypersensitivity, white blood cell (WBC) or 
platelet count decreases is 20% greater in canakinumab arm compared to placebo arm 
when enrollment is ≥10; when enrollment is below 10, at least 2 more patients with SAEs 
in the active arm than in the placebo arm.

A series of similar, new unexpected serious adverse events considered related to 
canakinumab in more than 3 individuals on active therapy.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
patients must be seen as soon as possible and treated as a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing IRBs/IECs of the early termination of the trial.


Novartis
Confidential
Page 53
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
8
Procedures and assessments
8.1
Assessment schedule
Study Phase
Screening
Randomized Treatment
Open Label Treatment
Post-Treatment Follow-Up
Visit Name Screening Baseline
Randomized treatment
Open label treatment
EOS
Visit Numbers1
1
2
101
102 103 104 105 1062
201
202 203 204 205 206 2072
3013
Study Day(s) -28 to -14 -14 to -1
1
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
225
±3
253
±3
281
±3
309
±3
337
±3
393
±7
Time (post-dose)
-
-
-1h4
0h
-
-
-
-
-
-1h
0h
-
-
-
-
-
-
-
Informed consent
X
Inclusion / Exclusion criteria
S
S
Concomitant therapies
X
X
Medical history/current medical 
conditions
X
Demography
X
Alcohol Test and Drug Screen 
S
S
Tuberculosis status
S
Hepatitis screen
S
HIV screen
S
Pregnancy test
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body height
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulse rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration10
X
X
X
X
X
X
X
X
X
X
X
X
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 54
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Study Phase
Screening
Randomized Treatment
Open Label Treatment
Post-Treatment Follow-Up
Visit Name Screening Baseline
Randomized treatment
Open label treatment
EOS
Visit Numbers1
1
2
101
102 103 104 105 1062
201
202 203 204 205 206 2072
3013
Study Day(s) -28 to -14 -14 to -1
1
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
225
±3
253
±3
281
±3
309
±3
337
±3
393
±7
Time (post-dose)
-
-
-1h4
0h
-
-
-
-
-
-1h
0h
-
-
-
-
-
-
-
PK blood collection5
X
X
X
X
X
Blood collection for IL-1β
X
X
X
X
X
X
X
Immunogenicity
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X9
X9
X9
X9
X9
X9
X9
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oxygen Saturation
X
X
X
X
eDiary (Daily Pain VAS, Fatigue VAS, 
School/Work absence)
X8
X8
X
X
Adverse events
X
X
Serious adverse events
X
X
Study completion information
X
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 55
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
1 Visit structure given for internal programming purpose only
2 The end of each epoch is marked by the completion of the disposition CRF (X99) in the summary CRF section.
3 For patients refusing the open label part or who stop the study early, the EOS will be conducted about 8 weeks after the last dosing.
4 Baseline assessments can be performed on Day -1.
5 The PK samples are taken pre-dose.
6
.
7
8
9 Haptoglobin is not measured in these samples. Haptoglobin will only be measured at screening, randomized treatment period and V201.
10 ACZ885 will be administered to the subject at the study site via subcutaneous injection, followed by a minimum, post-dose monitoring period of 15 minutes to monitor 
for evidence of hypersensitivity reaction to the IMP (e.g., altered vital signs, rash, headache).
11
S Source data only, not captured in the eCRF.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 56
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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 incapable of doing so, in cases where the subject’s representative gives consent (if allowed 
according to local requirements), the subject must be informed about the study to the extent 
possible given his/her understanding. If the subject is capable of doing so, he/she must 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research.  
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.3
Subject screening
Information on what data should be collected for screening failures is outlined in the Site 
Operations Manual.
Commercially Confidential Information


Novartis
Confidential
Page 57
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent. Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.1
Alcohol Test and Drug Screen 
All subjects will be screened for substances of abuse. See the Site Operations Manual for 
details.
8.4.2
Tuberculosis status
Determination of TB status will be required before administration of study treatment and 
should be performed as defined by local guidelines. For those patients in whom the presence 
of TB infection is established, then the TB must be first adequately treated and definitive cure 
demonstrated. 
Any significant findings will be recorded in the "Relevant medical history/Current medical 
conditions" section of the eCRF. 
8.4.3
HIV screen
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a 
second technique available at the laboratory site, e.g., Western blot.
Appropriate counseling will be made available by the Investigator in the event of a positive 
finding. Notification of state and local authorities, as required by law, will be the 
responsibility of the Investigator.
Results will be available as source data and will not be recorded within the CRF.
8.4.4
Hepatitis screen
All subjects will be screened for Hepatitis B and C. See the Site Operations 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 timepoint(s) defined 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.


Novartis
Confidential
Page 58
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
8.5.1
Clinical Outcome Assessments (COAs)
8.5.1.2
eDiary
Pain diaries are commonly used to assess pain symptoms and response to treatment in 
children and adolescents with recurrent and chronic pain, with a recommended assessment 
time frame of at least 3 months (McGrath et al 2008). In SCA patients, daily diaries have been 
shown a more sensitive means of capturing reported pain frequency than through retrospective 
interviews (Porter et al 1998). Furthermore, electronic diaries have been shown in adolescents 
to have additional advantages over the paper format of accuracy as well as compliance in 
recording patient-reported outcomes (McGrath et al 2008). In this study, we will use e-diaries 
to record the following 5 daily outcomes:
a. Pain intensity. Most pain diaries use a simple visual analog scale (VAS) to record severity.
Children with SCA have been shown in numerous studies to reliably self-report pain that is
specifically attributable to sickle cell vaso-occlusion (Shapiro et al 1995; Dampier et al 2002a;
Dampier et al 2004). In this study, pediatric and young adult patients will rate their daily
sickle cell-associated pain intensity once each day in the evening using an 11-point numerical
rating scale from 0 to 10 with higher ratings associated with more intense pain (0 = no pain,
10 = worst pain). Numerical rating scales are a valid and reliable assessment tool and have
been recommended for assessment of pain intensity for both acute (Pagé et al 2012) and
chronic pain (Ruskin et al 2014) in adolescents. In addition, patients noting pain above the
level of 0 will be prompted to provide the approximate duration of their pain (<2hours, 2-6
hours, >6 hours).
b. Fatigue. Similar to pain intensity, a single item measure can be used for accurately
capturing fatigue data in daily diaries, with convergent validity to validated, multiple-item
measures of fatigue (Van Hooff et al 2007). In this study patients will be instructed to answer
the question, “how fatigued do you currently feel?” using an 11-point numerical rating scale
with higher rating associated with more severe fatigue (0 = not at all, 10 = extremely).
c. Interference with daily tasks. Study subjects will rate the extent that their sickle cell pain
kept them from daily activities, such as seeing friends, doing chores, playing, sports, etc.,
using an 11-point numerical rating scale (0 = not at all, 10 = completely).
d. Medication use. Study subjects who respond, ‘yes’ for medication use are instructed to
record the category of pain medication (acetaminophen/paracetamol, NSAID/COX-2 inhibitor,
Narcotic, Other).
e. Absence from school and/or work. Study subjects will answer whether they have missed
any school or job time. (Yes, missed due to SCA; Yes, missed due to other reasons; No, did
not miss; No, but I am not a student/have no job; No school/work today (weekend, break,
holiday, etc.).
Commercially Confidential Information


