Conditions: Juvenile Psoriatic Arthritis Enthesitis-related Arthritis
Keywords: JIA JPsA ERA Secukinumab ILAR Arthritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 86
Healthy volunteers: no

Brief summary:
This was a double-blind, placebo-controlled, event-driven randomized withdrawal study to investigate the efficacy and safety of secukinumab treatment in the Juvenile Idiopathic Arthritis (JIA) categories of Juvenile Psoriatic Arthritis (JPsA) and Enthesitis-related Arthritis (ERA). The study was divided into 3 parts (plus a post-treatment follow-up period) consisting of open-label, single-arm active treatment in Treatment Periods 1 and 3 and a randomized, double-blind, placebo controlled, event-driven withdrawal design in Treatment Period 2

Detailed description:
TP1: All eligible subjects entered TP1 to receive 12-weeks of open-label secukinumab at a dose predicted to achieve secukinumab serum levels equivalent to adults administered a 150 mg dose regimen. Secukinumab was administered s.c. weekly for the first 4 weeks (Baseline, Weeks 1, 2, 3, 4) and then every 4 weeks thereafter. Clinical response (JIA ACR 30) was assessed at Week 12. Responders advanced to TP2 and non-responders exited the trial (early termination visit and entered into the Post-treatment follow-up period).

TP2: Subjects who were a responder (JIA ACR 30) at Week 12 entered the double-blind withdrawal TP2 and were randomized 1:1 to either secukinumab or placebo on that visit and then every 4 weeks, until either experiencing a disease flare or completion of TP2. TP2 was event driven and was planned to be closed when 33 subjects experienced a disease flare as per JIA definition. Alternatively, the study could be closed when all subjects reached the total study duration of 104 Weeks and therefore subjects who did not experience a disease flare remained in TP2 for the duration of the study and completed the study without entering into TP3

TP3: Subjects experiencing a disease flare in TP2 immediately entered TP3 to receive openlabel secukinumab every 4 weeks until total study duration of 104 weeks for that subject was achieved.

Post-treatment follow-up: The post-treatment follow-up period (lasting 12 weeks from the last study drug administration) was required for all subjects, unless they qualified and entered the secukinumab extension trial. All subjects were expected to participate in the post-treatment follow up period, except for those entering the extension study.

Arms:
arm 1: secukinumab (AIN457 - pre-filled syringe) for patients with a minimum American college of Rheumatology (ACR) 30 response in Treatment Period 1 arm 2: placebo comparator (matched to secukinumab treatment) for patients with a minimum American college of Rheumatology (ACR) 30 response in Treatment Period 1

Interventions: intervention 1: secukinumab intervention 2: placebo
Intervention descriptions: intervention 1: secukinumab is a high-affinity fully human monoclonal anti-human antibody that targets IL-17A and neutralizes activity. intervention 2: Matched placebo to AIN457 for use in the double blind Treatment Period 2

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 2  (04 Jun 2020) ...................................................................................................11
Amendment 1 (April 2017) ......................................................................................................11
Protocol summary..............................................................................................................13
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................19
2.1
Primary objective(s)...............................................................................................19
2.2
Secondary objective(s)...........................................................................................19
19
2.4
Objectives and related endpoints...........................................................................20
3
Investigational plan ...........................................................................................................23
3.1
Study design...........................................................................................................23
3.2
Rationale for study design .....................................................................................25
3.3
Rationale for dose/regimen, route of administration and duration of treatment....26
3.4
Rationale for choice of comparator .......................................................................28
3.5
Purpose and timing of interim analyses/design adaptations..................................29
3.6
Risks and benefits..................................................................................................29
4
Population..........................................................................................................................30
4.1
Inclusion criteria ....................................................................................................30
4.2
Exclusion criteria...................................................................................................31
5
Treatment...........................................................................................................................33
5.1
Study treatment......................................................................................................33
5.1.1
Investigational and control drugs..........................................................33
5.1.2
Additional treatment..............................................................................34
5.2
Treatment arms......................................................................................................34
5.3
Treatment assignment and randomization.............................................................34
5.4
Treatment blinding.................................................................................................35
5.5
Treating the patient................................................................................................35
5.5.1
Patient numbering .................................................................................35


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5.5.2
Dispensing the study drug.....................................................................36
5.5.3
Handling of study and additional treatment..........................................37
5.5.4
Instructions for prescribing and taking study treatment........................37
5.5.5
Permitted dose adjustments and interruptions of study treatment ........39
5.5.6
Rescue medication ................................................................................39
5.5.7
Concomitant medication .......................................................................40
5.5.8
Prohibited medication ...........................................................................41
5.5.9
Emergency breaking of assigned treatment code..................................43
5.6
Study Completion and Discontinuation.................................................................44
5.6.1
Study completion and post-study treatment..........................................44
5.6.2
Discontinuation of study treatment .......................................................44
5.6.3
Withdrawal of informed consent...........................................................45
5.6.4
Loss to follow-up ..................................................................................46
5.6.5
Early study termination by the sponsor.................................................46
6
Visit schedule and assessments .........................................................................................46
6.1
Information to be collected on screening failures..................................................56
6.2
Patient demographics/other baseline characteristics .............................................56
6.3
Treatment exposure and compliance .....................................................................56
6.4
Efficacy..................................................................................................................56
6.4.1
JIA ACR response criteria ....................................................................57
6.4.2
Physician’s Global Assessment of disease activity (VAS)...................58
6.4.3
Parent’s/patient’s Global Assessment of subject’s overall well-
being (VAS) ..........................................................................................58
6.4.4
Childhood Health Assessment Questionnaire (CHAQCopyright).............58
6.4.5
Active joint count..................................................................................58
6.4.6
Joint counts with limitation of motion ..................................................59
6.4.7
C-reactive Protein (CRP) ......................................................................59
6.4.8
Tender and Swollen Joint Count...........................................................59
60
6.4.10
Assessment of Uveitis due to JIA .........................................................60
6.4.11
Total dactylitis count.............................................................................60
6.4.12
Total enthesitis count ............................................................................60
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62
63
6.4.20
Juvenile Arthritis Disease Activity Score (JADAS).............................63
63
6.4.22
Inactive Disease status ..........................................................................64
64
64
6.5
Safety.....................................................................................................................64
6.5.1
Physical examination ............................................................................65
6.5.2
Vital signs..............................................................................................65
6.5.3
Height and weight .................................................................................65
6.5.4
QuantiFERON TB-Gold test or PPD skin test......................................65
6.5.5
Laboratory evaluations..........................................................................66
6.5.6
Electrocardiogram (ECG) .....................................................................67
6.5.7
Pregnancy and assessments of fertility .................................................67
6.5.8
Tolerability of secukinumab .................................................................68
6.5.9
Immunogenicity ....................................................................................68
6.5.10
Appropriateness of safety measurements..............................................69
6.6
Other assessments..................................................................................................69
6.6.1
Resource utilization...............................................................................69
6.6.2
Pharmacokinetics ..................................................................................69
71
71
7
Safety monitoring..............................................................................................................72
7.1
Adverse events.......................................................................................................72
7.2
Serious adverse events...........................................................................................73
7.2.1
Definition of SAE .................................................................................73
7.2.2
SAE reporting........................................................................................74
7.3
Liver safety monitoring .........................................................................................75
7.4
Renal safety monitoring.........................................................................................76
7.5
Reporting of study treatment errors including misuse/abuse ................................76
7.6
Pregnancy reporting...............................................................................................77
8
Data review and database management.............................................................................77
8.1
Site monitoring ......................................................................................................77
8.2
Data collection.......................................................................................................78


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8.3
Database management and quality control............................................................78
8.4
Data Monitoring Committee..................................................................................79
8.5
Adjudication Committee........................................................................................79
9
Data analysis......................................................................................................................80
9.1
Analysis sets ..........................................................................................................80
9.2
Patient demographics and other baseline characteristics.......................................81
9.3
Treatments .............................................................................................................81
9.4
Analysis of the primary variable(s) .......................................................................81
9.4.1
Variable(s).............................................................................................81
9.4.2
Efficacy variables..................................................................................82
83
9.4.4
Safety variables .....................................................................................84
9.5
Interim analyses.....................................................................................................85
9.6
Sample size calculation..........................................................................................85
10 Ethical considerations........................................................................................................86
10.1
Regulatory and ethical compliance........................................................................86
10.2
Informed consent procedures.................................................................................86
10.3
Responsibilities of the Investigator and IRB/IEC .................................................87
10.4
Publication of study protocol and results...............................................................87
11 Protocol adherence ............................................................................................................87
11.1
Protocol Amendments ...........................................................................................88
12 References (available upon request)..................................................................................89
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................91
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................95
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................98
16 Appendix 4: Weight ranges: recommended maximum sample blood volume per 
blood draw.........................................................................................................................99
17 Appendix 5: Physician’s global assessment of disease activity (VAS) ............................99
18 Appendix 6: Childhood Health Assessment Questionnaire (CHAQ) .............................100
19 Appendix 7: ILAR classification criteria ........................................................................102
20 Appendix 8: ACR definition of flare for JIA ..................................................................103
21 Appendix 9: ACR response criteria.................................................................................104
22 Appendix 10: Criteria for deﬁning clinical inactive disease ...........................................105
106
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List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 5-1
Prohibited medication ...........................................................................41
Table 6-1
Assessment schedule.............................................................................49
62
63
Table 6-4
IG sample log........................................................................................69
Table 6-5
PK sample log .......................................................................................70
71
71
Table 7-1
Treatment Errors ...................................................................................77
Table 13-1
Reference ranges for systolic and diastolic blood pressures and 
pulse. .....................................................................................................93
Table 13-2
Recommended dimensions for blood pressure cuff bladders ...............94
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................95
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...95
Table 15-1
Specific Renal Alert Criteria and Actions.............................................98
Table 16-1
Weight range: Recommended maximum blood volume drawn per 
visit, and per 4 week period ..................................................................99
108
List of figures
Figure 3-1
Study design..........................................................................................25
Figure 3-2
2000 CDC growth chart (median weight and 5 to 95% range).............27
Figure 3-3
Simulated values for average concentration over the dosing interval
(Cavg) by weight based on RA patients................................................28


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List of abbreviations
ACR
American College of Rheumatology 
ADA
Anti-drug antibody 
AE
Adverse Event
AG
Aktien Gesellschaft
Alb
Albumin
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANA
Antinuclear antibody
ANCOVA
Analysis of covariance
AS
Ankylosing Spondylitis
AST
Aspartate Aminotransferase
BDR
Bioanalytical data report
BP
Blood pressure
Cavg
Average concentration 
CDC
Center for Disease Control and Prevention
CDER
Center for Drug Evaluation and Research
CFR
US Code of Federal Regulations 
CHAQ
Childhood Health Assessment Questionnaire
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CRO
Contract Research Organization
CRP
C-reactive Protein
CS
Corticosteroid
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DDE
Direct data entry
DMARD
Disease modifying anti-rheumatic drug
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicine Agency
ERA
Enthesitis-Related Arthritis
 
FAS
Full analysis set
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
hCG
Human Chorionic Gonadotropin


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HDL
High-density lipoprotein
HIV
Human Immunodeficiency Virus
HLA
Human leukocyte antigen
IA
Interim Analysis
IB
Investigators Brochure
IBD
Inflammatory bowel disease
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
Immunogenicity
IL
Interleukin
ILAR
International League of Associations for Rheumatology
IN
Investigator Notification
INH
isonicotinylhydrazide
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
Intrauterine system
JADAS
Juvenile Arthritis Disease Activity Score
JIA
Juvenile Idiopathic Arthritis
JPsA
Juvenile Psoriatic Arthritis
LDL
Low-density lipoprotein
LFT
Liver function test 
LLOQ
Lower level of quantification
MedDRA
Medical dictionary for regulatory activities 
MTX
Methotrexate
NSAID
Non-steroidal anti-inflammatory drug
OC/RDC
Oracle Clinical/Remote Data Capture
PCR
Polymerase chain reaction
PFS
Prefilled Syringe
PK
Pharmacokinetics
PPD
Purified protein derivative
PsA
Psoriatic Arthritis
PRO
Patient Reported Outcome
PRN
As required
PSW
Premature subject withdrawal
PUVA
Photochemotherapy
QTcF
QTc Interval by Fridericia’s equation


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RA
Rheumatoid Arthritis
RBC
Red blood cell
REB
Research Ethics Board
RF
Rheumatoid Factor
RU
Healthcare Resource Utilization
SAE
Serious Adverse Event
s.c.
Subcutaneous
sCr
Serum creatinine
SGOT
Serum glutaminc oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SI
Sacroiliac (joint)
SJC
Swollen Joint Count
SNP
Single Nucleotide Polymorphism
SpA
Spondyloarthropathy (or spondyloarthritis)
SSZ
Sulfasalazine
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TBL
Serum total bilirubin
TD
Study Treatment Discontinuation
tid
Twice daily
TJC
Tender Joint Count
TNF
Tumor Necrosis Factor
Tx
Treatment
ULN
Upper limit of normal
UK
United Kingdom
US
United States
UV
Ultraviolet
VAS
Visual Analogue Score
WBC
White blood cell
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort 
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at the 
point of care.
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Study Period
A portion of the study which serves a specific purpose. Typical periods 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition is 
consistent with US Code of Federal Regulations (CFR) 21 Section 312.3 
and is synonymous with “investigational new drug” or “investigational 
medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
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/subjects 
with established disease and in those with newly-diagnosed disease.
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Randomization number
A unique identifier assigned to each randomized patient, corresponding to 
a specific treatment arm assignment
Source Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper.
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study related 
contact, and does not allow analysis of already obtained biologic material


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Amendment 2 (04 Jun 2020)
Amendment rationale 
The reason for this amendment is to adapt the protocol to COVID 19 pandemic/epidemic 
related challenges and the potential impact on the conduct of clinical trials
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  
Section 5.5.2 is updated to include text allowing for shipment of IMP to the patient’s home 
during a major health care disruption (e.g., COVID 19 pandemic/epidemic). Section 5.5.4 also 
includes this language with the addition of guidance on collecting pregnancy test for patients 
where IMP is shipped to the patient’s home and how to report the home administration. 
Additional clarifications for instances where the IMP is shipped to the patient’s home are 
added to Section 6 and Section 6.3.
Other minor points have been updated or corrected as well to further optimize the clinical trial 
protocol. 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
This amended protocol is considered non-substantial as it includes measures in 
response/relation to the pandemic/epidemic COVID 19 situation and will not be submitted to 
IRB/IEC approval prior to implementation in line with the guidance from multiple health 
authorities worldwide.
The changes herein does not affect the main Global Model Informed Consent.  Sites are 
required to submit for approval an additional Informed Consent that takes into account 
delivery of IMP directly to a participant’s home and home administration.
Summary of previous amendments 
Amendment 1 (April 2017)
Amendment rationale
At the time of this amendment no subjects have been randomized in the study. No change to 
the study population is proposed by this amendment 
This protocol amendment is issued for the following reason:
1. To clarify and correct errors in the ILAR diagnostic criteria detailed in Appendix 7.  