Novartis
Confidential
Page 59
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Schedule (Section 8.1) detailing when each 
assessment is to be performed.
8.6.1
Blood pressure
Blood pressure (BP) will be measured
8.6.2
Body height
Height will be measured.
8.6.3
Body temperature
Body temperature will be measured.
8.6.4
Body weight

Body weight will be measured

Body mass index (BMI) will be calculated as (body weight (kg) / [height (m)]2)
8.6.5
Clinical Chemistry
Sodium, potassium, magnesium, protein, creatinine, BUN/urea, uric acid, chloride, albumin, 
calcium, alkaline phosphatase, total bilirubin, direct and indirect bilirubin, bicarbonate/HCO3, 
LDH, γ-GT AST, ALT, amylase, lipase, CK, glucose, total cholesterol, triglycerides, LDL, 
HDL, hs-CRP, haptoglobin. 
8.6.6
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differentials and 
reticulocyte count will be measured.
8.6.7
Immunogenicity
To assess potential immunogenicity, serum samples for detection of anti-canakinumab 
antibodies will be collected during the study (see Assessment Schedule).
The instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing, and shipment will be followed.
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.
Immunogenicity analytical method
An ELISA-based method will be used for the detection of potential anti-canakinumab 
antibody formation. The detailed method description to assess immunogenicity will be 
described alongside the bioanalytical raw data of the study in the respective Bioanalytical 
Data Report (BDR).


Novartis
Confidential
Page 60
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
8.6.8
Pulse rate
Pulse rate will be measured
8.6.9
Urinalysis
Dipstick measurements for specific gravity, albumin, protein, glucose and blood will be 
performed. Microscopy, WBC, RBC and sediments will also be assessed in case of an 
abnormal dipstick test.
8.6.10
Pregnancy test
All pre-menopausal women who are not surgically sterile will have pregnancy testing.  
See the Assessment Schedule Section 8.1, for 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.
8.6.11
Physical examination
See Site Operations Manual for details.
8.7
Pharmacokinetics
PK samples will be collected at the time points defined in the Assessment schedule, 
Section 8.1. The instructions outlined in the Site Operations Manual regarding sample 
collection, numbering, processing and shipment will be followed. See Section 8.9 regarding 
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 (PK) samples will be obtained and evaluated in all subjects at all dose levels.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 61
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
zero in summary statistics. The geometric mean will not be reported if the dataset includes 
zero values.
8.8
Other assessments
Commercially Confidential Information


Novartis
Confidential
Page 62
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 63
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
8.9
Use of residual biological samples
Residual blood and urine samples may be used for another protocol specified endpoint.
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 or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section 9.5 for 
an overview of the reporting requirements.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 64
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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 adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and 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 an SAE (see Section 9.2 for definition of SAE) and which
seriousness criteria have been met
5. Action taken regarding investigational treatment.
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 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).


Novartis
Confidential
Page 65
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (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
Serious adverse 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

elective or pre-planned treatment for a pre-existing condition (that is unrelated to the
indication under study and has not worsened since the start of study drug

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 subject or may
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of an 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 


Novartis
Confidential
Page 66
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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 period 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 previously reported 
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 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
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.


Novartis
Confidential
Page 67
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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 Table 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should 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 Table 15-2-Appendix 1. 

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, 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 on the unscheduled local laboratory 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

Thorough follow-up of the liver event should include:

Repeating liver chemistry tests two or three times weekly. Testing should include
ALT, AST, ALP, PT/INR, and γ-GT. 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 retesting can decrease to once a week or less if abnormalities stabilize
or the study drug has been discontinued and the subject is asymptomatic. Retesting
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.


Novartis
Confidential
Page 68
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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 
Section 16-Appendix 2.
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 adverse event (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 also to be reported using the SAE form/CRF. Table 9-1
summarizes the reporting requirements.
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 an 
SAE
For more information on AE and SAE definition and reporting requirements, 
please see Section 9.1 and Section 9.2, respectively.


Novartis
Confidential
Page 69
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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.
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 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. 
Such evaluations 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.
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. 
During the 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 


Novartis
Confidential
Page 70
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
protocol and to Good Clinical Practice, the progress of enrollment, and 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 (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
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 will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the Contract Research Organization (CRO) working on behalf of 
Novartis. The Investigator must certify that the data entered into the Electronic Case Report 
Forms are complete and accurate. After database lock, the investigator will receive copies of 
the 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 schedule and 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.
10.3
Database management and quality control
Cmed review the data entered into the CRFs by investigational staff for completeness and 
accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. 
Site personnel will complete and sign the faxed copy and fax it back to Cmed who will make 
the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.


Novartis
Confidential
Page 71
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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).
Diary data will be entered into an electronic diary by the subject. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis (or a designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to 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.
10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Infection Adjudication Committee
An external, independent Infection Adjudication Committee (IAC) has been formed on a 
program level and will review pertinent data from this trial.
The mission of the canakinumab IAC is to independently and blinding review, evaluate and 
categorize new reports of pre-defined infections as they become available during the conduct 
of this trial.
The members, detailed mission and procedures of the IAC are detailed in the IAC charter 
which is available upon request.
Commercially Confidential Information


Novartis
Confidential
Page 72
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Malignancy Adjudication Committee
An external, independent Malignancy Adjudication Committee (MAC) has been formed on a 
program level and will review pertinent data from this trial.
The mission of the MAC is to independently and blinding review, evaluate and categorize 
reports of malignancy events across all potential indications and therapeutic areas in the 
canakinumab development program.
The members, detailed mission and procedures of the MAC are detailed in the MAC charter 
which is available upon request.
11
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. The key safety and efficacy endpoints will also be reported for 
pediatric (<18 years old) and adult (>=18 years old) cohorts separately per internal SOP 
requirement. Details will be explained in statistical analysis plan document. 
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 all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The primary PD analysis set will include all subjects with available PD data and no protocol 
deviations with relevant impact on PD data. For example, patients missing more than two 
consecutive doses or more during the blinded treatment period will be excluded from the 
primary PD analysis set. The secondary PD analysis set will include all subjects with 
available 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. Subject demographics will 
include age, gender, race, ethnicity, country, height, weight and BMI. Baseline disease 
characteristics include but are not limited to: baseline average daily pain VAS, baseline 
hs-CRP, the number of VOPE in the previous year.
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.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.