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Protocol summary
Protocol number
CAIN457F2304
Title
A three-part randomized, double-blind, placebo-controlled study to 
investigate the efficacy and safety of secukinumab treatment in Juvenile 
Idiopathic arthritis subtypes of psoriatic and enthesitis-related arthritis 
Brief title
Secukinumab safety and efficacy in JPsA and ERA
Sponsor and Clinical 
Phase
Novartis Pharma AG
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to demonstrate the efficacy and safety of 
secukinumab treatment in children ≥2 to < 18 years of age with active ERA
(Enthesitis-Related Arthritis) and JPsA (Juvenile Psoriatic Arthritis) 
categories of JIA (Juvenile Idiopathic Arthritis) and to demonstrate the 
sustained efficacy of secukinumab by using a flare prevention design in a 
double-blind placebo control treatment withdrawal part of the trial. 
Additionally, this study will evaluate predicted pediatric doses to achieve 
secukinumab level equivalency of adult 150 mg dosing
Primary Objective(s) 
To demonstrate that the time to flare in Treatment Period 2 is longer with 
secukinumab for combined ERA and JPsA groups than with placebo
Secondary 
Objectives
1.
To evaluate the effect of secukinumab treatment for all patients and 
each JIA category in Treatment Period 1 up to Week 12 (end of 
Treatment period 1) with respect to:

JIA ACR (American College of Rheumatology) 30/50/70/90/100 and 
inactive disease status 

Each JIA ACR core component 

Change from baseline Juvenile Arthritis Disease Activity Score 
(JADAS) 

Total enthesitis count

Total dactylitis count
2. To evaluate withdrawal effect of secukinumab treatment for all patients 
and each JIA category during and at the end of Treatment Period 2 with 
respect to:

JIA ACR 30/50/70/90/100 and inactive disease status 
3. To evaluate Pharmacokinetics (PK) of secukinumab and confirm the 
predicted dose in Treatment Period 1 
4. To evaluate the safety/tolerability and immunogenicity of Secukinumab
Study design
This is a double-blind, placebo-controlled, event-driven randomized 
withdrawal study to investigate the efficacy and safety of secukinumab 
treatment in the JIA categories of JPsA and ERA. The study is divided into 3 
parts (plus a post-treatment follow-up period) consisting of open-label, 
single-arm active treatment in Treatment Periods 1 and 3 and a randomized, 
double-blind, placebo controlled, event-driven withdrawal design in 
Treatment Period 2.
Population
Male and female patients aged from ≥2 years to < 18 years who are 
diagnosed with either enthesitis-related arthritis (ERA) based on fulfilling the 
ILAR (International League of Associations for Rheumatology) JIA 


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classification criteria or JPsA based on fulfilling a modified ILAR JIA 
classification criteria and who are naïve to biologic treatments.
Key Inclusion criteria
1. Males and females ≥2 years old and < 18 years old at the time of 
screening.
2. Confirmed diagnosis of ERA according to the ILAR classification criteria 
or JPsA according to the modified ILAR classification criteria that must 
have occurred at least 6 months prior to Screening.
3. Active disease (ERA or JPsA) defined as having both: 

≥ 3 active joints (swollen or if not swollen must be both tender and 
limited range of motion) at Baseline.

≥1 site of active enthesitis at Baseline or documented by history 
4. Inadequate response (≥ 1 month) or intolerance to ≥ 1 NSAID (Non-
Steroidal Anti-inflammatory Drug) 
5. Inadequate response (≥ 2 months) or intolerance to ≥ 1 DMARD (Disease 
Modifying Anti-rheumatic Drugs)
6. No concomitant use of second line agents such as disease-modifying 
and/or immunosuppressive drugs will be allowed with the exception of 
the following agents which must remain at stable dose during trial 
Treatment Periods 1 and 2.

Stable dose of methotrexate (maximum of 20 mg/ m2 BSA (body 
surface area)/ week) for at least 4 weeks prior to the baseline visit, 
and folic/folinic acid supplementation (according to standard medical 
practice of the center)

Stable dose of SSZ (Sulfasalazine) (ERA patients only) < 50 
mg/kg/day with max of 3000 mg/day for at least 4 weeks prior to the 
baseline visit

Stable dose of an oral corticosteroid (CS) at a prednisone equivalent 
dose of < 0.2 mg/kg/day or up to 10 mg/day maximum, whichever is 
less, for at least 7 days prior to baseline

Stable dose of no more than 1 NSAID for at least 1 week prior to 
baseline
7. Negative QuantiFERON (QF) test. Negative Purified Protein Derivative 
(PPD) test is also acceptable if either required by local guidelines or if 
the patient is < 5 years of age. A positive PPD is defined as > 15mm 
induration for children > 4 years and > 10mm for children < 4 years.
Key Exclusion 
criteria
1. Use of other investigational drugs within 4 weeks or 5 half-lives of 
Baseline, or until the expected pharmacodynamic effect has returned to 
baseline, whichever is longer.
2. History of hypersensitivity to any of the study drugs or its excipients or to 
drugs of similar chemical classes.
3. Subjects who have ever received biologic immunomodulating agents, 
including but not limited to TNFα (Tumor Necrosis Factor alpha) 
inhibitors, T-cell costimulatory, Anti-IL6 (interleukin), Anti-IL1, cell-
depleting therapies including but not limited to anti-CD20 (e.g., 
alemtuzumab, anti-CD4, anti-CD5, anti-CD3, and anti-CD19), 
secukinumab or other biologic drugs directly targeting IL-17 or IL-17 
receptor or any investigational immunomodulating agent.
4. Subjects taking any non-biologic DMARD except for MTX (Methotrexate) 
(or sulfasalazine [SSZ] for ERA patients only).
5. Patients fulfilling any ILAR diagnostic JIA category other than ERA or 
JPsA.


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6. Patients taking medications prohibited by the protocol.
7. Any intramuscular/intravenous/intra-articular corticosteroid treatment 
within 4 weeks before baseline.
8. Active or recurrent bacterial, fungal or viral infection including known 
infection with Human Immunodeficiency Virus (HIV), Hepatitis B, and 
Hepatitis C at baseline.
9. History or evidence of active tuberculosis (TB) or evidence of Latent TB 
(positive QuantiFERON or PPD at screening) but unwilling or unable to 
complete a minimum of 4 weeks of latent TB treatment before initiating 
treatment with secukinumab. 
10.Pregnant or nursing (lactating) females, where pregnancy is defined as 
the state of a female after conception and until the termination of 
gestation, confirmed by a positive hCG (human chorionic gonadotropin) 
laboratory test.
11.Female patients (< 18 years of age) of childbearing potential (menarchal 
or becoming menarchal during the study) who do not agree to 
abstinence or, if sexually active, do not agree to the use of contraception 
as defined in the protocol.
Study treatment
Investigational treatment

Secukinumab 150mg/1mL, liquid formulation provided in 1 mL PFS 
(Pre-filled syringe)

Secukinumab 75mg/0.5mL, liquid formulation provided in 0.5 mL 
PFS 
Reference treatment

Placebo, liquid formulation in a 1 mL and 0.5 mL PFS
Efficacy 
assessments

JIA ACR 30, 50, 70, 90 and 100 response criteria

Physician’s Global Assessment of disease activity (VAS) (Visual 
Analogue Score)

Parent’s/patient’s Global Assessment of subject’s overall well-being (VAS 
included within CHAQ©)

Childhood Health Assessment Questionnaire (CHAQ©)

Active joint count

Joint count with limited range of motion

CRP (C-Reactive Protein) (local)

Inactive disease status
 
 

JADAS score

Total dactylitis count

Total enthesitis count
 


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Key safety 
assessments

Adverse events/serious adverse events (AE/SAE)

Electrocardiogram (ECG)

Laboratory evaluations

Immunogenicity
Other assessments

Secukinumab levels
Data analysis
The primary objective for Treatment Period 2 of the study is to show 
superiority of Secukinumab over placebo regarding the primary variable in 
Treatment Period 2.
The following statistical hypothesis will be tested once the required number 
of flares has been observed and the study has been stopped:
H0: 1-SA N(t) ≥ 1- SPla(t) 
HA: 1-SA N(t) < 1- SPla(t)
at each time point t, with SAIN(t) and SPla(t) being the survivor functions in the 
Secukinumab and placebo treatment group at time t.
The two treatment groups will be compared using a one-sided stratified 
Logrank test with the stratification factor of JIA category (ERA or JPsA) at 
the 2.5% level of significance. Hazard ratios and their associated 95% 
confidence intervals will be estimated based on a Cox proportional hazards 
model with treatment and stratification factor as explanatory variables.
Safety analyses will include summaries of AEs, laboratory measurements, 
and vital signs.
Key words
JIA, JPsA, ERA, Secukinumab, ILAR


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1
Introduction
1.1
Background 
Juvenile idiopathic arthritis (JIA) represents a heterogeneous group of chronic idiopathic 
arthritides of at least 6 weeks duration which presents in children less than 16 years of age.  
These conditions have variable clinical presentations and prognoses, variable age of onset, 
and are a major cause of morbidity. The reported prevalence and incidence of JIA varies 
widely. The prevalence in Europe ranges from 0.2 to 2.0 per 1000 children, and in the US 
(United States), the prevalence has been reported to be approximately 0.45 per 1000 children.  
The International League of Associations for Rheumatology (ILAR) classification criteria 
(Petty et al 2004) identify the following seven JIA categories characterized by different 
clinical presentations: 

Polyarticular (Rheumatoid Factor (RF) positive); 

Polyarticular (RF negative); 

Oligoarticular; 

Juvenile psoriatic Arthritis (JPsA); 

Enthesitis-related Arthritis (ERA) and;

Systemic

Undifferentiated
Of the seven JIA categories, Juvenile Psoriatic Arthritis (JPsA) and Enthesitis Related 
Arthritis 
(ERA) 
represent 
a 
spondyloarthropathy 
(SpA) 
similar 
to 
the 
adult 
spondyloarthropathies of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) 
respectively.
Juvenile psoriatic arthritis (JPsA) is an inflammatory arthritis which can present with or 
without psoriasis skin involvement and accounts for approximately 5 to 10% of the total JIA 
population. The current ILAR classification criteria for JPsA include two distinct groups of 
patients; one clinically similar to JIA oligoarthritis and the other clinically similar to the adult 
spondyloarthritis condition of PsA (Horneff 2009, Martini 2003, Martini 2012). Those with an 
oligoarthritis-like condition usually present at a young age (2 to 4 years old) with asymmetric 
oligoarthritis, are at risk for the development of iridocyclitis, and are frequently ANA 
(Antinuclear antibodies) positive. Those with a more adult PsA-like condition usually present 
at a later age (> 6-9 years old) with a lower extremity arthritis, enthesitis and, in a minority of 
patients, axial involvement, and are often HLA-B27 positive. (Human Leukocyte Antigen)
Enthesitis-related arthritis (ERA) is a clinically heterogeneous group including some who 
have predominantly enthesitis, enthesitis and arthritis, juvenile ankylosing spondylitis, or 
inflammatory bowel disease-associated (IBD) arthropathy. ERA accounts for approximately 
3%–11% of JIA. 
ERA has a strong genetic predisposition as evidenced by a positive family history and the 
high frequency of the presence of HLA-B27 in affected patients. The hallmarks of the disease 
are pain, stiffness, and eventual loss of mobility of the back, similar to adult ankylosing 


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spondylitis. ERA should be suspected in any child with chronic arthritis of the axial and 
peripheral skeleton, enthesitis (inflammation at points where tendons insert to bone), and 
Rheumatoid Factor (RF) and Anti-nuclear antibody (ANA) seronegativity. Peripheral arthritis, 
also similar to adult AS, usually affecting few joints of the lower extremity, precedes axial 
involvement, and arthritis of the sacroiliac joints may take years to develop.  Unlike adults 
with AS, the arthritis in children with ERA can be very aggressive and lead to hip 
replacement more often than in adult AS patients. Radiographic changes of the sacroiliac joint 
include joint space narrowing, erosions, sclerosis, osteoporosis of the pelvis, and fusion (a late 
finding).
In 2011, the American College of Rheumatology (ACR) established JIA treatment guidelines 
which are applicable to all JIA categories, including the spondyloarthropathies JPsA and ERA 
(Beuckelman et al 2011). The guidelines aim to quickly control active inflammation and 
patient symptoms and to prevent/minimize disease and/or treatment-related morbidities (e.g. 
growth disturbances, joint damage, and functional limitations).    In general, the treatment 
goal is to target controlling the inflammation with NSAIDs (Non-steroidal anti-inflammatory 
drugs), corticosteroids as intraarticular injections, DMARDs (Disease modifying anti-
rheumatic drugs) and biologic agents either as monotherapy or in combination with other 
therapies (DMARD and/or NSAID).  Successful management requires careful long-term 
monitoring of disease activity and willingness to adjust treatments as necessary to achieve and 
maintain the lowest level of disease activity.
Secukinumab (AIN457) is a high-affinity fully human monoclonal anti-human antibody that 
targets IL-17A and neutralizes activity.  Secukinumab treatment has demonstrated significant 
and clinically meaningful efficacy in treating adults with ankylosing spondylitis (AS) and 
psoriatic arthritis (PsA), both approved indications. 
The adult AS and PsA secukinumab data support the proposed secukinumab study in children 
with similar pediatric spondyloarthritic conditions: ERA and JPsA. This study will investigate 
secukinumab treatment in children ≥ 2 to < 18 years of age with active JPsA or ERA JIA 
using a pediatric dose equivalent to the adult 150mg dose.  To ensure children with a more 
SpA-like condition (Martini 2012) are not excluded, the ILAR diagnostic criteria for JPsA are 
modified NOT to exclude those who are:

HLA–B27-positive male beginning after the 6th birthday; 

those who have AS, ERA, sacroiliitis with Inflammatory Bowel Disease (IBD), reactive 
arthritis (Reiter’s syndrome), or acute anterior uveitis, or a history of one of these 
disorders in a first-degree relative.
This 2-year study consists of 3 parts plus a post-treatment follow-up period: The initial 
Treatment Period 1 will entail open-label secukinumab administered subcutaneously every 
week for the first 4 weeks (loading dose period) and at Week 8. Responders (minimum JIA 
ACR30 response) at the end of Treatment Period 1 (Week 12) will enter into Treatment 
Period 2 and be randomized 1:1 at Week 12 to either continue secukinumab or begin placebo 
in a blinded fashion every 4 weeks. Non-responders will not be dosed and will undergo an end 
of study visit on the same day and enter the Post-treatment follow-up period.  Treatment 
Period 2 will continue until 33 patients experience a disease flare (as per American College of 
Rheumatology (ACR) flare definition). Patients experiencing a flare and those who remain (in 


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Treatment Period 1 or 2) when Treatment Period 2 completes will enter Treatment Period 3 to 
receive open-label secukinumab every 4 weeks until week 100. A total study duration of 104 
weeks at the patient level is reached. A Post-treatment follow-up visit is performed 12 weeks 
after last study treatment administration for all patients unless the patient enters the extension 
trial.  
All patients who successfully complete the study (104 weeks) will be eligible to continue 
secukinumab treatment in an extension trial.  
1.2
Purpose 
The purpose of this study is to demonstrate the efficacy and safety of secukinumab treatment 
in children ≥2 to <18 years of age with active ERA and JPsA categories of JIA and to 
demonstrate the sustained efficacy of secukinumab by using a flare prevention design in a 
double-blind placebo control treatment withdrawal part of the trial. Additionally, this study 
will evaluate predicted pediatric doses to achieve secukinumab level equivalency of adult 
150mg dosing. 
2
Study objectives and endpoints
2.1
Primary objective(s)
To demonstrate that the time to flare in Treatment Period 2 is longer with secukinumab for 
combined ERA and JPsA groups than with placebo.
2.2
Secondary objective(s)
1. To evaluate effect of secukinumab treatment for all patients and each JIA category in 
Treatment Period 1 up to Week 12 (end of Treatment period 1) with respect to:

JIA ACR 30/50/70/90/100 and inactive disease status 

Each JIA ACR core component 

Change from baseline Juvenile Arthritis Disease Activity Score (JADAS) 

Total enthesitis count

Total dactylitis count
2. To evaluate withdrawal effect of secukinumab treatment for all patients and each JIA 
category during and at the end of Treatment Period 2 with respect to:

JIA ACR 30/50/70/90/100 and inactive disease status 
3. To evaluate Pharmacokinetics (PK) of secukinumab and confirm the predicted dose in 
Treatment Period 1 
4. To evaluate the safety/tolerability and immunogenicity of Secukinumab


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2.4
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
OBJECTIVE
Endpoint Title, Description and 
Reporting Time Frame for 
analysis and Unit of Measure
Stat 
Analysis Section
Primary
To demonstrate that the time to flare in  
Treatment Period 2 is longer with 
secukinumab for combined ERA and 
JPsA groups than with placebo
Time to disease flare (active vs. 
control). Flare definition (see 
Appendix 8)
Section 9.4.1
Timeframe: Treatment Period 2 
Secondary
1. To evaluate the effect of 
secukinumab treatment for all 
patients and each JIA category in 
Treatment Period 1 up to Week 12 
Section 9.4.2


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(end of Treatment Period 1) with 
respect to:

JIA ACR 30/50/70/90/100 and 
inactive disease status 

JIA ACR 30/50/70/90/100 (see 
Appendix 9)

inactive disease status

Each JIA ACR core component 
JIA ACR core components

Change from baseline JADAS 
score
JADAS score

Total enthesitis count
Total enthesitis count

Total dactylitis count
Total dactylitis count
Timeframe: Treatment Period 1
2. To evaluate  withdrawal effect of 
secukinumab treatment for all 
patients and each JIA category 
during and at the end of Treatment 
Period 2 with respect to:

JIA ACR 30/50/70/90/100 and 
inactive disease status 

JIA ACR 30/50/70/90/100 (see 
Appendix 9)

inactive disease status
Timeframe: Treatment Period 2
3. To evaluate PK of secukinumab and 
confirm the predicted dose 
Secukinumab serum 
concentrations and derived PK 
parameters
Timeframe: Treatment Period 1
4. To evaluate the safety/tolerability 
and immunogenicity of 
secukinumab
AEs, laboratory values, vital 
signs, Anti-Drug Antibodies (ADA) 
Timeframe: Entire study


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3
Investigational plan
3.1
Study design
This is a double-blind, placebo-controlled, event-driven randomized withdrawal study to 
investigate the efficacy and safety of secukinumab treatment in the JIA categories of JPsA and 
ERA. The study is divided into 3 parts (plus a post-treatment follow-up period) consisting of 
open-label, single-arm active treatment in Treatment Periods 1 and 3 and a randomized, 
double-blind, placebo controlled, event-driven withdrawal design in Treatment Period 2, as 
described below:
Treatment Period 1: A maximum 8-week screening period is used to assess patient 
eligibility. All eligible patients will enter Treatment Period 1 to receive 12-weeks of open-
label secukinumab at a dose predicted to achieve secukinumab serum levels equivalent to 
adults administered a 150 mg dose regimen (see Section 3.3 for details). Secukinumab will be 
administered subcutaneously (s.c.) weekly for the first 4 weeks (Baseline, Weeks 1, 2, 3, 4) 
and then every 4 weeks thereafter. Clinical response (JIA ACR 30) will be assessed at Week 
12. Responders will advance to Treatment Period 2 and non-responders must exit the trial 
(early termination visit and enter into the Post-treatment follow-up period).
Treatment Period 2: Patients with a clinical response (JIA ACR30) at Week 12 will enter 
double-blind withdrawal Treatment Period 2 to be randomized 1:1 to either secukinumab or 
placebo on that visit. Treatment Period 2 is event driven and will close when 33 patients 
experience a disease flare as per JIA definition (Appendix 8). If Treatment Period 2 is closed 
when a patient becomes eligible to enter Treatment Period 2, the patient will skip Treatment 
Period 2 and advance directly to Treatment Period 3. When the 33rd flare is observed, all 
investigators will be informed that Treatment Period 2 is closed and all remaining patients 
will enter Treatment Period 3 at their next scheduled visit. Because Treatment Period 2 is 
event driven, it is possible that a patient remains in Treatment Period 2 for the duration of the 
study (Week 104) before 33 disease flares are observed.  Such patients will complete the 
study without having entered Treatment Period 3.
Treatment Period 3: Patients experiencing a disease flare in Treatment Period 2 will 
immediately enter Treatment Period 3 to receive open label secukinumab every 4 weeks until 
total study duration of 104 weeks for that patient is achieved. Additionally, when Treatment 
Period 2 closes, all remaining patients in Treatment Period 2 will enter Treatment Period 3 at 
their next scheduled visit and all remaining Treatment Period 1 patients who become eligible 
to enter Treatment Period 2 will skip Treatment Period 2 and enter Treatment Period 3 
directly. Consequently, the starting time point of Treatment Period 3 for each patient may be 
different. 
Post-treatment follow-up: All patients completing the study (Week 104) or who discontinue 
early will enter the Post-treatment follow-up period lasting 12 weeks from the last study drug 
dose administration.  Only patients who qualify and enter the secukinumab extension trial 
without interruption of secukinumab treatment will not require this Post-treatment follow-up 
visit.
Due to the event driven design of Treatment Period 2, the lengths of Treatment Periods 2 and 
3 will be variable and patient-specific. Based on the study design, a patient may participate in:


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1. Treatment Period 1 only if the patient is a non-responder at the end of Treatment Period 
1 and must discontinue from the study.
2. Treatment Periods 1, 2, and 3.
3. Treatment Periods 1 and 2 only if the patient never experiences a disease flare after 
randomization into Treatment Period 2 and reaches a total study duration of 104 weeks 
before a total 33 flares in Treatment Period 2 are observed.
4. Treatment Periods 1 and 3 only if 33 flares are observed in Treatment Period 2 prior to 
or at the time the patient reaches Week12 (end of Treatment Period 1) and is eligible to 
enter Treatment Period 2.  In this situation, the patient will enter Treatment Period 3 
directly from Treatment Period 1 to receive open-label secukinumab.
All patients will participate in the Post-treatment follow up period, except for those entering 
the extension study.
Enrollment will be staggered such that enrollment will be held in each dose weight group (< 
or ≥50kg) when 10 patients in that weight group have enrolled.  Patients discontinued before 
Week 12 may be replaced. In order to confirm the predicted pediatric dosing regimen, a 
Pharmacokinetics (PK) interim analysis (IA) will be conducted for each of these 2 weight 
dose groups after completion of the Week 12 visit.  Separate PK IAs may be performed for 
each dose weight group depending on enrollment rate in each.  When the adequacy of the 
predicted dose is confirmed, enrollment for that weight group will reopen until full enrollment 
is reached.  The interim analysis for one or both dose weight groups may not be necessary if 
the adequacy of the secukinumab dose is confirmed by evidence obtained in an ongoing 
pediatric psoriasis study.  
The primary analysis is planned when 33 disease flares in Treatment Period 2 have been 
observed (Treatment Period 2 is completed). 
Treatment: Secukinumab prefilled syringes (PFS), available as a 150mg/1mL PFS and as a 
75mg/0.5mL PFS, and matching placebo will be used in the study.

Treatment Period 1 open-label: Secukinumab 75 mg (< 50kg, 0.5 mL PFS) or 150 mg 
(≥50 kg, 1 mL PFS) s.c will be administered at Baseline, Weeks 1, 2, 3, 4, and 8.  The end 
of Treatment Period 1 visit at Week 12 will determine if the patient continues directly into 
Treatment Period 2 at that visit (minimum  JIA ACR30 response) to begin blinded study 
drug administration or is not a responder and must have the early termination visit 
performed and enter directly into the Post-treatment follow-up period without any further 
study drug administration.  

Treatment Period 2 treatment withdrawal: Patients who are a responder (minimum JIA 
ACR30) at the end of Treatment Period 1 visit at Week 12, will move directly into 
Treatment Period 2 at that same visit to be randomized 1:1 to receive blinded 
secukinumab (75mg for < 50kg [ 0.5 mL PFS] or 150 mg for ≥ 50 kg [ 1mL PFS] or 
matching placebo administered in Treatment Period 2 and then every four weeks until 
either experiencing a disease flare or completion of Treatment Period 2 (33 disease flares 
observed in the overall study population).  For patients who are eligible to enter Treatment 
Period 2, but it has closed (because 33 disease flares were observed), they will skip 
Treatment Period 2 and enter directly into Treatment Period 3 at that visit to begin open-
label secukinumab administration.


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
Treatment Period 3 open-label: Secukinumab 75 mg (< 50 kg, 0.5 mL PFS) or 150 mg (≥ 
50 kg, 1mL PFS) s.c will be administered every 4 weeks until Week 100 included.  
Figure 3-1
Study design
The time point for entering Treatment Period 3 will be either when the patient experiences a 
disease flare, or on/after the completion of Treatment Period 2. Consequently, the duration in 
Treatment Period 2 will be up to 92 weeks for patients without a disease flare if Treatment 
Period 2 does not close before the patient reaches 104 weeks of total study participation. 
Patients could enter Treatment Period 3 at any point from Week 12 to Week 104.
All patients completing the Week 104 visit or who discontinue early will have a Post-
treatment follow-up visit 12 weeks from the last study drug dose. Only patients who enter the 
extension trial without interruption of their secukinumab treatment will not require this Post-
treatment follow-up visit.
3.2
Rationale for study design
Although the cause for arthritis in children and adults is not known, children are expected to 
respond similarly to adults with similar conditions. Data from multiple secukinumab studies 
evaluating a range of doses (75 mg to 300 mg) are available for two adult spondyloarthritides 
(AS (Ankylosing Spondylitis) and PsA (Psoriatic Arthritis)) and RA (Rheumatoid Arthritis). 


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A favourable benefit risk was established in adult ankylosing spondylitis and psoriatic arthritis 
patients and approved for these indications in multiple countries including the European 
Union and the US. 
Based on the totality of the adult arthritis clinical data where secukinumab treatment resulted 
in robust efficacy in adults with a spondyloarthropathy (PsA or AS), the appropriate paediatric 
arthritic population to study secukinumab treatment is children aged ≥ 2 to < 18 years 
diagnosed with enthesitis-related arthritis or juvenile psoriatic arthritis JIA which are the two 
JIA categories which represent pediatric correlates of the approved adult SpA indications. The 
present study is adequately powered to demonstrate effectiveness of secukinumab treatment in 
a placebo-controlled study design following EMA (European Medicine Agency) JIA 
treatment guidelines evaluating a paediatric dose regimen equivalent to the 150 mg adult AS 
and PsA dose regimen. No additional safety risks or vulnerabilities are expected from 
exposure to secukinumab at this dose in the proposed paediatric population. 
The patient population will be described in more detail in the Section 4 below.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The dose selection for secukinumab in pediatric JPsA and ERA is based on the expectation 
that children will respond similarly to adults with similar conditions.  In the pivotal adult 
psoriatic arthritis and ankylosing spondylitis Phase III randomized placebo-controlled studies, 
secukinumab 150 mg administered weekly for the first 4 weeks and monthly thereafter 
demonstrated significant efficacy and a favorable safety profile. In both adult AS and PsA, 
secukinumab treatment led to significant improvement in patient’s clinical signs and 
symptoms as well as improved quality of life. Based on this data, secukinumab has received 
approval in multiple countries, including the European Union and the US, for these 
indications at this dose.  For adults with PsA, a 300mg dose regimen was a more effective 
dose in treating the psoriasis of patients with moderate to severe skin involvement and in 
treating the arthritic component in patients who did not respond adequately to a TNF inhibitor. 
For both indications, the recommended dose in TNF-α naïve patients is 150 mg by 
subcutaneous injection at Weeks 0, 1, 2 and 3, followed by monthly dosing starting at Week 4 
(Cosentyx® (Secukinumab) label 2016) 


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3.4
Rationale for choice of comparator
A placebo group is included in this study at Week 12. Due to the nature of the disease and the 
primary outcome measure used (JIA ACR30 response), a placebo group is necessary to obtain 
reliable efficacy measurements for comparison between the active treatment and placebo 
groups in a controlled fashion. This is in accordance with health authority guidelines, 
including (EMA 2015). Placebo exposure is kept to a minimum by advancing all patients who 
experience a disease flare in Treatment Period 2 to Treatment Period 3 where they receive 


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open-label secukinumab and by stopping Treatment Period 2 when 33 flares occur and 
advance all remaining patients to Treatment Period 3 to receive open-label secukinumab.  
3.5
Purpose and timing of interim analyses/design adaptations
A PK interim analysis will be conducted for the first 10 patients enrolled in each weight dose 
group (< or ≥50kg) after completion of the Week 12 visit in order to confirm the predicted 
pediatric dosing regimen.
Enrollment will be held in each dose weight group (< or ≥ 50kg) when 10 patients in that 
group have entered Treatment Period 1. Patients discontinued before Week 12 may be 
replaced. Separate PK IAs may be performed depending on enrollment rate in each weight 
dose group. When the adequacy of the predicted exposure is confirmed, recruitment for that 
weight group will reopen until the planned study population is fully enrolled. The interim 
analysis for one or both dose weight groups may not be necessary if the secukinumab dose is 
confirmed by evidence obtained in ongoing Secukinumab pediatric studies. Any change in the 
dose regimen to be implemented based on the PK IA results or available data from the 
ongoing pediatric psoriasis study will be communicated in written format from Novartis. 
3.6
Risks and benefits 
Secukinumab has shown efficacy in several inflammatory diseases, including PsA, AS, and 
psoriasis. The large safety dataset of secukinumab cross-indication did not show unexpected 
safety issues relative to the known mode of action. In general, secukinumab is safe and well-
tolerated and has demonstrated a similar safety profile to other mAbs (including etanercept 
and ustekinumab). The most frequently reported AEs are non-serious infections, especially 
upper respiratory tract infections. In addition, there is an increase in mucosal or cutaneous 
candidiasis with secukinumab compared with placebo, but the cases were generally mild or 
moderate in severity, non-serious, and responsive to standard treatment. There is also a small 
increase in neutropenia cases with secukinumab compared with placebo. Common 
Terminology Criteria for adverse event (CTCAE) grade 3 neutropenia (<1.0-0.5 x 109/L) was 
uncommonly observed with secukinumab, most were mild to moderate, transient and 
reversible, and without a temporal relationship to serious infections. Hypersensitivity 
reactions include urticaria. Rare events of anaphylactic reaction to secukinumab have also 
been observed in clinical studies. 
The immunogenicity potential, e.g. eliciting the production of anti-drug antibodies (ADA) is 
low. In psoriasis, psoriatic arthritis and ankylosing spondylitis clinical studies, less than 1% of 
patients treated with secukinumab (n>9600) developed antibodies over up to 52 weeks of 
treatment. 
Taking into account the individual risks as outlined above, the expected risk profile of 
secukinumab from its mechanism of action is anticipated to be similar or improved compared 
to the other approved inflammatory cytokine-targeting therapies. The risk to subjects in this 
trial will be minimized by compliance with the eligibility criteria, close clinical monitoring, 
and extensive guidance to the investigators provided by Novartis and in the current version of 
the Investigator Brochure (IB) for Secukinumab. Based on overall risk-benefit assessment, the 
current trial with secukinumab is justified.


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4
Population
The study population will consist of male and female patients aged from ≥2 years to <18 years 
at screening  who are diagnosed with either enthesitis-related arthritis (ERA) based on 
fulfilling the ILAR JIA classification criteria or JPsA based on fulfilling a modified ILAR JIA 
classification criteria. Every effort will be made in order to randomize at least 20 patients 
from each JIA category to Treatment Period 2. A 1:1 stratified randomization for Treatment 
Period 2, will be put in place ensuring an equal number of patients from each JIA category 
(JPsA and ERA) will receive either secukinumab or placebo treatment. Patients included must 
be biologic treatment naïve and have active disease despite current or previous NSAID and 
DMARD therapy. 
All non-biologic DMARDs except MTX (or sulfasalazine [SSZ] for ERA patients only) are to 
be withdrawn with adequate washout before Baseline (see Table 5-1). 
Concomitant therapy with MTX, (or SSZ for ERA patients only) and oral corticosteroids (CS) 
will be acceptable at stipulated maximum doses, but the dose and route of administration must 
have been stable for at least four weeks prior to Baseline for the DMARD and 7 days for the 
CS and remain at that dose during the study Treatment Period 1, while dose adjustments will 
be permitted according to investigator’s judgement in Treatment Period 2 only after 3 
consecutive months of minimum ACR50 response or at any time in Treatment Period 3. 
A total of approximately 80 patients to Treatment Period 1 in approximately 40 – 50 centers 
worldwide is anticipated to enroll in order to reach the minimum required sample size of 60 
patients in Treatment Period 2 (see also section 9.6). Depending on the responder rate in 
Treatment Period 1 and the dropout rate in Treatment Periods 1 and 2, more patients may 
need to be enrolled in Treatment Period 1 to reach the 33 flares in Treatment Period 2. A 20% 
screen failure rate is anticipated which will then require approximate 100 children to be 
screened. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Parent’s or legal guardian’s written informed consent and child’s assent, if appropriate, 
must be obtained before any study related activity or assessment is performed. Of note, if 
the subject reaches age of consent (age as per local law) during the study, they will also 
need to sign the corresponding study ICF (Informed Consent Form).
2. Males and females ≥2 years old and <18 years old at the time of screening.
3. Confirmed diagnosis of ERA according to the ILAR classification criteria or JPsA 
according to the modified ILAR classification criteria (See Appendix 7) that must have 
occurred at least 6 months prior to Screening.  
4. Active disease (ERA or JPsA) defined as having both: 

≥ 3 active joints (swollen or if not swollen must be both tender and limited range of 
motion) at Baseline

≥1 site of active enthesitis at Baseline or documented by history 
5. Inadequate response (≥1 month) or intolerance to ≥1 NSAID. 
6. Inadequate response (≥2 months) or intolerance to ≥ 1 DMARD. 