Novartis
Confidential
Page 73
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
11.4
Analysis of the primary variable(s)
The primary aim of this study is to assess if inhibition of IL-1β by canakinumab will reduce 
average daily pain in pediatric and young adult patients with sickle cell anemia. 
Statistical analysis plan for this primary endpoint will be described below in details.
11.4.1
Variable(s)
A numerical pain VAS score between 0 and 10 will be recorded by each patient once daily. 
An average daily pain VAS will be calculated for every 4 weeks and the reduction from 
baseline of the 4-week average daily pain VAS will be the primary variable for this study.
11.4.2
Statistical model, hypothesis, and method of analysis
The post-baseline average daily pain VAS will be calculated for each dose from the start of 
the dose till the day before the next dose, i.e. in an averagely 4-week interval (e.g., Week 0-4, 
Week 4-8, etc. depending on the actual dosing days). The baseline average pain VAS will be 
calculated as the average of daily pain scores from screening up to pre-dosing over a period of 
at least 7 days. Reduction from baseline in the average daily pain VAS, i.e., baseline minus 
post-baseline, will be analyzed using a Bayesian model for repeated measures using Proc 
MCMC in SAS (Chen 2011). The model will include baseline average daily pain score as a 
continuous covariate; treatment group, time and hydroxyurea use history (Yes/No) as fixed 
factors. Interactions of time by treatment group and time by baseline covariates will also be 
included in the model. Non-informative priors will be used for the fixed effects and weakly 
informative prior, for the covariance. Unstructured covariance structure will be used and other 
covariance structure will be investigated if there is convergence problem. Interaction of 
hydroxyurea use and treatment group will be explored via visualizations; if substantial 
interaction is suspected it will be further explored by including this interaction term in the 
whole model.
A comparison of canakinumab 300 mg s.c. versus placebo for the period of Week 8-12 is of primary 
interest. Data up to Week 12 will be included in the primary model. Bayesian posterior probabilities
will be used to assess the following PoC criteria as a guidance for decision making
(Fisch et al 2015):
Prob (the reduction of average pain score over the period of Week 8-12 in canakinumab is 
greater than Placebo) > 90%, and
Prob (the reduction of average pain score over the period of Week 8-12 in canakinumab is 
greater than Placebo by 1) > 50%.
The target difference of 1 is chosen based on the literature search on the Minimally Clinical 
Important Difference (MCID) in pain studies (see Section 11.7).
Data up to Week 24 will also be analyzed with the same model specifications when there are 
at least about 50% completers at Week 24 and also upon the study completion. Pain data in 
the open label period when available will also be summarized, visualized and explored in 
Commercially Confidential Information


Novartis
Confidential
Page 74
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
appropriate statistical models, to evaluate the maintenance of the efficacy in patients 
randomized to canakinumab group and/or improvements in patients randomized in placebo 
group. 
11.4.3
Handling of missing values/censoring/discontinuations
For the primary analysis, data for those patients who have received acute blood transfusion(s) 
during the study will be truncated up to the first occurrence of acute blood transfusion, i.e. 
data since the first blood transfusion will be considered as missing. Assuming the occurrence 
of acute blood transfusion being random to this patient population, such missing data are 
considered Missing at Random (MAR). As a supportive analysis, the complete data will be 
analyzed as if the patients did not receive any blood transfusion (Section 11.4.5). 
Early discontinuations not due to lack of efficacy support the assumption of Missing at 
Random (MAR). In such scenarios MMRM remains valid. In the primary analysis for the 
blinded treatment period, if there were any patients who discontinued early due to lack of 
efficacy, LOCF (last observation carried forward) approach will be applied as a sensitivity 
analysis to deal with such missing data.
11.4.4
Sensitivity analyses
An Intention-To-Treat (ITT) analysis will also be explored as a sensitivity analysis to include 
all patients who received at least one study drug treatment (the second PD analysis set), 
if there are patients excluded in the primary PD analysis set, for example those who have 
missed two consecutive dosing or more.
11.4.5
Supportive analyses
As a supportive analysis, all collected data in the double-blinded period will be analyzed in 
the same way as described in Section 11.4.2, without truncation of data due to acute blood 
transfusions. This is to explore the possible impact of such rescue therapy to the treatment 
effect.
Non-convergence of the primary analysis may occur when there is a great amount of truncated 
data due to acute blood transfusion. In that scenario the evaluation of efficacy may focus on 
the analysis of the rate of acute blood transfusion (Section 11.5.4). 
11.5
Analysis of secondary variable(s)
For the double-blinded period, the main analysis on secondary efficacy data, including 
inflammation and hemolysis biomarkers, absence from school/work will also be based on 
truncated data up to the time of the first acute blood transfusion where applicable. Complete 
data will also be summarized and visualized.
11.5.1
Efficacy / Pharmacodynamics
To determine the duration of effects of canakinumab versus placebo on daily pain, the average 
daily pain VAS data after Week 12 will be analyzed, as explained in Section 11.4.2. The daily 
pain data will also be explored using visualizations.


Novartis
Confidential
Page 75
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
11.5.2
Inflammation and hemolysis biomarkers at Week 12
The inflammation biomarkers, including hs-CRP, WBC count, absolute count of blood 
neutrophils and absolute count of blood monocytes, will be summarized and visualized by 
treatment group and visit/time. For each of the inflammation biomarkers, change from 
baseline taken from log transformed values will be analyzed using an MMRM with the log 
baseline value as continuous covariate, treatment group, time, hydroxyurea use history 
(Yes/No) and race as factors. Unstructured covariance structure will be used.
The hemolysis biomarkers, including hemoglobin concentration, reticulocyte count, 
haptoglobin, lactate dehydrogenase, total bilirubin, direct and indirect bilirubin and oxygen 
percent saturation (SaO2), will also be summarized and visualized by treatment group and 
visit/time. The same MMRM approach as for inflammation biomarkers will also be applied 
for each individual hemolysis biomarker with log transformation.
For each of the biomarkers, the difference between canakinumab and placebo groups at 
Week 12 will be presented in terms of ratio of geometric mean because of the log 
transformation.
11.5.3
Absence from school/work
The number of SCA-related days absent from school or work will be derived from eDairy 
records. The data will be summarized and visualized by treatment group and visit/time. 
A negative binomial Generalized Linear Model (GLM) will be fitted for the total number of 
SCA-related days absent from school/work up to Week 24 visit, with treatment group as the 
factor. The difference between canakinumab and placebo groups will be estimated.
11.5.4
Incidence of acute blood transfusion
The occurrence of acute blood transfusions will be summarized as the proportion of patients 
who receive at least one acute blood transfusion and the event rate of acute blood transfusions
per patient during double-blinded period and open-label period separately. 
The proportion of patients who receive at least one acute blood transfusion during the double-
blinded period will be analyzed in a binomial Bayesian model with non-informative prior for 
both groups (neutral prior Beta(1/3, 1/3), (Kerman 2011) and the posterior probability of the 
difference of the two proportions ( placebo – ACZ885) will be presented. 
If the data allows, the recurrent event analysis (at least one patient receiving more than one 
acute blood transfusion), the time to recurrent incidence of acute blood transfusions during the 
double-blinded period will be analyzed via the Andersen-Gill model (Andersen & Gill 1982), 
with treatment and hydroxyurea use as independent variables and time to last blood 
transfusion before study treatment (if available) as a continuous covariate. 
The incidence of acute blood transfusions will also be included in the visualizations of all 
efficacy endpoints where applicable.


Novartis
Confidential
Page 76
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
11.5.5
Safety
Vital signs
All vital signs data will be listed by treatment group, subject and visit/time, and where ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data 
 will be listed by treatment group, subject, and visit/time, and where normal 
ranges are available, abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group 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.
The proportion of patients receiving any rescue medication/therapy post baseline will be 
summarized by group and study period. 
Immunogenicity
All immunogenicity results will be listed by treatment group, subject and visit/time.
11.5.6
Pharmacokinetics
Canakinumab plasma concentration data will be listed by treatment, subject, and 
visit/sampling time point. Descriptive summary statistics will be provided by treatment and 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ 
(lower limit of quantification) which will be reported as zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. The impact of acute blood transfusions on PK 
data may be explored.
11.5.7
Pharmacokinetic / pharmacodynamic interactions
Not applicable.
11.5.8
Other assessments
Not applicable.
Commercially Confidential Information


Novartis
Confidential
Page 77
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
11.6
Analysis of exploratory variables
Commercially Confidential Information


Novartis
Confidential
Page 78
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Commercially Confidential Information


Novartis
Confidential
Page 79
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
11.7
Sample size calculation
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 80
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
11.8
Power for analysis of key secondary variables
Not applicable.
11.9
Interim analyses
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 81
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
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 signatory for 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 safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
Commercially Confidential Information


Novartis
Confidential
Page 82
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.
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.


Novartis
Confidential
Page 83
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
14
References
Ataga KI, Kutlar A, Kanter J, et al (2017) Crizanlizumab for the prevention of pain crises in 
sickle cell disease. N Engl J Med; 376:429-39.
Akohoue SA, Shankar S, Milne GL, et al (2007) Energy expenditure, inflammation, and 
oxidative stress in steady-state adolescents with sickle cell anemia. Pediatr. Res. p. 233-8.
Andersen PK, Gill RD (1982) Cox’s regression model for counting processes: A large sample 
study. Ann Stat.; 10: 1100-20. 
Booth C, Inusa B, Obaro SK (2010) Infection in sickle cell disease: a review. Int J Infect Dis. 
2010; 14:e2-e12.
Cain DM, Vang D, Simone DA, et al (2012) Mouse models for studying pain in sickle 
disease: effects of strain, age and acuteness. Br J Haematol; 156:535-44.
Chen F (2011) The RANDOM statement and more: moving on with PROC MCMC. 
SAS Global Forum Proceedings, p. 334-2011.
Church LD, Cook GP, McDermott MF (2008) Primer: inflammasomes and interleukin 1beta 
in inflammatory disorders. Nat Clin Pract Rheumatol p. 34-42.
Dampier C, Ely B, Brodecki D, et al (2002a) Characteristics of pain management at home in 
children and adolescents with sickle cell disease by using diary self-reports. J Pain; 3(6):461-470.
Dampier C, Ely E, Brodecki D, et al (2002b) Home management of pain in sickle cell disease: 
a daily diary study in children and adolescents. J. Pediatr. Hematol. Oncol. p. 643-7.
Dampier C, Ely E, Eggleston B, et al (2004) Physical and cognitive-behavioral activities used 
in the home management of sickle pain: a daily diary study in children and adolescents. 
Pediatr Blood Cancer p. 674-8.
Dampier C, Lieff S, LeBeau P, et al (2010) Health-related quality of life in children with 
sickle cell disease: a report from the Comprehensive Sickle Cell Centers Clinical Trial 
Consortium. Pediatr Blood Cancer p. 485-94.
Dinarello (1999) IL-18: A Th1-inducing, proinflammatory cytokine and new member of the 
IL-1 family.  J Allergy Clin Immunol. 103:11-24.
Dutra FF, Alves LLS, Rodrigues D, et al (2014) Hemolysis-induced lethality involves 
inflammsome activation by heme. PNAS; 111:E4110-8.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 84
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Fisch R, Jones I, Jones J, et al (2015) Bayesian Design of Proof-of-Concept Trials. 
Therapeutic Innovation & Regulatory Science; 49:155-162.
Ford ES, Giles WH, Myers GL, et al (2003) C-reactive protein concentration distribution 
among US children and young adults: findings from the National Health and Nutrition 
Examination Survey, 1999-2000. Clin. Chem. p. 1353-7.
Heeney MM, Hoppe CC, Abboud MR, et al (2016) A multinational trial of Prasugrel for 
sickle cell vaso-occlusive events. New Engl J Med; 374:625-35.
Jacob E, Duran J, Stinson J, et al (2013) Remote monitoring of pain and symptoms using 
wireless technology in children and aadolescents with sickle cell disease. J Am Assoc Nurse 
Pract; 25:42-54.
Kanavaki I, Makrythanasis P, Lazaropoulou C, et al (2012) Adhesion molecules and high-
sensitivity C-reactive protein levels in patients with sickle cell beta-thalassasemia. Eur J Clin 
Invest; 42:27-33.
Kauf TL, Coates TD, Huazhi L, et al (2009) The cost of health care for children and adults 
with sickle cell disease. Am J Hematol; 84:323-7.
Kaul TL & Gram H (2011) Anti-IL-β antibody-based therapy to ameliorate inflammation and 
vaso-occlusion in sickle cell disease. ASH Annual Meeting Abstracts;118:848.
Kerman J (2011) Neutral noninformative and informative conjugate beta and gamma prior 
distributions. Electron. J. Statist. 5: 1450-70.
Kieser M and Friede T (2003). Simple procedures for blinded sample size adjustment that do 
not affect the type I error rate. Statist. Med.; 22:3571-81.
Krishnan S, Setty Y, Betal SG, et al (2010) Increased levels of the inflammatory biomarker C-
reactive protein at baseline are associated with childhood sickle cell vasocclusive crises. Br. J. 
Haematol. p. 797-804.
Lagunju I, Sodeinde O, Brown B, et al (2014) Transcranial Doppler ultrasonography in 
children with sickle cell anemia: Clinical and laboratory correlates for elevated blood flow 
velocities. J Clin Ultrasound p. 89-95.
Maikler VE, Broome ME, Bailey P, et al (2001) Childrens’ and Adolescents’ use of diaries 
for sickle cell pain. J Soc Ped Nurses:6:161-69.
McGrath PJ, Walco GA, Turk DC, et al (2008) Core outcomes domains and measures for 
pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations. J 
Pain; 9:771-783.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 85
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Mohammed FA, Mahdi N, Sater MA, et al (2010) The relation of C-reactive protein to vaso-
occlusive crisis in children with sickle cell disease. Blood Cells, Molec Dis; 45:293-96.
Morel JC, Parkc CC, Woods JM, et al (2001) A Novel Role for Interleukin-18 in Adhesion 
Molecule Induction through NFkB and Phosphatidylinositol (PI) 3-Kinase-dependent Signal 
Transduction Pathways  J Biol Chem; 276:37069–75.
Nouraie M, Lee JS, Zhang Y, et al (2013) The relationship between the severity of hemolysis, 
clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and 
Europe. Haematologica. p. 464-72.
Qari MH, Dier U, Mousa SA (2012) Biomarkers of inflammation, growth factor and 
coagulation activation in patients with sickle cell disease. Clin Applied Thromb/Hemostas; 
18:195-200.
Pagé MG, Katz J, Stinson J, et al (2012) Validation of the numerical rating scale for pain 
intensity and unpleasantness in pediatric acute postoperative pain: sensitivity to change over 
time. J Pain p. 359-69.
Panepinto JA, Torres S, Bendo CB, et al (2014) PedsQLtm Multidimensional Fatigue Scale in 
sickle cell disease: feasibility, reliability and validity. Pediatr Blood Cancer; 61:171-7.
Pashankar FD, Manwani D, Lee MT, et al (2015) Hydroxyurea Improves Oxygen Saturation 
in Children With Sickle Cell Disease. J. Pediatr. Hematol. Oncol. p. 242-3.
Porter LS, Gil KM, Sedway JA, et al (1998) Pain and stress in sickle cell disease: an analysis 
of daily pain records. Int J Behav Med p. 185-203.
Rigante D, Frediani B, Cantarini L (2016) A comprehensive overview of the hereditary 
periodic fever syndromes. Clin Rev Alleg Immunol; https://doi.org/10.1007/s12016-016-
8537-8.
Ruskin D, Lalloo C, Amaria K, et al (2014) Assessing pain intensity in children with chronic 
pain: convergent and discriminant validity of the 0 to 10 numerical rating scale in clinical 
practice. Pain Res Manag p. 141-8.
Saraf SL, Molokie RE, Nouraie M, et al (2014) Differences in the clinical and genotypic 
presentation of sickle cell disease around the world. Paediatr Respir Rev p. 4-12.
Setty BN, Stuart MJ, Dampier C, et al (2003) Hypoxaemia in sickle cell disease: biomarker 
modulation and relevance to pathophysiology. Lancet p. 1450-5.
Shapiro BS, Dinges DF, Orne EC, et al (1995) Home management of sickle cell-related pain 
in children and adolescents: Natural history and impact on school attendance. Pain; 61:139-
144.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 86
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Van Beers EJ, Yang Y, Raghavochari N, et al (2015) Iron, inflammation, and early death in 
adults with sickle cell disease. Circ Res; 116:298-306.
Van Hooff ML, Geurts SA, Kompier MA, et al (2007) "How fatigued do you currently feel?" 
Convergent and discriminant validity of a single-item fatigue measure. J Occup Health p. 224-34.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 87
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT > 3 × ULN and TBL > 2 × ULN without initial 
increase in ALP to > 2 × ULN
ALT elevation with coagulopathy