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7. No concomitant use of second line agents such as disease-modifying and/or 
immunosuppressive drugs will be allowed with the exception of the following agents 
which must remain at stable dose during trial Treatment Periods 1 and 2 (See Section 
5.5.7 for additional details and for required wash-out period):

Stable dose of methotrexate (maximum of 20 mg/ m2 BSA/ week) for at least 4 weeks 
prior to the Baseline visit, and folic/folinic acid supplementation (according to 
standard medical practice of the center)

Stable dose of SSZ (ERA patients only) <50 mg/kg/day with max of 3000 mg/day for 
at least 4 weeks prior to the Baseline visit

Stable dose of an oral corticosteroid (CS) at a prednisone equivalent dose of <0.2 
mg/kg/day or up to  10 mg/day maximum, whichever is less, for at least 7 days prior 
to Baseline

Stable dose of no more than one NSAID for at least 1 week prior to Baseline
8. Negative QuantiFERON (QF) test. Negative Purified Protein Derivative [PPD] test is also 
acceptable if either required by local guidelines or if the patient is <5 years of age. A 
positive PPD is defined as >15mm induration for children >4 years and >10mm for 
children <4 years.

Subjects with a positive test may participate in the study if further work up (according 
to local practice/guidelines) establishes conclusively that the subject has no evidence 
of active tuberculosis. If presence of latent tuberculosis is established then treatment 
according to local country guidelines must have been initiated and for a minimum of 
4 weeks before Baseline.

In the absence of local guidelines the US CDC (Centers for Disease Control and 
Prevention) guidelines for treatment of latent TB must be followed i.e. INH 
(isonicotinylhydrazide) treatment for 9 months. Patients diagnosed with active TB 
should be referred for treatment as deemed appropriate and are not eligible to 
participate in this study.  
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Use of other investigational drugs within 4 weeks or 5 half-lives of Baseline, or until the 
expected pharmacodynamic effect has returned to baseline, whichever is longer.
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
3. Patients with active uncontrolled inflammatory bowel disease or active uncontrolled 
uveitis.
4. Patients who have ever received biologic immunomodulating agents, including but not 
limited to TNFα inhibitors, T-cell costimulatory, Anti-IL6, Anti-IL1, cell-depleting 
therapies including but not limited to anti-CD20 (e.g., alemtuzumab, anti-CD4, anti-CD5, 
anti-CD3, and anti-CD19), secukinumab or other biologic drugs directly targeting IL-17 or 
IL-17 receptor or any investigational immunomodulating agent.


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5. Patients taking any non-biologic DMARD except for MTX (or sulfasalazine [SSZ] for 
ERA patients only) (see Section 5.5.7 and Table 5-1 for additional details).
6. Patients fulfilling any ILAR diagnostic JIA category other than ERA or JPsA.
7. Patients taking medications prohibited by the protocol (see Section 5.5.8, 
Table 5-1) (e.g., topical corticosteroids or ultraviolet (UV) therapy at screening). The 
washout periods to be observed before Baseline are given in Table 5-1.
8. Patients taking high potency opioid analgesics (morphine equianalgesic or higher) 
including but not limited to methadone, hydromorphone and morphine.
9. Any intramuscular/intravenous/intra-articular corticosteroid treatment within 4 weeks 
before Baseline.
10. Active or recurrent bacterial, fungal or viral infection including known infection with 
Human Immunodeficiency Virus (HIV), Hepatitis B, and Hepatitis C at Baseline.
11. History or evidence of active tuberculosis (TB) or evidence of Latent TB (positive 
QuantiFERON or PPD at screening) but unwilling or unable to complete a minimum of 4 
weeks of latent TB treatment before initiating treatment with secukinumab. 
12. History or current diagnosis of Electrocardiogram (ECG) abnormalities indicating 
significant risk of safety for patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes
13. Pregnant or nursing (lactating) females, 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.
14. Female patients (< 18 years of age) of childbearing potential (menarchal or becoming 
menarchal during the study) who do not agree to abstinence or, if sexually active, do not
agree to the use of contraception as defined in Section 6.5.7.
15. Active ongoing inflammatory diseases other than JPsA / ERA that might confound the 
evaluation of the benefit of secukinumab therapy.
16. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, 
cardiac, infectious or gastrointestinal conditions which in the opinion of the Investigator 
immunocompromises the subject and/or places the subject at unacceptable risk for 
participation in a study with an immunomodulatory treatment.
17. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension and uncontrolled diabetes (can be discussed on a case-by-case 
basis with Novartis).
18. History of clinically significant liver disease or liver injury as indicated by abnormal liver 
function tests (LFT) such as aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase (AST/SGOT), alanine aminotransferase/ serum glutamic pyruvic 
transaminase (ALT/SGPT), alkaline phosphatase, or serum bilirubin. The Investigator 
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a. Any single parameter may not exceed 2 x upper limit of normal (ULN). A single 
parameter elevated up to and including 2 x ULN should be re-checked once more as 
soon as possible, and in all cases, at least prior to baseline, to rule out lab error.
b. If the total bilirubin (TBL) concentration is increased above 2 x ULN, total bilirubin 
should be differentiated into the direct and indirect reacting bilirubin. In any case, 
serum bilirubin should not exceed the value of 1.6 mg/dL (27 µmol/L).
19. Screening total white blood cell (WBC) count < 3 000/µL, or platelets < 100 000/µL or 
neutrophils < 1 500/µL or hemoglobin < 8.5 g/dL (85 g/L).
20. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for basal cell carcinoma or actinic 
keratoses that have been treated with no evidence of recurrence in the past 3 months, 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been 
removed).
21. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
Investigator renders the subject unsuitable for the trial.
22. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins).
23. Any medical or psychiatric condition which, in the investigator’s opinion, would preclude 
the participant from adhering to the protocol or completing the study per protocol (can be 
discussed on a case-by-case basis with Novartis).
24. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
Baseline.
25. Plans for administration of live vaccines during the study period or within 6 weeks 
preceding Baseline.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Novartis will supply the following study drugs:
Investigational treatment

Secukinumab 150 mg/1 mL, liquid formulation provided in 1 mL PFS 

Secukinumab 75 mg/0.5 mL, liquid formulation provided in 0.5 mL PFS 
Reference treatment

Placebo, liquid formulation in a 1 mL and 0.5 mL PFS
Secukinumab 75 mg/0.5 mL and 150 mg/1 mL pre-filled syringes and matching placebo pre-
filled syringes will be provided in a double blind fashion and have identical appearance 
All study drugs will be labeled accordingly:
For the open-label parts (Treatment Periods 1 and 3):


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
AIN457 150 mg/1 mL

AIN457 75 mg/0. 5mL
For the double-blind part (Treatment Period 2):

AIN457 150 mg/1 mL/Placebo

AIN457 75 mg/0.5 mL/Placebo
For detailed instructions on storage of the study drugs, please refer to Section 5.5.3
5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms
Patients will enter Treatment Period 1 to receive 12-weeks open label active treatment of 
either s.c. secukinumab 75 or 150 mg, based on their body weight (< 50 kg or ≥ 50 kg) at each 
dosing visit starting at Baseline. They will receive further doses at Weeks 1, 2, 3, 4, and 8. 
At the End of Treatment Part 1 visit at Week 12, efficacy assessments must be performed and 
ACR response criteria evaluated to determine future patient disposition in the study.  Patients 
who are assessed as a responder (minimum JIA ACR30 response) will enter Treatment Period 
2 at that same visit to be randomized to either continue their active treatment or matching 
placebo every 4 weeks, in a blinded manner, in a 1:1 ratio until 33 patients experience a 
disease flare and Treatment Period 2 is completed.  If Treatment Period 2 is closed at the time 
of the Week 12 visit, the patient will skip Treatment Period 2 and enter Treatment Period 3 
directly to receive open-label secukinumab. Patients who are not a responder at the Week 12 
visit will have the early termination visit done on the same day and enter into the Post-
treatment follow-up period at that visit without receiving any further study drug 
administration. 
Patients will enter Treatment Period 3 from Treatment Period 2 because of either experiencing 
a flare or when 33 flares in Treatment Period 2 are overall observed and Treatment Period 2 is 
closed. Patients in Treatment Period 1 when Treatment Period 2 closes will skip Treatment 
Period 2 and advance directly into Treatment Period 3 after successfully completing 
Treatment Period 1. During Treatment Period 3, patients will receive open-label secukinumab 
(either 75 or 150 mg, based on body weight) every 4 weeks until study Week 100 is reached. 
5.3
Treatment assignment and randomization 
All patients fulfilling all entry criteria will be assigned to AIN457/secukinumab 75 or 150 mg, 
based on body weight (< 50 kg or ≥ 50 kg) and continue to receive an appropriate 
secukinumab dose at each visit based on their weight at that visit. At the Week 12 visit, all 
responders will be eligible to enter Treatment Period 2 where they will be randomized via 
Interactive Response Technology (IRT) to one of the two treatment arms, active as 
secukinumab 75 or 150 mg, or matching placebo based on their weight at that visit. 
In Treatment Period 2, patients will be randomized by each JIA category (strata: JPsA and 
ERA) in a 1:1 ratio to receive AIN457 or placebo so that approximately an equal number from 
each category will receive either active or placebo.


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At each subsequent dosing visit body weight will be checked and the patients will be assigned 
the correct blinded dose based on their weight at that visit.
The Investigator or his/her delegate will contact the IRT after confirming that the patient 
fulfills the response criteria. The IRT will assign a randomization number to the patient, 
which will be used to link the patient to a treatment arm and will specify a unique medication 
number for the first package of study drug to be dispensed to the patient. The randomization 
number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/parents and Investigator staff. 
A patient randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms and to study strata, which in 
turn are linked to medication numbers. A separate medication list will be produced by or 
under the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of medication numbers to packs containing the 
investigational drug(s). 
The randomization scheme for patients/subjects will be reviewed and approved by a member 
of the Randomization Group.
5.4
Treatment blinding 
Patients/parents, Investigator staff, persons performing the assessments, and data analysts will 
remain blinded to the identity of the treatment (Treatment Period 2) from the time of 
randomization until database lock, using the following methods:
(1) Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the exception of the bioanalyst, 
independent statistician, programmer and DMC (Data Monitoring Committee) members.
(2) The identity of the treatments will be concealed by the use of study drug that are all 
identical in packaging, labeling, schedule of administration, administration route and 
appearance.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and after the 
primary efficacy analysis. 
5.5
Treating the patient 
Sponsor qualified scientific and medical personnel will be readily available to advise on trial 
related medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 


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Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The Investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site must 
select the CRF book with a matching Subject Number from the Electronic Data Capture (EDC)
system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated.  
If for any reason the subject is a screen failure, the subject may be rescreened. There is no 
restriction on the number of times a potential subject may be rescreened or on how much time 
must pass from the date of screen failure and the date of rescreening. If a subject rescreens for 
the study, then the subject must sign a new ICF and be issued a new subject number prior to 
any screening assessment being conducted for the subject under the new screening subject 
number. For all subjects, the investigator/qualified site staff will record if the subject was 
rescreened on the rescreening CRF page and any applicable screening numbers the subject 
was issued prior to the current screening number.
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to placebo or active treatment. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the patient, 
Investigator staff will detach the tear-off part of the label from the packaging and affix it to 
the source document (Drug Label Form) for that patient’s unique subject number. For delivery 
of IMP to a participant's home, the pharmacist/qualified site personnel will dispense, via IRT, 
the investigational treatment package and detach outer part of the label from the packaging 
and affix it to the source document for that patient’s unique subject number.
During a major health care disruption (e.g., COVID 19 pandemic/epidemic) that limits or 
prevents on-site study visits, delivery of IMP directly to a participant’s home would be 
permitted in the event the Investigator has decided that an on-site visit by the participant is no 
longer appropriate or possible, and that it is in the interest of the participant’s health to 
administer the study treatment even without performing an on-site visit.  Delivery of IMP 
directly to a participant’s home would be permitted only during the duration of the health care 
disruption and for patients whom the Investigator deems that delaying/skipping a dose is not 
an option. The shipment/provisioning will be for a maximum quantity covering a 1-month 
supply.
In this case, regular phone calls or virtual contacts (every 4 weeks or more frequently if 
needed; prior to drug shipment and just before dosing) will occur between the site and the 
participant for instructional purposes, safety monitoring, and discussion of the participant´s 
health status until the participant can again visit the site. Where home dosing is performed, 
patient’s body weight will be collected and transmitted to the site prior to shipment. 
Appropriate safety assessments (e.g., evaluation of AEs and SAEs) should be conducted after 


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the dose is administered. Scheduled efficacy assessments are not required for home 
administration. 
The dispatch of IMP from the site to the participant’s home remains under the accountability 
of the Investigator. Home administration can be performed by the patient or 
parent/guardian/caregiver, provided they are familiar or have been trained on how to inject 
with the PFS as per investigators judgment. The patient/parent/guardian/caregiver should be 
provided with the PFS Instructions For Use.
It must be noted that subjects 12-<18 years of age can self-inject only under 
Parent/Guardian/Caregivers or health care professional supervision. Subjects < 12 years of 
age should not self –inject.
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the Investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Pharma Organization (CPO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number.
The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients/subjects will 
be asked to return all unused study treatment and packaging at the end of the study or at the 
time of discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the 
Investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the Investigator folder at each site.
5.5.3.2
Handling of additional treatment  
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Study treatment (secukinumab 75 mg, 150 mg or placebo) will be administered by s.c. PFS
throughout the study. Administration of study treatment will occur at the study site for the 
whole study duration (104 weeks), except in cases of a major healthcare disruption that 
impedes on-site drug administration. Apart for the exceptional circumstances created by the 
current pandemic that may apply to some cases, administration of study treatment must occur 


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only after the study assessments for the visit have been completed, and with the timing 
indicated in Table 6-1 (Assessment Schedule).
The first study treatment administration will occur at the Baseline visit only after eligibility 
criteria have been confirmed, all study baseline assessments have been performed, and the 
scheduled blood samples have been drawn. At each subsequent visit, all study assessments (as 
applicable per Table 6-1) should be completed prior to the injection of study treatment. 
Administration of study treatment should occur after sample collection for PK assessments (at 
visits specified in Table 6-1).
All investigational treatment kits assigned by the IRT will be recorded in the IRT. The 
Investigator must promote compliance by instructing the subject/guardian to attend the study 
visits as scheduled and by stating that compliance is necessary for the subject’s safety and the 
validity of the study. The subject/guardian should be instructed to contact the Investigator if 
he/she is unable for any reason to attend a study visit as scheduled. 
During a major health care disruption (e.g., COVID 19 pandemic / epidemic) that limits or 
prevents on-site study visits, delivery of IMP directly to a participant’s home would be 
permitted in the event the Investigator has decided that an on-site visit by the participant is no 
longer appropriate or possible, and that it is in the interest of the participant’s health to 
administer the study treatment even without performing an on-site visit.  Delivery of IMP 
directly to a participant’s home would be permitted only during the duration of the health care 
disruption and for patients whom the Investigator deems that delaying/skipping a dose is not 
an option. The shipment/provisioning will be for a maximum quantity covering a 1-month 
supply.
In this case, regular phone calls or virtual contacts (every 4 weeks or more frequently if 
needed; prior to drug shipment and just before dosing) will occur between the site and the 
participant for instructional purposes, safety monitoring, and discussion of the participant´s 
health status until the participant can again visit the site. Where home dosing is performed, 
patient’s body weight will be collected and transmitted to the site prior to shipment. 
Appropriate safety assessments (e.g., evaluation of AEs and SAEs) should be conducted after 
the dose is administered. Scheduled efficacy assessments are not required for home 
administration. 
The dispatch of IMP from the site to the participant’s home remains under the accountability 
of the Investigator. Home administration can be performed by the patient or 
parent/guardian/caregiver, provided they have been trained on how to inject with the PFS as 
per investigators judgment. The patient/parent/guardian/caregiver should be provided with the 
PFS Instructions For Use.
It must be noted that subjects 12-<18 years of age can self-inject only under 
Parent/Guardian/Caregivers or health care professional supervision. Subjects < 12 years of 
age should not self –inject.
For the visits where a urine pregnancy test is required or deemed necessary, if the patient 
cannot visit the site to have urine pregnancy test done, the urine pregnancy test kit can be 
provided to the patient/parent/guardian/caregiver or shipped directly to the their home (e.g., 
together with the study drug). After appropriate instruction, patient/parent/guardian/caregiver 


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can perform the urine pregnancy test at home and report the result to the site. It is important 
that a negative pregnancy test is confirmed prior to the administration of the study drug. 
The patient/parent/guardian/caregiver will record the date of administration and will return the 
packaging at their next visit to the site. Used syringes should be disposed immediately after 
use in a sharps container OR according to the regulatory requirements in the respective 
country.
Site staff are to transcribe this information into the appropriate Dosage Administration Record 
eCRF. The investigator must maintain an accurate record of the shipment and dispensing of 
study treatment in a drug accountability log.
In case a flare is suspected between two scheduled visits in Treatment Period 2, the patient 
can be evaluated at that time by the investigator during an unscheduled visit.  If a flare is 
confirmed at that visit, he/she will advance to Treatment Period 3 and receive open-label 
secukinumab at a dose according to their body weight. Subsequent visits will be carried out as 
scheduled.
Should a visit be delayed, every attempt should be made to bring the patient back on schedule 
for the next visit (referring to Baseline visit).
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments are not permitted. For subjects who are unable to tolerate 
the protocol-specified dosing scheme (including subjects who in the opinion of the 
Investigator are at significant safety risk unless dosing is temporarily interrupted), study 
treatment interruption is permitted in order to keep the subject on study drug. In such cases, 
study treatment should be interrupted only during the time that a risk is present and ongoing. 
Study treatment can be restarted at the next scheduled visit after resolution of the safety risk.
The effect of secukinumab on live vaccines is unknown; therefore live vaccines should not be 
administered during participation in the study. In case a live vaccine has been administered 
due to a medical urgency, study treatment should be interrupted for 12 weeks.
Any study treatment interruption must be recorded on the corresponding eCRF page.
5.5.6
Rescue medication
Rescue medication is defined as medication used to control symptoms that are not adequately 
controlled on investigational and other study treatment. 
Use of rescue medication is prohibited. Please see Section 5.5.7 and Section 5.5.8 for details 
on concomitant medications. Although no subject will be restricted from receiving necessary 
rescue medications for lack of benefit or worsening of disease, subjects will be discontinued 
from the study if treated with prohibited medications (as described in Section 5.5.8) and 
should complete an Early termination visit at the earliest possible time-point and enter the 
Post-treatment follow-up period. Efficacy and safety will be assessed in detail at every study 
visit and, subjects who are deemed by the Investigator not to be benefiting from study 
treatment, or for any reason on the subject’s own accord, will be free to discontinue study 
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Use of rescue medication must be recorded on the corresponding eCRF page.
5.5.7
Concomitant medication
The Investigator must instruct the patient/guardian to notify the study site about any new 
medications the patient takes after he/she was enrolled into the study. All medications, 
procedures and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient was enrolled into the study must be recorded in the 
concomitant medications/significant non-drug therapies eCRF page. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the Investigator should contact the Novartis medical monitor before 
enrolling a patient or allowing a new medication to be started. Medications /treatments not 
explicitly mentioned in the protocol can be evaluated by Novartis for suitability with the study 
on a case-by-case basis.
Guidelines for the use of specific medications are provided below.
Leflunomide wash-out with cholestyramine
In case of leflunomide treatment before study Baseline, a drug wash-out of 8 weeks must be 
performed. However, another wash-out procedure can be considered. Cholestyramine may be 
given orally at a dose of 8 g three times daily (t.i.d) to wash-out leflunomide. Cholestyramine 
reduced plasma levels of the active leflunomide metabolite by approximately 40% in 24 hours 
and by 49% to 65% in 48 hours in three healthy volunteers. The administration of 
cholestyramine is recommended in subjects who require a drug elimination procedure. If a 
subject receives 8 g t.i.d. for 11 days, the subject can be safely enrolled 4 weeks after the 
beginning of the 11-day treatment period.
Non-biologic DMARDs (limited to MTX or SSZ) 
All non-biologic DMARDs, with the exception of stable dose of SSZ (for ERA patients only), 
or MTX are prohibited as concomitant medications and must undergo a washout period before 
Baseline administration, as indicated in Table 5-1.
Concomitant MTX (maximum of 20 mg/ m2/ BSA week) and folic/folinic acid 
supplementation (according to standard medical practice of the center), or SSZ (only for ERA 
patients, stable dose of < 50 mg/kg/day and up to max 3000 mg/day) treatment may be used if 
the dose and route of administration are stable for at least 4 weeks before the Baseline visit 
and remain stable for the duration of the study. Dose reductions are permitted only in case of 
adverse events.  
Systemic corticosteroids
Treatment with oral corticosteroids ≤ 0.2 mg/kg/day (or maximum 10 mg/day whichever is 
lower) of oral prednisone (or equivalent) is permitted if the dose was stable at least 7 days 
preceding Baseline visit and remains stable. Otherwise a washout period of 1 week prior to 
Baseline is needed. 
Corticosteroids can be tapered down to discontinuation beginning in Treatment Period 2 based 
on investigator clinical judgment for patients with at least 3 consecutive months of minimum 


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ACR50 response and at any time in Treatment Period 3 based on investigator clinical 
judgment. No corticosteroid dose tapering will be allowed in Treatment Period 1. 
Any change in the dose of oral corticosteroids during the trial should be recorded on the 
corresponding eCRF page.
Intra-articular corticosteroid injections are not permitted within 4 weeks prior to Baseline or at 
any time in Treatment Period 1 or 2.  Intra-articular corticosteroid injections will be permitted 
in Treatment Period 3.  No more than 4 joints per 24-week period may be injected and no 
single injection should exceed 40 mg of triamcinolone (or equivalent) during any 52-week 
period.
Non-steroidal anti-inflammatory drugs (NSAIDs) (including selective COX-2 
inhibitors), low strength opioids and acetaminophen/paracetamol
Subjects are permitted to enter the trial using regular dose of a single NSAID for their arthritis.   
The dose must be stable for at least 1 week before the baseline visit and remain at this dose 
during the trial.  Other NSAIDs, low strength opioids, and paracetamol/acetaminophen are 
permitted during the trial only if used on an as required (PRN) basis for non-arthritis 
treatment.  In such cases, the subject must refrain from intake of the PRN medication during 
at least 24 hours before a visit with a disease activity assessment.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-1 is NOT allowed after screening due to their 
confounding effect and/or safety interactions. 
Note: Live vaccination is NOT allowed within 6 weeks before baseline and until after 3 
months following the last study dose. Killed or inactivated vaccines may be permitted 
according to the investigator’s discretion.
It is recommended not to initiate biologic treatment until 3 months after the last dose of study 
drug. Therefore, biologic treatment should not be used any time during study participation.
Table 5-1
Prohibited medication
Medication
Prohibition period / washout 
before baseline
Action taken
Any biologic drugs, including but 
not limited to TNFα inhibitors, 
secukinumab, or other biologic 
drug directly targeting IL-17 or 
IL-17 receptor, any biological 
DMARD (bDMARDs)
Previous exposure at any time: 
exclusion criterion 
Discontinue investigational 
treatment
Any cell-depleting therapies 
including but not limited to anti-
CD20 or investigational agents 
[e.g., alemtuzumab (Campath), 
anti-CD4, anti-CD5, anti-CD3, 
and anti-CD19].
Previous exposure at any time: 
exclusion criterion
Discontinue investigational 
treatment
Conventional DMARDs (except 
SSZ (for ERA only) or MTX) 
4 weeks 
Discontinue investigational 
treatment


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Medication
Prohibition period / washout 
before baseline
Action taken
including apremilast 
Leflunomide
8 weeks
Discontinue investigational 
treatment
Leflunomide with 
cholestyramine washout
4 weeks
Discontinue investigational 
treatment
Any investigational treatment or 
participation in any 
interventional trial
4 weeks, or until the expected 
pharmacodynamics effect has 
returned to baseline or 5 half-lives 
(whichever is longer)
Discontinue investigational 
treatment
Analgesics other than NSAIDs, 
paracetamol/acetaminophen, 
and low strength opioids PRN 
2 weeks
Systemic corticosteroids at a 
prednisone equivalent dose of 
≤0.2 mg/kg/day or up to 10 
mg/day maximum, whichever is 
less, is permitted if the dose is 
stable at least 7 days before 
baseline. 
*Corticosteroid dose can be 
tapered down to discontinuation 
in Treatment Period 2 for 
patients with 3 consecutive 
months of minimum ACR50 
response or at any time in 
Treatment Period 3 based on 
investigator judgment. No 
changes in corticosteroid dose 
will be allowed in Treatment 
Period 1.
1 week
If administered due to a 
medical urgency unrelated 
to the patient’s arthritis, 
study treatment should be  
interrupted until the steroid 
is discontinued – if not 
medical urgency or if 
related to the patient’s 
arthritis, then discontinue 
from the study may be 
required on a case by case 
basis. 
Intra-articular corticosteroids are 
not permitted within 4 weeks 
prior to baseline or at any time 
in Treatment Period 1 or 2.  
Intra-articular corticosteroid 
injections will be permitted in 
Treatment Period 3 but no more 
than 4 joints per 24-week period 
may be injected and no single 
injection should exceed 40 mg 
of triamcinolone (or equivalent) 
during any 52-week period. The 
joints injected with intra-articular 
corticosteroids will be assessed 
as both swollen and tender in 
the SJC and TJC, from injection 
time onwards.
4 weeks
Discontinue investigational 
treatment, (see Section 
5.5.7)
Intramuscular or intravenous 
corticosteroid treatment are not 
permitted
4 weeks
Discontinue investigational 
treatment or from study 
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Medication
Prohibition period / washout 
before baseline
Action taken
by case basis.
Live vaccinations
6 weeks
Discontinue investigational 
treatment for 12 weeks and 
patient should remain in 
the study and follow visit 
schedule.
Oral or topical retinoids
4 weeks
Discontinue investigational 
treatment
Photochemotherapy (e.g. 
PUVA)
4 weeks
Discontinue investigational 
treatment
Phototherapy (UVA or UVB)
2 weeks
Discontinue investigational 
treatment
Topical skin treatments (except 
in face, eyes, scalp and genital 
area during screening period 
only, and if topical 
corticosteroids,  only those with 
mild to moderate potency)
2 weeks
Discontinue investigational 
treatment may be required 
on a case by case basis.
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The Investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The Investigator 
will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject/guardian must be provided on how to 
contact his/her backup in cases of emergency, or when he/she is unavailable, to ensure that 
un-blinding can be performed at any time. 
Study drug must be discontinued in Treatment Period 2 after emergency unblinding.
The possibility to enroll a patient after an emergency break in Treatment Period 2 into an 
extension study, if available, will be evaluated on a case-by-case basis.


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5.6
Study Completion and Discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has received a 
maximum of 104 weeks  of study treatment and completed all of the scheduled study 
assessment and procedures up to and including the Week 112 visit. All patients who complete 
the scheduled study assessments and procedures up to and including Week 104 will be 
eligible to enter an extension trial to continue secukinumab treatment without interruption. 
Patients who enter the extension study will be considered study completers at Week 104 and 
the follow-up visit at Week 112 will not be performed.
Information on the subject’s completion or premature discontinuation of the study and the 
reason for discontinuation of the study will be recorded on the appropriate eCRFpage.  
Additionally, the investigator or site staff must contact the IRT as soon as possible to record 
the subject’s study completion and/or discontinuation.
The Investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include initiating another treatment outside of the study as deemed appropriate by the 
investigator. This treatment may be any non-biologic DMARD. In case of a biologic 
treatment, a waiting period of 3 months before initiating the treatment is recommended.
5.6.2
Discontinuation of study treatment
The Investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient/Guardian wish  /withdrawal of informed consent

Pregnancy (see Section 6.5.7 and Section 7.6)

Use of prohibited treatment as per recommendations in Table 5-1

Any situation in which study participation might result in a safety risk to the patient

Emergence of the following adverse events: 

Any severe or serious AE that is not compatible with administration of study 
medication, including AEs that require treatment with an unacceptable co-medication

Onset of lymphoproliferative disease or any malignancy except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or non-
invasive malignant colon polyps which are being or have been removed

Life-threatening infection

Severe hypersensitivity reaction or anaphylactic reaction

Any laboratory abnormalities that in the judgment of the Investigator are clinically 
significant and are deemed to place the subject at a safety risk for continuation in the study 
(A general guidance on clinically notable laboratory values is provided in Appendix 1).

Use of any biologic immunomodulating agent except secukinumab

Any protocol deviation that results in a significant risk to the subject’s safety.


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If permanent discontinuation of study treatment prior to Week 100 occurs, the patient should 
NOT be considered withdrawn from the study. The patient should return to the clinic 4 weeks 
after last study drug administration, for a premature discontinuation visit and 12 weeks after 
“last study drug administration” for a Post-treatment follow-up visit. Assessments performed 
at these two visits are detailed in the “premature discontinuation visit” and “Post-treatment 
follow-up visit” respectively in Table 6-1 and should be completed and recorded in the 
appropriate eCRF page. The Investigator must determine the primary reason for the patient’s 
premature discontinuation of study and record this information on the Dosage Administration 
eCRF page and also contact the IRT to register the patient’s discontinuation from study 
treatment. 
If the patient/guardian cannot or is unwilling to attend any visit(s), the site staff should 
maintain regular telephone contact with the patient/guardian, or with a person pre-designated 
by the patient/guardian. This telephone contact should preferably be done according to the 
study visit schedule.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
5.6.3
Withdrawal of informed consent
Patients in consultation with the guardian or the guardian may voluntarily withdraw patient’s 
consent to participate in the study for any reasons at any time, without being obliged to give 
any explanation. Withdrawal of consent from the study is defined as when a patient/guardian:

Does not want to participate in the study anymore
and

Discontinues all elements outlined in the protocol
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 patient/guardian’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.  All biological 
material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.


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All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in 
Table 6-1.
5.6.4
Loss 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/guardian, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a premature subject withdrawal (PSW) 
(see Table 6-1). The Investigator may be informed of additional procedures to be followed in 
order to ensure that adequate consideration is given to the protection of the patient’s interests. 
The Investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” or an “s” when the visits are 
performed. The “x” indicates data collected on the eCRF page, the “s” indicates data collected 
in the source documents only.
Patients must be seen for all visits on the designated day, or as close to it as possible.
Should a visit be delayed, every attempt should be made to bring the patient back on schedule 
for the next visit (referring to Baseline visit). 

For visits scheduled through Week 4, the study treatment should not be administered less 
than 5 days from the previous administration.

For visits scheduled after Week 4, the study treatment should not be administered less than 
14 days from the previous administration, except in case of a flare in Treatment Period 2.
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who 
prematurely discontinue the study for any reason should be scheduled for a visit 4 weeks after 
last study drug administration, at which time all of the assessments listed for the Week 
104/PSW visit) will be performed and a visit 12 weeks after last study drug administration at 
which time all of the assessments listed for the Week 104/Post-Treatment safety follow up
visit will be performed. At this final visit, all dispensed investigational product should be 
reconciled and the adverse event and concomitant medications reconciled on the eCRF page.
If patients/guardians refuse to return for these assessments or are unable to do so, every effort 
should be made to contact them or a knowledgeable informant by telephone to determine the 
reason. Attempts to contact the patient/guardian should be recorded in the source 


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documentation. Patients/guardians will be contacted for safety evaluations during the 12 
weeks following the last administration of study treatment. 
In the event of a major health care disruption (e.g., pandemic, epidemic) that limits or 
prevents on-site study visits, regular phone calls or virtual contacts (every 4 weeks or more 
frequently, if needed) will occur until the subject can again visit the site. Events qualifying for 
being reported in the case report form (e.g., AE, procedure) should be entered as appropriate.  
Special effort should be made to collect information related to TD/PSW visits. If it is not 
feasible to conduct the TD or the PSW visit on-site, phone calls should be attempted instead.
Screening will be flexible in duration based on the time required to wash out prior anti-
rheumatic medications and have duration of up to 8 weeks, during which time, after signature 
of ICF, the subject be evaluated for eligibility and allowed sufficient time for potential 
medication washout (see Table 5-1, in addition to all other assessments indicated in Table 6-
1). 
Screening will consist of two consecutive visits. During the first screening visit, initial 
assessments will be performed as outlined in Table 6-1. At that visit the duration of the 
washout period will be determined. The second screening visit will be performed as follows:

If the washout period is ≤ 4 weeks the investigator should proceed directly to Screening 
visit 2 on the same day and complete all assessments within the next 4 weeks prior to 
Baseline.