ALT > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT elevation accompanied by symptoms

ALT > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, 
or eosinophilia
Isolated ALT elevation

ALT > 8 × ULN

5 x ULN < ALT ≤8 x ULN

3 x ULN < ALT ≤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 elevation with coagulopathy
ALT elevation accompanied by 
symptoms
Isolated ALT elevation > 8 × ULN
Jaundice
Isolated ALT 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
Isolated ALT elevation > 3 to ≤5 × 
ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance


Novartis
Confidential
Page 88
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
Criteria
Actions required
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or discontinuation

Hospitalize if clinically 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, γ-GT, 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


Novartis
Confidential
Page 89
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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.)


Novartis
Confidential
Page 90
Amended Protocol Version v05 (Clean)
Protocol No. CACZ885X2206
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 or abdominal 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 
diagnostic procedures (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
CACZ885
CACZ885X2206
A multiple-dose, subject- and investigator-blinded, 
placebo-controlled, parallel design study to assess the 
efficacy, safety and tolerability of ACZ885 (canakinumab) 
in pediatric and young adult patients with sickle cell 
anemia
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
FINAL
Release date:
20-JUN-2019
Number of pages:
23
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


Novartis
For business use only
Page 2
SAP Amendment 1
CACZ885X2206
Commercially Confidential Information


Novartis
For business use only
Page 3
SAP Amendment 1
CACZ885X2206
Table of contents
Table of contents..................................................................................................................3
List of tables.........................................................................................................................4
1
Introduction..........................................................................................................................6
1.1
Scope of document...................................................................................................6
1.2
Study reference documentation................................................................................6
1.3
Study objectives .......................................................................................................7
1.3.1
Primary objective.....................................................................................7
1.3.2
Secondary objectives...............................................................................7
1.3.3
Exploratory objectives.............................................................................8
1.4
Study design and treatment......................................................................................8
2
First interpretable results (FIR)..........................................................................................10
3
Interim analyses .................................................................................................................10
4
Statistical methods: Analysis sets......................................................................................11
5
Statistical methods for Pharmacokinetic (PK) parameters ................................................12
5.1
Variables ................................................................................................................12
5.2
Descriptive analyses...............................................................................................12
5.3
Statistical model, assumptions and hypotheses......................................................12
6
Statistical methods for Pharmacodynamic (PD) parameters .............................................12
6.1
Primary objective...................................................................................................12
6.1.1
Variables................................................................................................12
6.1.2
Descriptive analyses ..............................................................................13
6.1.3
Statistical model, assumptions and hypotheses.....................................13
6.2
Secondary objectives..............................................................................................15
6.2.1
Reduction from baseline of the 4-week average daily pain up to 
Week 24.................................................................................................15
6.2.2
Novel metrics of pain measurement......................................................15
6.2.3
Inflammation and hemolysis biomarkers ..............................................15
6.2.4
Absence from school/work....................................................................16
6.2.5
Incidence of acute blood transfusion.....................................................16
6.3
Exploratory objectives ...........................................................................................16
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 4
SAP Amendment 1
CACZ885X2206
7
Statistical methods for safety and tolerability data............................................................19
7.1
Variables ................................................................................................................19
7.2
Descriptive analyses...............................................................................................19
7.2.1
Subject demographics and other baseline characteristics......................19
7.2.2
Treatment...............................................................................................19
7.2.3
Vital signs..............................................................................................19
7.2.4
ECG evaluations....................................................................................19
7.2.5
Clinical laboratory evaluations..............................................................19
7.2.6
Adverse events.......................................................................................20
7.2.7
Immunogenicity.....................................................................................20
7.2.8
Pregnancy test........................................................................................20
7.3
Graphical presentation ...........................................................................................20
8
Statistical methods for Biomarker data..............................................................................21
9
Reference list .....................................................................................................................23
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................11
Table 8-1
Information on biomarker parameters to be reported in the CSR .........21
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 5
SAP Amendment 1
CACZ885X2206
Commercially Confidential Information


Novartis
For business use only
Page 6
SAP Amendment 1
CACZ885X2206
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 “CACZ885X2206”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This SAP has been developed using Clinical Trial Protocol version v05 dated 22 March 2018.


Novartis
For business use only
Page 7
SAP Amendment 1
CACZ885X2206
1.3
Study objectives
1.3.1
Primary objective
Primary objective
Endpoints related to primary objective

To determine the effect of ACZ885 versus
placebo on daily pain experienced by sickle
cell anemia patients

Reduction of average daily pain VAS over
the period of Week 8 to 12 as compared to
baseline levels
1.3.2
Secondary objectives
Secondary objectives
Endpoints related to secondary objectives

To determine the duration of effects of
canakinumab versus placebo on daily pain
experienced by SCA patients

Reduction of average daily pain VAS over 4-
week intervals up to Week 24 as compared
to baseline levels

To determine the effect of canakinumab
versus placebo on laboratory markers of
inflammation

Week 12 versus baseline of:

Serum hs-CRP

WBC count

Absolute counts of blood neutrophils

Absolute counts of blood monocytes

To determine the effect of canakinumab
versus placebo on laboratory and
functional markers of hemolysis

Week 12 versus baseline of:

Hemoglobin concentration

Reticulocyte count

Haptoglobin

LDH

Bilirubin (total, direct and indirect)

Oxygen percent saturation (SaO2)

To determine the effect of canakinumab
versus placebo on SCA-related days
missed from school or work

Number of days absent from school or work
due to pain as recorded by daily eDiary

To determine the effect of canakinumab
versus placebo on reducing the need for
acute blood transfusion

The rate of SCA-related acute transfusion

To assess the safety, including
immunogenicity, and tolerability of
canakinumab in patients with SCA as
measured by adverse events (AEs)

Adverse events in patients taking ACZ885
compared to placebo up to a total of 56
weeks treatment.

To determine the PK of ACZ885 in SCA
patients

Serial serum PK determinations in patients
with SCA


Novartis
For business use only
Page 8
SAP Amendment 1
CACZ885X2206
1.3.3
Exploratory objectives
1.4
Study design and treatment
This study (Figure 1-1) is an ambulatory-based study of 24 weeks duration followed by an 
additional 24-week open label phase and is subject- and investigator-blinded, randomized, 
placebo-controlled, parallel group, non-confirmatory to assess the clinical efficacy of 
canakinumab administered s.c. in 6 injections given 28 days apart. This study will randomize 
approximately 60 pediatric and young adult patients (targeting 48 completers of 8 to 20 years 
old) diagnosed with SCA who experience chronic or episodic pain, i.e., detectable average 
daily pain level over a 1-2 week screening period and at least 2 painful episodes in the past 
year of likely sickle cell etiology requiring analgesia and interfering with the patient’s normal 
daily routine.
Commercially Confidential Information


Novartis
For business use only
Page 9
SAP Amendment 1
CACZ885X2206
Figure 1-1
Study Design
Acceptable prior established background therapy includes hydroxyurea and supportive 
antibiotic and analgesic medications. Patients will be randomized to either ACZ885 treatment 
or placebo treatment in a 1:1 ratio, with treatment stratification based on concurrent 
hydroxyurea therapy (yes/no).
Subjects who are prematurely withdrawn from the study for reasons other than safety or lack 
of efficacy will be replaced on a case-by-case basis. Re-screening of subjects may be allowed 
under the guidance of the Sponsor’s medical expert.
For each subject, there will be a maximum 28-day screening period that will include 
recording of daily pain frequency and intensity by e-diary for at least 1 week.
Subjects who meet the eligibility criteria at screening will undergo evaluation of full baseline 
clinical and biomarker assessments prior to first dose administration. The screening daily 
pain results will be used to derive the baseline value for this primary endpoint of average 
daily pain. All safety evaluations must be available prior to dosing and results must 
demonstrate all eligibility criteria are met. Enrolled subjects will be randomized at a 1:1 ratio 
to receive treatment with either canakinumab or placebo with stratification based on 
concurrent hydroxyurea therapy. On Day 1, monthly s.c. dosing with canakinumab will begin 
at 4 mg/kg for patients weighing ≤ 40 kg and 300 mg for all other patients. Patients in the 
placebo treatment arm will be injected in a like manner with placebo. All patients will return 
to the study centers for safety checks on a monthly basis when they will receive treatment 
with either canakinumab or placebo. Additionally, patients will undergo clinical and 
laboratory evaluations as outlined in the Assessment Schedule (Section 8.1 within the 
protocol) every 28 days. The final blinded dosing will take place on Week 20, followed by 
blinded clinical assessments at Week 24. Patients from both study arms are then offered 
optional, open label monthly dosing of ACZ885 for an additional 24 weeks (Weeks 24-48), 
with clinical outcomes again assessed according to the Assessment schedule. Patients return 
for the end of study (EOS) visit at Week 56. For patients who choose not to participate in the 
optional, open label portion of the study, or for patients stopping treatment early for any other 
reason, an EOS visit will occur approximately 8 weeks after last dose received.
The EOS for an individual patient is defined as the EOS visit described above, which will 
occur approximately 8 weeks after last dose received. The global EOS is defined as the EOS 
visit of the last patient in the trial performing the EOS.
The mechanism of action of canakinumab is anticipated to effect relatively rapid attenuation 
of intravascular inflammation and associated daily pain and fatigue. Twelve-week data from 
the first 24 enrolled patients and the full recruitment will be assessed in two separate interim 


Novartis
For business use only
Page 10
SAP Amendment 1
CACZ885X2206
analyses for safety and study treatment effects upon clinical markers of pain and intravascular 
inflammation. To better demonstrate treatment effects upon additional key outcomes such as 
frequency of vaso-occlusive pain events and reductions in work or school absences, another 
assessment will occur when all enrolled patients have successfully achieved 24 weeks of 
treatment.
A follow-up visit or phone call for SAEs must be performed 8 weeks following end-of-
treatment visit or early discontinuation, or 8 weeks after last injection of study drug, 
whichever is later. If anaphylactic reactions occur after injection, two more immunogenicity 
samples (at the time of the event and 8 weeks later) need to be taken.
2
First interpretable results (FIR)
3
Interim analyses 
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 11
SAP Amendment 1
CACZ885X2206
4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The PD analysis set will include all subjects with available PD data, who received any study 
drug and no critical protocol deviations with relevant impact on PD data. Subjects missing 
two consecutive doses or more during the blinded treatment period will be excluded from the 
primary PD analysis set. All PDs will be captured as such within the database.
The analysis sets and protocol deviation codes are related as follows:
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
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
INCL02
Written Informed Consent Form not obtained
Yes
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis sets
INCL02
Written Informed Consent Form not obtained
Yes
Subjects are excluded from primary PD analysis in case of these 
PDs:
Exclude subject from 
primary PD analysis set
TRT01
Missing two consecutive doses or more during 
blinded treatment period
To be assessed on a case 
by case basis
If updates to this table are needed, an amendment to the SAP needs to be implemented prior
to DBL.
The primary efficacy endpoint (average daily pain VAS) and key safety endpoints (AE/SAEs, 
blood chemistry and hematology) will be reported for pediatric (<18 years old) and adult 
(>=18 years old) cohorts separately per Novartis internal SOP requirement in the final CSR. 
Selected tables and figures for these data will therefore be summarized split by pediatric/adult 
subgroup as well as overall.
Commercially Confidential Information