If the washout period is more than 4 weeks, the patient/guardian will be instructed to 
initiate necessary washout regimen and return for Screening visit 2 within 4 weeks prior to 
Baseline to complete all assessments prior to Baseline.
The rationale is that in all cases screening visit 2 must occur within the 4 weeks prior to 
Baseline.
All patients evaluated at Screening visits 1 and 2 for eligibility should not be screen failed on 
the basis of a medication requiring washout, unless the patient will be unable to complete the 
washout in the appropriate time frame before Baseline.
If for any reason the patient is a screen failure, the patient may be rescreened. There is no 
restriction on how much time must pass from the date of screen failure and the date of 
rescreening, but > 1 rescreens must be approved by Novartis on a case by case basis (see also 
Section 5.5.1).
For rescreened patients, a new ICF has to be obtained. The date of the new informed consent 
signature must be entered on the Informed consent CRF page to correspond to the new 
screening subject number. Informed Consent for a rescreened subject must be obtained prior 
to performing any study related assessment or collecting any data for the Screening Visit.
For rescreening, all screening assessments must be performed as per protocol, except for the 
tuberculosis (TB) work up, if applicable, if performed within 12 weeks of Baseline. However, 
the subject must repeat the QuantiFERON test. 


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At the discretion of the investigator, laboratory assessments at Baseline visit need not to be 
performed if screening laboratory assessments were performed within 7 days from Baseline. 
Urine pregnancy for appropriate female patients and local CRP assessments should be 
performed at Baseline.
Suggested order of assessments:
Suggested guidelines for conduct of the visit assessments are below:

Laboratory sample collection, including local CRP sample 

Parent/Guardian/Subject to complete patient reported outcomes (PRO) at the study site 
prior to any other study assessments.

Investigator to complete investigator assessments

ACR components sent centrally for ACR derivation/flare occurrence  - results must 
be reviewed prior to Week 12/Treatment Period 2 administration of study treatment

Physical exam (at applicable visits)

All remaining study visit procedures (e.g. vital signs measurements) must be completed 
prior to study treatment dosing.

Contact IRT to register the subject visit, as applicable

Administration of study treatment, as applicable


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Table 6-1
Assessment schedule
Screening1
Treatment Period 1
Treatment Period 2 / 3 (Primary Treatment 
Period)
(Note: a patient enters Tx Period 3 in case 
of flare or when Tx Period 2 completes)
Unscheduled 
visit 
Post-
Treatment 
Safety 
follow-up 
Notes
1
2
Week
Up 
to 
-8
-4 to 
BL
BL 
1
2
3
4
8 
12/
PSW
16 
to 
20
24
28 
to 
48
52
56 
to    
72
76
80 
to 
100
104 / 
TD/ 
PSW
12 Weeks 
after last  
study drug 
dosed
Informed consent 
and optional PG 
informed consent
X
Inclusion/exclusion 
criteria
X2
X2
X2
Demography
X
JPsA/ ERA date of 
diagnosis
X
Cardiovascular 
History
X
X2
X2
Smoking History
X
X2
X2
Relevant Medical 
History / current 
medical conditions
X
X2
X2
Prior / Concomitant 
Medications and 
non-drug therapies
X
X
Update as necessary
Surgeries and  non-
drug  procedures
X
X
Update as necessary
Washout evaluation
instruction
S
Physical Examination S
S
S
S
S
S
S
S
S
S
S
S
Height
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
For correct 


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Screening1
Treatment Period 1
Treatment Period 2 / 3 (Primary Treatment 
Period)
(Note: a patient enters Tx Period 3 in case 
of flare or when Tx Period 2 completes)
Unscheduled 
visit 
Post-
Treatment 
Safety 
follow-up 
Notes
1
2
Week
Up 
to 
-8
-4 to 
BL
BL 
1
2
3
4
8 
12/
PSW
16 
to 
20
24
28 
to 
48
52
56 
to    
72
76
80 
to 
100
104 / 
TD/ 
PSW
12 Weeks 
after last  
study drug 
dosed
dose 
assignment
Vital signs: BP 
and pulse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quantiferon (or PPD 
skin test if required 
by local regulation)
X
Results to be 
available prior 
to BL 
Hepatitis B, C and 
HIV serology3
(only in countries 
where it is required)
S
Results to be 
available prior 
to BL 
ECG
X
X
X
X
X
X
Contact IRT
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Randomization via 
IRT
X
Only 
responders will 
be randomized
Study Drug 
administration4,5
X
X
X
X
X
X
X5
X5
X5
X5
X5
X5
X5
X5
X5
If flare 
confirmed at 
an 
unscheduled 
Tx Period 2 
visit, patient 
will receive Tx 
Period 3 OL 
secukinumab 
and continue to 
next scheduled 
visit


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Screening1
Treatment Period 1
Treatment Period 2 / 3 (Primary Treatment 
Period)
(Note: a patient enters Tx Period 3 in case 
of flare or when Tx Period 2 completes)
Unscheduled 
visit 
Post-
Treatment 
Safety 
follow-up 
Notes
1
2
Week
Up 
to 
-8
-4 to 
BL
BL 
1
2
3
4
8 
12/
PSW
16 
to 
20
24
28 
to 
48
52
56 
to    
72
76
80 
to 
100
104 / 
TD/ 
PSW
12 Weeks 
after last  
study drug 
dosed
PK sampling (pre-
dose)6
X
X
X
X
X
X
X
X
X
X6
X
Immunogenicity7
X
X
X
X
X7
X
Central laboratory 
Hematology/  Clinical 
Blood chemistry/ 
urinalysis (local)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Results to be 
available prior 
to BL. If 
screening labs 
are <7 days 
prior to BL, 
then repeat
labs at BL are 
not necessary
Lipids  (fasting)
X
X
X
X
X
CRP (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Results to be 
available prior 
to BL
Serum pregnancy 
test (for females of  
X


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Screening1
Treatment Period 1
Treatment Period 2 / 3 (Primary Treatment 
Period)
(Note: a patient enters Tx Period 3 in case 
of flare or when Tx Period 2 completes)
Unscheduled 
visit 
Post-
Treatment 
Safety 
follow-up 
Notes
1
2
Week
Up 
to 
-8
-4 to 
BL
BL 
1
2
3
4
8 
12/
PSW
16 
to 
20
24
28 
to 
48
52
56 
to    
72
76
80 
to 
100
104 / 
TD/ 
PSW
12 Weeks 
after last  
study drug 
dosed
childbearing 
potential)
Urine pregnancy test 
(for females of 
childbearing 
potential)
X
X
X
X
X
X
May also be 
performed at 
the 
investigator’s 
discretion at 
any time during 
the study
AEs / SAEs (incl. 
injection site 
reaction)
X
X
Update as necessary
X
X
Physician global 
assessment of 
disease activity 
(PGA) VAS10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CHAQ©
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CHAQ©
includes the 
parent/patient’s 
global 
assessment of 
subject’s 
overall well-
being (VAS).
Active joint count

TJC/SJC

Joint count with 
limited range of 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Screening1
Treatment Period 1
Treatment Period 2 / 3 (Primary Treatment 
Period)
(Note: a patient enters Tx Period 3 in case 
of flare or when Tx Period 2 completes)
Unscheduled 
visit 
Post-
Treatment 
Safety 
follow-up 
Notes
1
2
Week
Up 
to 
-8
-4 to 
BL
BL 
1
2
3
4
8 
12/
PSW
16 
to 
20
24
28 
to 
48
52
56 
to    
72
76
80 
to 
100
104 / 
TD/ 
PSW
12 Weeks 
after last  
study drug 
dosed
motion
Tot. Dactylitis count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tot. Enthesitis count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
Uveitis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Screening1
Treatment Period 1
Treatment Period 2 / 3 (Primary Treatment 
Period)
(Note: a patient enters Tx Period 3 in case 
of flare or when Tx Period 2 completes)
Unscheduled 
visit 
Post-
Treatment 
Safety 
follow-up 
Notes
1
2
Week
Up 
to 
-8
-4 to 
BL
BL 
1
2
3
4
8 
12/
PSW
16 
to 
20
24
28 
to 
48
52
56 
to    
72
76
80 
to 
100
104 / 
TD/ 
PSW
12 Weeks 
after last  
study drug 
dosed
Treatment period 1 
completion form
X
Treatment period 2 
completion form
X
X
X
X
X
X
X
X
X
To be 
performed at 
the completion 
of Tx Period 2.
Study Treatment 
Completion form
X
Follow-up period  
Completion form
X
Scheduled visits in Treatment Periods 2 and 3 are every 4 weeks.
X = assessment to be recorded in clinical data base; S = assessment to be recorded in source documentation; 
BL= baseline; Tx = Treatment; TD = study treatment discontinuation; PSW = Premature subject withdrawal




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6.1
Information to be collected on screening failures 
All patients from whom informed consent was obtained but did not enter into the next study 
period will have the study completion page for the screening period, demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the Investigator and collected only in the source data. Subject 
may discontinue from the study prior to first study drug administration. These subjects are 
considered screening failures. All subjects who have signed informed consent and have 
received the first study drug administration will have all AEs occurring after informed consent 
is signed recorded on the Adverse Event eCRF page. If a patient discontinued prior to 
Baseline IRT provider must be notified within 5 days and the reason for patient not being 
enrolled in Treatment Period 1 will be entered on the screening page disposition CRF page.
6.2
Patient demographics/other baseline characteristics
Subject demographic and baseline characteristic data to be collected on all subjects and 
recorded in the eCRFinclude:

Age, gender, race, ethnicity and source of subject referral.

Relevant JPsA/ERA JIA and relevant medical history/current medical condition data until 
the start of study treatment, such as date of diagnosis of JPsA / ERA, previous JPsA / ERA 
therapies, cardiovascular medical history, smoking history, and surgical history including 
sterilization for females, if applicable.
Whenever possible, diagnoses and not symptoms will be recorded.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF page whenever in their judgment, the test abnormality occurred prior to the informed 
consent signature.
6.3
Treatment exposure and compliance 
All dates and times of study treatment administration will be recorded on the appropriate 
Dosage Administration Record eCRF page.
Drugs administered prior to start of treatment and other drugs/procedures continuing or started 
during the study treatment period will be entered in the Prior/Concomitant medications or 
Significant non-drug therapies eCRF page.
The study treatment will be administered by the study staff directly at the site (except in case 
of healthcare disruption, such as the COVID-19 pandemic/epidemic-refer to Section 5.5.4),
thus compliance is expected to be 100%, unless temporary interruption is needed for safety 
reasons as described in Section 5.5.5. Compliance will also be assessed by a Novartis monitor 
using information provided by the authorized site personnel.
6.4
Efficacy
The efficacy outcome measures used in this study are standard measures used across JIA trials.

JIA ACR 30, 50, 70, 90 and 100 response criteria


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
Physician’s Global Assessment of disease activity (VAS)

Parent’s/patient’s Global Assessment of subject’s overall well-being (VAS included 
within CHAQ©)

Childhood Health Assessment Questionnaire (CHAQ©)

Active joint count

Joint count with limited range of motion

CRP (local)

Inactive disease status
 
 

JADAS score

Total dactylitis count

Total enthesitis count
 
All efficacy assessments should be performed prior to administration of study treatment. 
6.4.1
JIA ACR response criteria
Standard ACR paediatric Criteria (JIA ACR criteria) consist of 6 core components which will 
be assessed as scheduled in Table 6-1.  JIA ACR 30/50/70/90/100 are defined as 30%, 50%, 
70%, 90% and 100% improvement from baseline respectively in a minimum of three 
variables in the core set with no more than one variable worsening more than 30% as defined 
in the ACR criteria.
The 6 core set variables are summarized below:

Physician global assessment of disease activity on a 0 - 100 mm VAS from 0 mm = no 
disease activity to 100 mm = very severe disease activity

Parent or patient’s (if appropriate in age) Global Assessment of Subject’s overall well-
being on a 0-100 mm VAS from 0 mm = very well to 100 mm = very poor.

Functional ability: Childhood Health Assessment Questionnaire (CHAQ©) 

Number of active joints using the ACR definition (any joint with swelling or in the 
absence of swelling, limitation of motion accompanied by either pain on motion or 
tenderness not due to deformity)

Number of joints with limited range of motion

Laboratory measure of inflammation: CRP (mg/L)


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The respective response variables listed above will be used by a central vendor to determine 
ACR Pediatric response, responder status at Week 12, and flare occurrence in Treatment 
Period 2. These results will be communicated to the investigator prior to the patient leaving 
the study site. Additionally, these components will be used to determine JADAS and inactive 
disease status (Wallace et al. 2011) as part of secondary 
 analyses. 
6.4.2
Physician’s Global Assessment of disease activity (VAS)
The physician will rate the patient’s current condition on a 0-100 mm VAS (Appendix 5), 
ranging from no disease activity (0 mm) to very severe disease activity (100 mm), at each 
scheduled visit for all patients throughout the study.
Scores on the 100 mm linear scale will be measured to the nearest millimeter from the left. To 
enhance objectivity, the physician must not be aware of the specific parent’s or patient’s 
global assessment of patient’s overall well-being, when performing his own assessment on 
that patient.
6.4.3
Parent’s/patient’s Global Assessment of subject’s overall well-being 
(VAS)
The parent’s or patient’s global assessment of the patient’s overall well-being will be assessed 
on the VAS that is part of the CHAQ©. The VAS scale ranges from 0-100 mm, from very well 
(0 mm) to very poor (100 mm). 
Scores on the 100 mm linear scale will be measured to the nearest millimeter from the left.
6.4.4
Childhood Health Assessment Questionnaire (CHAQCopyright)
The Childhood Health Assessment Questionnaire, CHAQ© (Appendix 6), will be used to 
assess physical ability and functional status of patients as well as quality of life. The disability 
dimension consists of multiple choice and VAS items concerning difficulty in performing 
eight common activities of daily living; dressing and grooming, arising, eating, walking, 
reaching, personal hygiene, gripping and activities. Subjects choose from four response 
categories, ranging from ‘without any difficulty’ to ‘unable to do’. 
This questionnaire should be completed by the parent (or, for patients 18 years and older, the 
questionnaire will be completed together by both the patient and parent) according to schedule 
in Table 6-1. The CHAQ© will be completed only in a validated version of the instrument in 
the language understandable to the parent and/or patient.
Completed questionnaires will be reviewed and examined by the investigator, before the 
clinical examination, for responses which may indicate potential AEs or SAEs. If AEs or 
SAEs are confirmed, then the physician must record the events as per instructions given in 
Section 7.1 and Section 7.2 of the protocol. Investigators should not encourage the patients 
and/or parents to change the responses reported in the PRO questionnaires.
6.4.5
Active joint count
The number of joints with active arthritis at each visit will determined by applying the ACR 
definition to the number of joints with swelling, tenderness and limited range of motion at 


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each scheduled visit for all patients throughout the study (see Section 6.4.6 and Section 6.4.8
for more detail).
Joint counts will be performed by an assessor who must be well trained and part of the site
personnel. For there to be consistency between the joint assessments, it is strongly 
recommended that the same evaluator perform these assessments at all visits.
The ACR definition of active arthritis is any joint with swelling or, in the absence of swelling, 
limitation of motion accompanied by either pain on motion or tenderness not due to deformity.  
The active joint count will therefore range from 0 to 73.
6.4.6
Joint counts with limitation of motion
A total of 69 joints will be assessed for limitation of motion at each scheduled visit for all 
patients throughout the study.  The same 75 joints assessed for tenderness (Section 6.4.8) will 
also be assessed for limitation of motion excluding the 2 sternoclavicular, 2 acromioclavicular 
joints as well as the 2 sacroiliac joints. 
For there to be consistency between the joint assessments, it is strongly recommended that the 
same evaluator perform these assessments at all visits.
6.4.7
C-reactive Protein (CRP) 
C-reactive Protein (CRP) will be determined at each scheduled visit for all patients throughout 
the study and during unscheduled visits where efficacy is assessed.
CRP is used as an inflammation marker, to determine its severity, and to monitor response to 
treatment.
CRP (mg/L) will be measured at the local lab, including during unscheduled visit for flares, 
and the actual sample collection date, time and result will be collected. 
6.4.8
Tender and Swollen Joint Count 
Tender 75 joint count (TJC)
The following 75 joints will be scored as either tender or not tender:   

Temporomandibular joints: 2 

Sternoclavicular joints: 2 

Acromioclavicular joints: 2 

Shoulders: 2 

Elbows: 2 

Wrists: 2

Hands: 

distal interphalangeal 

10 proximal interphalangeal 

10 metacarpophalangeal  

Hip: 2 




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
Anterior Entheses: Greater trochanter of the Femur; Medial condyle of the femur; Lateral 
condyle of the femur

Posterior Entheses: Greater tuberosity of humerus; medial epicondyle of humerus; lateral 
epicondyle of humerus, Achilles tendon; and calcaneal insertion of the plantar fascia.