Novartis
For business use only
Page 12
SAP Amendment 1
CACZ885X2206
All tables and figures will be summarized split by concurrent hydroxyurea subgroup (with 
and without) as well as overall. If the number of subjects without HU use is less than 10% of 
the total, the summary for this subgroup is not needed; and vice versa. 
5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
PK samples will be collected at the time points defined in the Assessment schedule.
Pharmacokinetic (PK) samples will be obtained and evaluated in all subjects at all dose levels.
5.2
Descriptive analyses
5.3
Statistical model, assumptions and hypotheses
No inferential statistical analyses are to be completed on the PK data.
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary aim of this study is to assess if inhibition of IL-1β by canakinumab will reduce 
average daily pain in pediatric and young adult patients with sickle cell anemia.
6.1.1
Variables 
A numerical pain VAS score between 0 and 10 will be recorded by each patient once daily.
The post-baseline average daily pain VAS will be calculated for each dose from the start of
the dose till the day before the next dose, i.e., in an averagely 4-week interval (e.g., Week 0-4,
Week 4-8, etc. depending on the actual dosing days). 
For double-blind period, the baseline average pain VAS will be calculated as the average of 
daily pain scores from screening up to pre-dosing over a period of at least 7 days. 
For subjects who switched from placebo to ACZ885 treatment in open-label, the average of 
Week 20-24 will be used as the new baseline to assess the effect of ACZ885 treatment in 
open-label period. For subjects who continued on ACZ885 treatment, the original baseline 
will continue to be used. 
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 13
SAP Amendment 1
CACZ885X2206
The reduction from baseline of the 4-week average daily pain VAS for Week 8-12 will be the 
primary variable for this study.
6.1.2
Descriptive analyses
Summary statistics for PD variables will include sample size (N), mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum and maximum. A 
geometric mean will not be reported if the dataset includes zero values. 
Summary statistics for the reduction from baseline in the 4-week average daily pain VAS will 
be provided by treatment, visit/time; and also by hydroxyurea use history.
6.1.3
Statistical model, assumptions and hypotheses
Reduction from baseline in the average daily pain VAS, i.e., baseline minus post-baseline, 
will be analyzed using a Bayesian model for repeated measures using Proc MCMC in SAS 
(Chen 2011). The model will include baseline average daily pain score as a continuous 
covariate; treatment group, time and hydroxyurea use history (Yes/No) as fixed factors. 
Interactions of time by treatment group and time by baseline covariates will also be included 
in the model. Non-informative priors will be used for the fixed effects and weakly 
informative prior, for the covariance. Unstructured covariance structure will be used and 
other covariance structure will be investigated if there is convergence problem. Posterior 
mean with 90% credible interval will be presented over time. Interaction of hydroxyurea use 
and treatment group will be explored graphically, please see section 6.1.3.3; if substantial 
interaction is suspected it will be further explored by including this interaction term in the 
whole model.
A comparison of canakinumab 300 mg s.c. versus placebo for the period of Week 8-12 is of 
primary interest. Data up to Week 24 will be included in the primary model. Bayesian
posterior probabilities will be used to assess the following PoC criteria as a guidance for 
decision making (Fisch et al 2015):

Prob (the reduction of average pain score over the period of Week 8-12 in
canakinumab is greater than Placebo) > 90%, and,

Prob (the reduction of average pain score over the period of Week 8-12 in
canakinumab is greater than Placebo by 1) > 50%.
The target difference of 1 is chosen based on the literature search on the Minimally Clinical 
Important Difference (MCID) in pain studies. 
At the first interim analysis, one futility rule will be assessed. The criterion is defined as:

Prob (the reduction of average pain score over the period of Week 8-12 in
canakinumab is less than Placebo) > 80%.
The dosing regimen of concurrent hydroxyurea remain fixed during the study except for any 
adjustment according to hematologic parameters or other standard of care clinical monitoring
(protocol Section 6.11). The number of patients with hydroxyurea dose adjustment during the 
study period (especially up to week 12 and up to week 24) will be summarized. Impact on the 
results for this group may be explored if the proportion of such patients is high.  
6.1.3.1
Handling of missing data/censoring/discontinuations
Handling of missing daily pain VAS entries for the calculation of average pain score


Novartis
For business use only
Page 14
SAP Amendment 1
CACZ885X2206
At each visit from Day 1, the 4-week average daily pain VAS score will be calculated based 
on available daily pain data. The proportion of missing data will first be derived at subject 
level for each time interval and then be summarized at treatment group level to evaluate 
possible impact on data interpretations. Information about reasons for missing data if 
available will be included in this consideration.
Handling of missing average pain score
Early discontinuations not due to lack of efficacy support the assumption of Missing at 
Random (MAR). In such scenarios the longitudinal model described earlier remains valid. In 
the primary analysis for the blinded treatment period, if there were any patients who 
discontinued early due to lack of efficacy, LOCF (last observation carried forward) approach 
will be explored. If the reasons of missing are known, other imputation methods such as 
multiple imputations may be considered. 
Handling of acute blood transfusion
Data for those patients who have received interventional acute blood transfusion(s) during the 
study will be truncated up to the first occurrence of interventional acute blood transfusion, i.e.,
data since the first interventional blood transfusion will be considered as missing. Data will 
be truncated at daily level first before the derivation of 4-week average score, i.e. eDiary data 
from the first date of blood transfusion during the double-blind treatment period will be 
truncated and then primary endpoint of 4-week average score will be derived using the 
truncated data. Assuming the occurrence of acute blood transfusion being random to this 
patient population, such missing data are considered Missing at Random (MAR). 
As a supportive analysis, the complete data will be analyzed as if the patients did not receive 
any blood transfusion.
6.1.3.2
Model checking procedures
In case of convergence issues, the covariance matrix that best fit the data will be chosen.
Diagnostic plots will be provided.
6.1.3.3
Graphical presentation of results
The reduction from baseline in 4-week average pain score will be visualized in Mean (SEM) 
plots over time by treatment group.
Interaction of hydroxyurea use and treatment will be explored in Mean (SEM) plots in 
reduction from baseline in 4-week average pain score over time by HU use and group.
Daily pain VAS data for individual patients will be visualized over time using heat map.
6.1.3.4
Supportive analyses
As a supportive analysis, all collected data in the double-blinded period will be analyzed in 
the same way as described in Section 6.1.3, without truncation of data due to acute blood 
transfusions. This is to explore the possible impact of such interventional therapy to the 
treatment effect.
Non-convergence of the primary analysis may occur when there is a great amount of 
truncated data due to acute blood transfusion. In that scenario the evaluation of efficacy may 
focus on the analysis of the rate of acute blood transfusion.


Novartis
For business use only
Page 15
SAP Amendment 1
CACZ885X2206
6.2
Secondary objectives
For the double-blinded period, the main analysis on secondary efficacy data, including 
inflammation and hemolysis biomarkers, absence from school/work will also be based on 
truncated data up to the time of the first acute blood transfusion where applicable. Complete 
data will also be summarized and visualized.
6.2.1
Reduction from baseline of the 4-week average daily pain up to Week 
24
As described in Section 6.1.3, the reduction from baseline of the 4-week average daily pain 
VAS for Week 12-16, Week 16-20 and Week 20-24 will be evaluated in the same model. 
Pain data in the open label period when available will also be summarized, visualized in plots 
as well as overlaid individual plots over time by treatment group and explored in appropriate 
statistical models, to evaluate the maintenance of the efficacy in patients randomized to 
canakinumab group and/or improvements in patients randomized in placebo group.
6.2.2
Novel metrics of pain measurement 
In addition to the average daily pain the following additional novel metrics will be calculated 
and summarized for the period of pre-dosing and every 4-week interval after dosing:

Mean daily pain (MDP) calculated by obtaining the mean of daily pain scores

Proportion of pain-free days (PPFD) calculated as the number of days without pain
divided by total number of reported days. Pain-free is to be defined as a reported pain
intensity score of <1.

p90 , the 90th percentile of daily pain scores which provides an indication of the
upper levels of pain experienced, indicating the point where 10% of pain scores are
above the statistic

Standard Deviation (SD) of daily pain scores

Coefficient of variation (CV) of daily pain scores (calculated as SD/mean).
6.2.3
Inflammation and hemolysis biomarkers
The inflammation biomarkers, including hs-CRP, WBC count, absolute count of blood 
neutrophils and absolute count of blood monocytes along with hemolysis biomarkers, 
including hemoglobin concentration, reticulocyte count, haptoglobin, lactate dehydrogenase, 
total bilirubin and oxygen percent saturation (SaO2), will be summarized and visualized in 
Mean (SEM) plots over time by treatment group, visit/time and subgroup (with and without 
concurrent hydroxyurea). Overlaid individual plots will also be presented. 
For each inflammation and hemolysis biomarker (excluding oxygen percent saturation 
(SaO2)), change from baseline on the log transformed values will be analyzed using an 
MMRM with the log baseline value as continuous covariate, treatment group, time, 
hydroxyurea use history (Yes/No) and race as factors. 
For oxygen percent saturation (SaO2), change from baseline will be analyzed using an 
MMRM with the baseline value as continuous covariate, treatment group, time, hydroxyurea 
use history (Yes/No) and race as factors. 


Novartis
For business use only
Page 16
SAP Amendment 1
CACZ885X2206
For both models, data up to Week 24 will be included and unstructured covariance structure 
will be used. In case of convergence issues, the covariance matrix that best fit the data will be 
chosen. 
For each of the biomarkers, the difference between canakinumab and placebo groups at Week 
12 and 24 will be presented in terms of ratio of geometric mean because of the log 
transformation.
6.2.4
Absence from school/work
The number of SCA-related days absent from school or work will be derived from eDiary
records. The data will be summarized and visualized in Mean (SEM) plots over time (with 4-
week interval) by treatment group, visit/time and subgroup. The total number of SCA-related 
absence days up to Week 24 visit will also be summarized by treatment group. A negative 
binomial Generalized Linear Model (GLM) will be fitted for the total number of SCA-related 
days absent from school/work up to Week 24 visit, with treatment group as the factor. The 
difference between canakinumab and placebo groups will be estimated.
6.2.5
Incidence of acute blood transfusion
Medical review will determine whether the blood transfusion is for disease acute intervention 
or for prophylactic purpose. The occurrence of acute blood transfusions will be summarized 
as the proportion of patients who receive at least one acute blood transfusion and the event 
rate of acute blood transfusions per patient, by study period, group and reason of transfusion.
The proportion of patients who receive at least one acute blood transfusion for disease acute 
intervention during the double-blinded period will be analyzed in a binomial Bayesian model 
with non-informative prior for both groups (neutral prior Beta(1/3, 1/3), (Kerman 2011) and 
the posterior probability of the difference of the two proportions (ACZ885 - placebo) will be 
presented.
If the data allows, the recurrent event analysis (at least one patient receiving more than one
acute blood transfusion), the time to recurrent incidence of acute blood transfusions during 
the double-blinded period will be analyzed via the Andersen-Gill model (Andersen & Gill 
1982), with treatment and hydroxyurea use as independent variables and time to last blood 
transfusion before study treatment (if available) as a continuous covariate.
The incidence of acute blood transfusions will also be included in the visualizations of all
efficacy endpoints where applicable.
6.3
Exploratory objectives
Commercially Confidential Information


Novartis
For business use only
Page 17
SAP Amendment 1
CACZ885X2206
Commercially Confidential Information


Novartis
For business use only
Page 18
SAP Amendment 1
CACZ885X2206
Commercially Confidential Information


Novartis
For business use only
Page 19
SAP Amendment 1
CACZ885X2206
7
Statistical methods for safety and tolerability data
7.1
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics (including a summary of 
Genotype), baseline characteristics (including baseline average pain score, baseline hsCRP, 
hydroxyurea use history, number of VOPE in previous year if available) and treatment 
information.
7.2
Descriptive analyses
7.2.1
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. Subject demographics will 
include age, gender, race, ethnicity, country, height, weight and BMI. Baseline disease 
characteristics include but are not limited to: baseline average daily pain VAS, baseline hs-
CRP, the number of VOPE in the previous year.
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.
7.2.2
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and subject.
The proportion of patients receiving any rescue medication/therapy post baseline will be 
summarized by group and study period.
7.2.2.1
Hydroxyurea Use
Hydroxyurea dose may need to be adjusted during the study in consideration of certain blood 
counts including neutrophils and platelets. The number of patients with a hydroxyurea dose 
change will be summarized.
7.2.3
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time, and where ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment, visit/time and subgroup.
7.2.4
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, visit/time and subgroup.
7.2.5
Clinical laboratory evaluations
All laboratory data
(including the exploratory variables, cholesterol subtypes and 
triglycerides from lipid panel) will be listed by treatment group, subject, and visit/time, and 
where normal ranges are available, abnormalities will be flagged. Shift tables will be 
provided by treatment, visit/time and subgroup.


Novartis
For business use only
Page 20
SAP Amendment 1
CACZ885X2206
Urine albumin-creatinine ratio (ACR), one renal function parameter, will be analyzed in the 
same way as for hsCRP.  
7.2.6
Adverse events
All information obtained on adverse events will be displayed by treatment group 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.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than X% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class 
and preferred term on the safety set population. The value of the cutoff value X will be 
decided with the team when disclosure tables are prepared.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
Inferential statistical methods may be explored should a reasonable number of 
incidences/patients with SAEs be reported.
7.2.7
Immunogenicity
All immunogenicity results will be listed by treatment group, subject and visit/time.
7.2.8
Pregnancy test
All pregnancy test results for women will be listed by patient and visit.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created, including reference lines for lower and upper limits for normal ranges where ranges 
are present within the data.


Novartis
For business use only
Page 21
SAP Amendment 1
CACZ885X2206
8
Statistical methods for Biomarker data
Commercially Confidential Information


Novartis
For business use only
Page 22
SAP Amendment 1
CACZ885X2206
Commercially Confidential Information


Novartis
For business use only
Page 23
SAP Amendment 1
CACZ885X2206
9
Reference list
Andersen PK, Gill RD (1982) Cox’s regression model for counting processes: A large sample 
study. Ann Stat.; 10: 1100-20.
Chen F (2011) The RANDOM statement and more: moving on with PROC MCMC. SAS 
Global Forum Proceedings, p. 334-2011.
Fisch R, Jones I, Jones J, Kerman J, Rosenkranz GK and Schmidli H (2015) Bayesian Design 
of Proof-of-Concept Trials. Therapeutic Innovation & Regulatory Science; 49: 155-162.
Kerman J (2011) Neutral noninformative and informative conjugate beta and gamma prior 
distributions. Electron. J. Statist. 5: 1450-70.
Commercially Confidential Information
Commercially Confidential Information