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6.4.20
Juvenile Arthritis Disease Activity Score (JADAS)
Juvenile Arthritis Disease Activity Score (JADAS) (Consolaro et al. 2009) will be derived 
from the following assessments performed at all scheduled visits:

physician global assessment of disease activity; 

parent/patient global assessment of overall well-being; 

active joint count; 

CRP (local)


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6.4.22
Inactive Disease status
Clinical inactive disease definition is adapted from the ACR criteria of Wallace et al 2011. All 
must be met:

No joints with active arthritis 

No uveitis

CRP value within normal limits for the laboratory where tested or, if elevated, not 
attributable to JIA

Physician’s global assessment of disease activity score ≤ 10mm

Duration of morning stiffness attributable to JIA  ≤15 min
6.5
Safety 
Evaluation of all AEs and SAEs including injection site reactions, abnormal findings in ECGs, 
physical examination, vital signs, and laboratory assessments will occur. Anti-secukinumab 
antibody development (immunogenicity) will also be evaluated.
All blood draws and safety assessments should be done prior to study treatment 
administration. Appropriate safety assessments (e.g., evaluation of AEs and SAEs including 
injection site reactions) should be repeated after the dose is administered.

Evaluation of AE/ SAEs

Physical examination

Vital signs

Height and weight

QuantiFERON TB-Gold test (or PPD skin test if <5 years of age or required by local 
regulation)

Hepatitis B, Hepatitis C and HIV serology (screening for patients who require it by local 
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
Electrocardiogram

Laboratory evaluations (Hematology, Clinical Chemistry, Lipid Panel, Urinalysis)

Pregnancy and assessment of fertility

Tolerability of secukinumab 

Immunogenicity
6.5.1
Physical examination
The physical examination will include the examination of general appearance, skin, neck, 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological system.
Information for all physical examinations must be included in the source documentation at the 
study site system. Significant findings that are present before signing the ICF must be 
included in the relevant medical history eCRF page. Significant findings made after signing 
the ICF which meet the definition of an AE must be recorded in the Adverse Event section of 
the eCRF.
6.5.2
Vital signs 
This will include blood pressure and pulse rate measurements after 5 minutes rest in sitting 
position. If possible, vital signs assessments should be performed by the same study site staff 
member using the same validated device throughout the study.
Clinically notable vital signs are defined in Appendix 1.
6.5.3
Height and weight 
Height in centimeters (cm) will be assessed with the patient wearing indoor clothing, but 
without shoes, socks, hats or hair accessories interfering with assessment, using a stadiometer 
that is calibrated on a regular basis. Height measurements will be performed twice and the 
reported height will be the mean of the 2 measurements.  
Body weight (to the nearest 0.1 kilogram (kg) will be assessed with the patient wearing 
similar clothing (indoor clothing but without shoes) at each visit and where possible, by the 
same study site staff member using the same scale throughout the study.
6.5.4
QuantiFERON TB-Gold test or PPD skin test
A QuantiFERON TB-Gold test (or a PPD skin test if patient < 5 years of age or required by
local regulations) must be performed at either Screening visit 1 or 2 and the results have to be 
known prior to Baseline to determine the subject’s eligibility for the trial. The QuantiFERON 
TB-Gold test will be performed by the central laboratory. Details on the collection, processing 
and shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual.
If a PPD skin test is required based on age or local regulations, it can be performed at either 
Screening visit 1 or 2, and read before Baseline visit to determine the subject’s eligibility for 
the trial. The test dose is bioequivalent to 5 tuberculin units of standard PPD injected 
intradermally, usually into the volar surface of the forearm. The site is cleaned and the PPD 


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extract is then injected into the most superficial layer under the skin. If given correctly, the 
injection should raise a small wheal of about 5 mm, which resolves within 10-15 minutes. 
Because the reaction (induration) will take 48 - 72 hours to develop, the subjects must return 
to the study site within that time for evaluation of the injection site. This will determine 
whether the subject has had a significant reaction to the PPD test. A reaction is measured in 
millimeters of induration (hard swelling) at the site. A PPD skin induration ≥ 15 mm for 
children ≥ 4 years and ≥ 10 mm for children < 4 years of age (or according to local 
practice/guidelines) is interpreted as a positive result.
Subjects with a positive test (QuantiFERON TB-Gold test or PPD skin test) may participate in 
the study if (1) active TB is ruled out and (2) the patient is willing and able to complete a 
minimum of 4 weeks of latent TB treatment prior to initiating treatment with secukinumab 
and (3) the patient is willing to continue and complete the latent TB treatment (according to 
local guidelines) in parallel with study treatments.  In the absence of local guidelines the US 
CDC guidelines for treatment of latent TB must be followed i.e. INH treatment for 9 months. 
Patients diagnosed with active TB should be referred for treatment as deemed appropriate and 
are not eligible to participate in this study.  
6.5.5
Laboratory evaluations
A central laboratory will be used for analysis of all specimens listed below (except dipstick 
urinalysis and CRP which are done locally). Details on the collection, processing and 
shipment of samples, and reporting of results by the central laboratory are provided in the 
laboratory manual. For the identification of clinically notable values, see Appendix 1. All 
subjects with laboratory tests containing clinically significant abnormal values are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 
related AE, is defined.
6.5.5.1
Hematology
Hemoglobin, platelets, red blood cell (RBC), white blood cell (WBC) and differential white 
blood cell counts will be measured at scheduled visits as per Table 6-1.
6.5.5.2
Clinical chemistry
Serum chemistries will include glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT (Gamma-glutamyl transferase), alkaline phosphatase, sodium, potassium, 
bicarbonate, calcium, phosphorus, total protein, albumin and uric acid will be measured at 
scheduled visits as per Assessment Schedule in Table 6-1.
6.5.5.3
Urinalysis 
Dipsticks will be provided by the central laboratory to the sites for local urinalysis 
assessments at scheduled visits as per Table 6-1. The urinalysis results for standard 
parameters such as protein, glucose, blood and WBCs will be recorded in the appropriate 
eCRF page.


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If the dipstick result is positive for protein, glucosuria and/or blood, a urine sample will be 
sent to central laboratory for microscopic analysis as indicated in the renal safety section 
(Section 7.4). 
6.5.5.4
Lipid panel
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
total cholesterol, and triglycerides will be measured from a fasting blood sample that will be 
collected at Baseline and at visits indicated in Table 6-1.
6.5.6
Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed as indicated in Table 6-1. All ECGs must be 
performed on the ECG machines provided for the study. ECGs must be recorded after 10 
minutes rest in the supine position to ensure a stable baseline. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection followed by vital signs 
and blood sampling. The Fridericia QT correction formula (QTcF) should be used for clinical 
decisions.
All ECGs will be centrally and independently reviewed. Instructions for the collection and 
transmission of the ECGs to the independent reviewer will be provided in the ECG 
Investigator manual.
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs should be performed to confirm the safety finding. Clinically 
significant ECG findings at baseline must be discussed with the sponsor before administration 
of investigational treatment. Clinically significant abnormalities should be recorded on the 
relevant section of the medical history/Current medical conditions eCRF page as appropriate.  
6.5.7
Pregnancy and assessments of fertility
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female adolescents who are menarchal or who become 
menarchal during the study. 
A serum β-hCG test will be performed in all women of childbearing potential at Screening 
visit 2.  Urine pregnancy tests are performed at Baseline and at visits indicated in Table 6-1 in 
all female subjects of childbearing potential. Additional pregnancy tests may be performed at 
the investigator’s discretion during the study. A positive urine pregnancy test requires 
immediate interruption of study treatment until serum β-hCG is performed and found to be 
negative. If positive, the subject must be discontinued from study drug. 
All menarchal girls and their parents/caregivers should be informed about the potential risks 
of pregnancy and the need to prevent pregnancy during the study. 
It is important to be sensitive in introducing this issue, as understanding and comprehension 
of puberty, sexual activity, pregnancy and contraception is influenced by age, as well as 
factors such as precocity, socio(educational) economic and familial background. These 
discussions with the patient and her parents/caregivers are therefore best performed by 


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investigators familiar with the adolescent and her family and should be guided by 
requirements of the local regulatory authorities. These discussions should take into account 
the socio-economic, cultural factors and religious beliefs of the adolescent participant and her 
family. The Investigator should also discuss the management of the pregnancy test results 
with the patient and her parents/caregivers. The privacy of the adolescent should be 
considered in accordance with the local law and ethics.
Female patients of child-bearing potential, who are or might become sexually active, must be 
informed of the need to prevent pregnancy during the study and for 20 weeks after study 
completion. At a minimum, the acceptable effective contraception is:

Abstinence

Barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps). For UK 
(United Kingdom): with spermicidal foam/gel/film/cream/vaginal suppository

Use of established oral, injected or implanted hormonal methods of contraception, 
intrauterine device (IUD) or intrauterine system (IUS)
The decision on the contraceptive method should be reviewed at least every 3 months to 
evaluate the individual need and compatibility of the method chosen and the need for 
additional pregnancy testing.
6.5.8
Tolerability of secukinumab
Tolerability will be assessed by adverse events, laboratory values, injection site reactions and 
immunogenicity.
6.5.9
Immunogenicity
Blood samples for immunogenicity (anti-AIN457 antibodies) will be taken pre-dose at the 
scheduled time points as indicated in Table 6-1. 
In addition, if a subject discontinues from the study at any time, he/she will need to provide a 
sample at the last visit. The actual sample collection date and exact time will be entered on the 
Immunogenicity Blood collection eCRF page. Sampling problems will be noted in the 
Comment section of the eCRF page.
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein.
A laboratory manual will be provided to investigators with detailed information on sample 
collection, handling and shipment.
Tubes and preprinted labels will be provided by the central lab to the sites. 
Analytical Method
An electrochemiluminescence method will be used for the detection of potential anti-
secukinumab antibody formation. The detailed method description to assess immunogenicity 
will be described in the bioanalytical raw data of the study and in the respective Bioanalytical 
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Table 6-4
IG sample log
Week
IG Sample log
0
301
12
302
52
303
104
304
112
305
If an IG sample is collected at an unscheduled visit, the sample numbers will follow the 
pattern: 3001, 3002, etc
6.5.10
Appropriateness of safety measurements 
The safety measures used in this study are standard for a use of a biologic in patients with 
JPsA / ERA and are standard and adequate for this indication/subject population. Quantiferon 
or PPD testing at screening is performed to rule out the presence of active tuberculosis. The 
frequency of the visits and the close medical monitoring will ensure possible safety concerns 
are properly addressed.
6.6
Other assessments
6.6.1
Resource utilization 
No measures of Healthcare Resource Utilization (RU) will be collected in the study.
6.6.2
Pharmacokinetics 
PK samples will be obtained for all subjects and the secukinumab concentrations will be 
assessed in serum. The PK samples will be collected pre-dose at scheduled visits/ time points 
as indicated in Table 6-1. 
All blood samples will be drawn by direct venipuncture in a forearm vein.
The actual sample collection date and exact time will be entered on the PK blood collection 
summary eCRF page. Sampling problems will be noted in the Comments section of the eCRF 
page.
The bioanalyst will receive a copy of the randomization schedule to facilitate analysis of the 
PK samples. The bioanalyst will provide the samples’ concentration data to the team under 
blinded conditions. Bioanalyst will keep this information confidential until clinical database 
lock.
PK sample handling, labeling and shipment instructions
Laboratory manuals will be provided by the central laboratory with detailed information on 
sample collection, sample handling and shipment.
Tubes and labels will be provided by the central laboratory with study/sample type 
information pre-printed on the label.


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PK samples should be collected at treatment Period 2 visits where a disease flare is confirmed.  
If a flare is confirmed at an unscheduled visit, the sample number will be 1001 as described in
Table 6-5.
Table 6-5
PK sample log 
Week
Time
Sample number
Dose reference ID
0 1
pre-dose
10
1
2 1
pre-dose
20
1
4 1
pre-dose
30
1
8 1
pre-dose
40
1
12 1
pre-dose
50
1
16 2
pre-dose
51
1
20 2
pre-dose
52
1
24 1
pre-dose
60
1
28 2
pre-dose
61
1
32 2
pre-dose
62
1
36 2
pre-dose
63
1
40 2
pre-dose
64
1
44 2
pre-dose
65
1
48 2
pre-dose
66
1
52 1
pre-dose
70
1
56 2
pre-dose
71
1
60 2
pre-dose
72
1
64 2
pre-dose
73
1
68 2
pre-dose
74
1
72 2
pre-dose
75
1
76 1
pre-dose
80
1
80 2
pre-dose
81
1
84 2
pre-dose
82
1
88 2
pre-dose
83
1
92 2
pre-dose
84
1
96 2
pre-dose
85
1
100 2
pre-dose
86
1
104 1,3
672h (Any time at visit)
90
2
112 1,3
2016h (Any time at visit)
100
2
Unscheduled4
Pre-dose
1001
1.
Required samples in every subject
2.
PK sample only taken only from subjects with flare at that visit
3.
Scheduled time is relative to last dose given at Week 100
4.
Sample collected for subjects with confirmed flare in Treatment Period 2 occurring at an 
unscheduled visit.
If a PK sample is collected at an unscheduled visit, the sample numbers will follow the pattern: 
1001, 1002, etc.




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7
Safety monitoring
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign, including abnormal laboratory findings, symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF page under the signs, symptoms 
or diagnosis associated with them, accompanied by the following information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment (no/yes), or other treatment (no/yes), or both, or 
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
its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (see Section 7.2.1 for definition of SAE)

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 adjusted/temporarily interrupted 

investigational treatment permanently discontinued due to this adverse event 

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2.1 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient/guardian during the study as 
needed. Any new information regarding the safety profile of the medicinal product that is 
identified between IB updates will be communicated as appropriate, for example, via an 
Investigator Notification or an Aggregate Safety Finding. New information might require an 
update to the informed consent and has then to be discussed with the patient/guardian.
The Investigator must also instruct each patient/guardian to report any new adverse event 
(beyond the protocol observation period) that the patient/guardian, or the patient’s personal 
physician, believes might reasonably be related to study treatment. This information must be 
recorded in the investigator’s source documents; however, if the AE meets the criteria of an 
SAE, it must be reported to Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect


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
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH)-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 12 weeks after last administered dose of study treatment 
or 30 days after the subject has stopped study participation (whichever is later) must be 
reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced 
after this period should only be reported to Novartis if the Investigator suspects a causal 
relationship to study treatment. 
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.


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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The Investigator must assess the relationship of each SAE to the study 
treatment, complete the SAE Report Form in English, and submit the completed form within 
24 hours to Novartis. Detailed instructions regarding the submission process and requirements 
for signature are to be found in the Investigator folder provided to each site. 
Follow-up information is submitted as instructed in the Investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
Investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
7.3
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the Investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-1 in Appendix 2.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 


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a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered 
during the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
which exceeds the normal limits for the patient’s gender and age during normal 
hydration status and continues for ≥3 consecutive months.

Urine event

new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the Investigator or designated personnel at the trial site as summarized in 
Appendix 3.
7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.


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Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF page irrespective of whether or not associated 
with an AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will 
be collected and reported in the safety database irrespective of it being associated with an 
AE/SAE.
Table 7-1
Treatment Errors
Treatment error 
type
Document in Dose 
Administration 
(DAR) eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an
SAE
Misuse/Abuse
Yes
Yes, 
Yes, even if not 
associated with a SAE
7.6
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. Where possible, 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.
Where possible, pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and 
reported by the Investigator to the local Novartis Drug Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and Good Clinical Practice (GCP) compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of patient records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.  Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis CRA organization. Additionally, a 
central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis Clinical Teams to assist with trial oversight.


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The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The Investigator must also keep the original informed consent form signed by 
the patient/guardian (a signed copy is given to the patient/guardian).
The Investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained.
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
Adapted ACR Pediatric response and disease flare occurrence will be determined centrally 
from data (ACR components) provided by the investigator.  These will be derived and 
communicated to the investigator the same day.
8.3
Database management and quality control
Novartis staff 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.
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and adverse 
events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Laboratory samples (except for CRP) will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO).




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9
Data analysis 
A general description of the statistical methods to be used to analyze the efficacy and safety 
data is outlined below. Specific details will be provided in the Statistical Analysis Plan.
This trial is conducted as a three-part study. Data summaries may be presented separately for 
each study part and for combined study parts where appropriate. 
Unless otherwise stated, all statistical tests will be two-sided at the 5% significance level and 
accompanied by two-sided 95% confidence intervals where appropriate.
Any data analysis carried out independently by the Investigator should be submitted to 
Novartis before publication or presentation.
The trial follows the recommendation of the Consolidated Standards of Reporting Trials 
(CONSORT) statement and results are reported for the intention-to-treat population (Schulz et 
al 2010).
9.1
Analysis sets 
The following analysis sets will be used in this trial:
The randomized set will be defined as all subjects who were randomized in Treatment Period 
2. Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be 
excluded from the randomized set.
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given in Treatment Period 2.
The Full Analysis Set (FAS) Treatment Period 2 will consist of all randomized patients who 
received at least one dose of study drug in Treatment Period 2. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment they were assigned to at 
randomization in Treatment Period 2.
The FAS Treatment Period 1 will consist of all patients who received at least one dose of 
study drug in Treatment Period 1.
The FAS Treatment Period 3 will consist of all patients who received at least one dose of 
study drug in Treatment Period 3. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment they were assigned to at randomization in Treatment 
Period 2.
The Safety Set for a treatment period will consist of all patients that received at least one dose 
of study drug in that treatment period. Patients will be analyzed according to treatment 
received. Of note, the statement that a patient had no adverse events also constitutes a safety 
assessment.


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9.2
Patient demographics and other baseline characteristics 
Demographics and baseline characteristics
Demographic and baseline characteristics will be summarized descriptively for the FAS for 
Treatment Period 1 and Treatment Period 2 by treatment group and overall. Continuous 
variables will be summarized by mean, standard deviation, median, minimum, maximum, 25% 
and 75% quantiles, and number of patients with non-missing data. Categorical variables will 
be summarized by absolute frequencies and percentages. 
Comparability of treatment groups in Treatment Period 2 with respect to the demographic and 
baseline characteristics will be assessed descriptively.
Relevant medical history/current medical conditions will be listed and summarized by system 
organ class and preferred term of the MedDRA dictionary.
9.3
Treatments 
Study treatment
The exposure to study drug (number of injections) and duration of exposure (days) will be 
summarized and listed.
The number and percentage of patients taking medication and non-drug therapies will be 
summarized by preferred term according to the WHO Drug Reference List dictionary (which 
employs the Anatomical Therapeutic Chemical classification system). Separate summaries 
will be provided for therapies that ended prior to Treatment Period 1 (prior therapies) and 
were active after the start of Treatment Period 1 (concomitant therapies).
The FAS corresponding to the study periods summarized will be used.
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
The primary efficacy endpoint will be time to disease flare event in Treatment Period 2, which 
is defined as the interval between the date of randomization to the date of first occurrence of 
disease flare event. The analysis of the primary efficacy endpoint will be based on the FAS 
Treatment Period 2.
All subjects who enter Treatment Period 2 will be followed until the sooner of either 
experiencing a disease flare or the end of Treatment Period 2 when 33 flare events are 
observed. Subjects who have not experienced flare event at the end of Treatment Period 2 data 
(as defined in Section 3.1) or discontinue prematurely from Treatment Period 2 before it 
closes for reasons other than experiencing a disease flare will be censored at the date of the 
last efficacy evaluation in Treatment Period 2.
Statistical model, hypothesis, and method of analysis
The primary objective for Treatment Period 2 of the study is to show superiority of 
secukinumab over placebo regarding the primary variable in Treatment Period 2.


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The following statistical hypothesis will be tested once the required number of flares has been 
observed and the study has been stopped:
H0: 1-SAIN(t) ≥ 1- SPla(t) 
HA: 1-SAIN(t) < 1- SPla(t)
at each time point t, with SAIN(t) and SPla(t) being the survivor functions in the secukinumab 
and placebo treatment group at time t.
The two treatment groups will be compared using a one-sided stratified Logrank test with the
stratification factor of JIA category (ERA or JPsA) at the 2.5% level of significance. Hazard 
ratios and their associated 95% confidence intervals will be estimated based on a Cox 
proportional hazards model with treatment and stratification factor as explanatory variables.
The Kaplan-Meier estimates of the proportion of patients with the flare event at selected 
landmark points, along with its 95% confidence intervals using Greenwood’s formula, will be 
provided. The primary analysis will be based on the FAS for Treatment Period 2.
Handling of missing values/censoring/discontinuations
All patients in Treatment Period 2 will have a value of time to flare either by having an event 
or being censored.
Supportive analyses 
For sensitivity purposes, the primary analysis will be repeated using an unstratified log-rank 
test.
The primary analysis will be repeated where patients discontinuing the study for any reason 
will be considered as having flare at the time of study discontinuation.
Subgroup analyses for the primary efficacy variable will be performed for stratification factor: 
JIA category (ERA or JPsA).
Analysis of secondary variables
9.4.2
Efficacy variables 
The analysis of secondary variables is descriptive only for FAS. Summary statistics will be 
presented. Summary statistics for continuous variables include N, mean, standard deviation, 
minimum, median, maximum, 25% and 75% quantiles, and number of patients with non-
missing data. For binary or discrete variables the number of subjects in each category and 
relative frequencies will be provided.
The following secondary efficacy endpoints will be analyzed for all patients and each JIA 
category by descriptive statistics in Treatment Period 1:

JIA ACR 30/50/70/90/100 and inactive disease status 

Each JIA ACR core component 

Change from baseline Juvenile Arthritis Disease Activity Score (JADAS) score

Total enthesitis count

Total dactylitis count


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The following secondary efficacy endpoints will be analyzed for all patients and each JIA 
category by descriptive statistics in Treatment Period 2, and/or other periods, as appropriate:

JIA ACR 30/50/70/90/100  and inactive disease status  


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9.4.4
Safety variables 
The analysis of safety data may be provided for each Treatment Period separately and all 
periods combined, as appropriate. The analysis of safety data will be conducted on the Safety 
Set, which includes subjects who receive any study treatment and have at least one post-
baseline safety assessment. All data will be analyzed according to the treatment actually 
received.
The safety variables to be analyzed include Adverse events (AEs), clinical laboratory tests 
(hematology and chemistry), physical examination results, ECGs, and deaths. Safety variables 
are to be tabulated by descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum; or n and percent). No formal statistical testing is planned.
9.4.4.1
Adverse events
Adverse events will be coded using the MedDRA dictionary that provides the primary system 
organ class and preferred term information. Adverse events will be presented in two parts:

Adverse events (including infections)

Infectious adverse events
Adverse events will be summarized by presenting, for each study period and each treatment 
group, the number and percentage of patients having any adverse event, having any adverse 
event in each primary system organ class and having each individual adverse event based on 
the preferred term. All other information collected (e.g. severity, relationship to study drug) 
will be tabulated and listed as appropriate. 
Deaths, serious adverse events, and adverse events leading to discontinuation of study drug 
will be summarized by primary system organ class and preferred term and listed.
9.4.4.2
Vital signs 
Vital signs data will be summarized by presenting descriptive statistics for the absolute values 
and changes from baseline. All information collected will be listed by patient and abnormal 
values (see Appendix 1) will be flagged.
9.4.4.3
Laboratory evaluations
Laboratory data will be summarized in the same way as vital signs. In addition, shift tables 
based on normal ranges and incidence rates of notable abnormalities (see Appendix 1) will be 
presented.
Pharmacokinetics
All completed subjects with quantifiable pharmacokinetic (PK) measurements of 
secukinumab will be included in the pharmacokinetic data analysis. Serum concentrations will 
be expressed in mass per volume units. All concentrations below the limit of quantification or 
missing data will be labeled as such in the concentration data listings. PK concentrations will 
be summarized by visit and treatment group. In addition to mean, standard deviation, 
coefficient of variation, median and quartiles, the geometric mean and geometric coefficient 
of variation and n(log) will be presented.




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is estimated to be at least 60 and at most 80 patients.  Assuming approximately 70% to 85% 
of patients respond in Treatment Period 1, the estimated minimum number of patients treated 
in Treatment Period 1 is between 70 and 86. Under the assumption of 12 months of accrual 
duration, the total maximum expected study duration is 33 months. The expected number of 
flare events is 12 and 21 respectively for secukinumab and placebo group in Treatment Period 
2.
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC)-approved informed consent, or, if incapable of doing so, after such consent 
has been provided by a legally acceptable representative(s) of the patient. In cases where the 
patient’s representative gives consent, the patient must be informed about the study to the 
extent possible given his/her understanding. If the patient is capable of doing so, he/she must 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form. Informed consent must be obtained before conducting any study-specific 
procedures (e.g. all of the procedures described in the protocol). The process of obtaining 
informed consent must be documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the Investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
In pediatric patients (< 18 years of age) parental permission and, whenever possible, child 
assent is needed instead of the procedure for informed consent used for research involving 
adults. In general, one or both parents or a guardian must be provided with the information 
ordinarily required for informed consent, so that they may decide whether to allow the child to 
participate, and children capable of assent must also express their willingness to participate. 
These forms will be submitted for IRB/IEC/REB approval.
Women of child bearing potential/guardian must be informed that taking the study treatment 
may involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study they must adhere to the contraception requirement for 
the duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.




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11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.


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References (available upon request)
Barba G, Buck C, Bammann K, et al (2014) Blood pressure reference values for European 
non-overweight school children: the IDEFICS study. Int J Obes (Lond); 38 Suppl 2:S48-56. 
Brunner H, Lovell D, Finck B et al (2002) Preliminary definition of disease flare in juvenile 
rheumatoid arthritis. J Rheumatol ;29:1058-1064.
Beuckelman T, Patkar N, Saag K, et al (2011) American College of Rheumatology 
Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Initiation and Safety 
Monitoring of Therapeutic Agents for the Treatment of Arthritis and Systemic Features. 
Arthritis Care & Research; Vol. 63 (4): 465-482.
Consolaro A, Ruperto N, Bazso A, et al (2009) Development and validation of a composite 
disease activity score for juvenile idiopathic arthritis. Arthritis Rheum; 61(5):658-66.
Consolaro A, Bracciolini G, Ruperto N, et al. (2012) Remission, minimal disease activity, and 
acceptable symptom state in juvenile idiopathic arthritis: defining criteria based on the 
juvenile arthritis disease activity score. Arthritis Rheum. Jul;64(7):2366-74. 
Cosentyx® (Secukinumab) label, 2016
EMA (2015). Guideline on clinical investigation of medicinal products for the treatment of 
juvenile idiopathic arthritis
Feld LG and Corey H (2007) Hypertension in childhood, Pediatric in Review 28: 283-98.
Horneff 2009, G. Horneff G and Burgos-Vargas R (2009) Juvenile idiopathic arthritis. 
Subgroup characteristics and comparisons between rheumatoid arthritis-like subgroups and 
ankylosing spondylitis-like subgroups.  Clin Exp Rheumatol; 27 (Suppl. 55): S131- 138.
Lovell DJ, Giannini EH, REIFF A, et al (2000)  Etanercept in Children with Polyarticular 
Juvenile Rheumatoid Arthritis. The New England Journal of Medicine 2000; volume 342 (11) 
763-69
Lovell DJ, Ruperto N, Giannini EH, et al (2013) Advances from clinical trials in juvenile 
idiopathic arthritis. Nat Rev Rheumatol 2013; 9: 557–563.
Magni-Manzoni S, Rossi F, Pistorio A et al. (2003) Prognostic factors for radiographic 
progression, radiographic damage, and disability in juvenile idiopathic arthritis. Arthritis
Rheum. 2003 Dec;48(12):3509-17.
Martini (2003) Are the Number of Joints Involved or the Presence of Psoriasis Still Useful 
Tools to Identify Homogeneous Disease Entities in Juvenile Idiopathic Arthritis? J 
Rheumatol;30;1900-1903.
Martini A. (2012) It is time to rethink juvenile idiopathic arthritis classification and 
nomenclature Ann Rheum Dis;71:1437–1439.
Petty RE, Southwood TR, Manners P, et al (2004) International League of Associations for 
Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 
2001; J Rheumatol. 2004 Feb;31(2):390-2.




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Appendix 1: Clinically notable laboratory values and vital 
signs
The following defined notable laboratory or vital sign abnormalities, except creatinine 
clearance, will be communicated at the same time as they are sent to investigators to Novartis.  
Novartis will determine if further consultations with Investigator(s) are appropriate.
Laboratory Criteria
Newly occurring selected notable laboratory abnormalities in pediatric patients at the time of 
the assessment:
Biochemistry

Alanine aminotransferase (ALT)(SGPT): 

> Upper Limit of Normal (ULN)

≥3 x ULN

≥5 x ULN

≥8 x ULN

≥10 x ULN

Aspartate aminotransferase (AST) (SGOT): 

>ULN

≥3 x ULN

≥5 x ULN

≥8 x ULN

≥10 x ULN

Total Bilirubin (TBL)

>ULN, 

≥1.5xULN, 

≥ 2xULN

ALP 

>ULN

≥1.5xULN, 

≥2xULN, 

≥3x ULN 

≥5xULN

ALT and/or AST >3x-, 5x-, 10x ULN accompanied by TBL >2xULN

ALT or AST >3x ULN and TBL >2x-, and ALP >2 x ULN.

ALP >3x ULN and TBL >2x ULN


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
Gamma-Glutamyltransferase (GGT): 

>ULN

≥3 x ULN

≥5 x ULN

Creatinine (serum): ≥1.5 x ULN

Creatinine clearance (Schwartz formula§): ≥ 25% decrease from baseline, ≥3 months in 
duration

Protein urine dipstick: 
New protein ≥1+, ≥3 months in duration

Creatinine clearance (Schwartz formula§): ≥ 25% decrease from baseline, ≥3 months in 
duration in combination with protein urine dipstick resulting in new protein ≥1+, ≥3 
months in duration

Total Cholesterol: ≥1.5xULN

Triglycerides: ≥5.7 mmol/L.
§Schwartz formula- Creatinine clearance (mL/min/1.73m2)  was derived using the following 
formula 0.413 x length (cm) / (serum creatinine (mg/dL) (Schwartz et al 2009).
For creatinine clearance only, baseline value for the decrease from baseline criterion will be 
calculated as the average of all values prior to the first dose (i.e. screening and baseline 
values).
Hematology

Hemoglobin: ≥ 20 g/L decrease from baseline, 
or < 85 g/L for < 16 years of age
< 100 g/L for ≥ 16 years of age

Absolute neutrophils:
Grade 1: <LLN – 1.5 x 10E9/L
Grade 2: <1.5 – 1.0 x 10E9/L
Grade 3: <1.0 – 0.5 x 10E9/L
Grade 4: <0.5 x 10E9/L

Criteria based on CTC grades for platelet count:
Grade 1: <LLN – 75.0 x 10E9/L
Grade 2: <75.0 – 50.0 x 10E9/L
Grade 3: <50.0 – 25.0 x 10E9/L
Grade 4: <25.0 x 10E9/L

Criteria based on CTC grades for WBC:
Grade 1:<LLN – 3.0 x10E9/L
Grade 2:<3.0 – 2.0 x10E9/L
Grade 3:<2.0 – 1.0 x10E9/L
Grade 4: <1.0 x10E9/L

Absolute Lymphocytes: < LLN 


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
Absolute Eosinophils: ≥ 1.1 x ULN

Absolute Eosinophils: ≥0.45 x 109/L 
Vital Signs
The following criteria will be used.
Note: The age is the age at the time of the visit. 
Systolic blood pressure (mmHg):

High: >ULN and Increased >20 in change from baseline
Diastolic blood pressure (mmHg):

High: >ULN and Increased >20 in change from baseline
Pulse (bpm)§: 

High: >ULN and Increased >20 in change from baseline

Low: <LLN and Decreased >20 in change from baseline
Note: Only post-baseline values will be flagged as notable abnormalities
Table 13-1
Reference ranges for systolic and diastolic blood pressures and pulse.
Age
Systolic Blood 
Pressure lower and 
upper limits
(mmHg)
Diastolic Blood 
pressure lower and 
upper limits
(mmHg)
Pulse lower and 
upper limits
(Beats per minute)
2 yrs
84-117
39-72
90-150
3 yrs
86-120
44-76
90-150
4 yrs
88-122
47-79
90-150
5 yrs
89-123
50-82
65-135
6 yrs
91-125
53-84
65-135
7 yrs
92-126
55-86
60-130
8 yrs
94-127
56-88
60-130
9 yrs
95-129
57-89
60-130
10 yrs
97-130
58-90
60-110
11 yrs
99-132
59-90
60-110
12 yrs
101-135
59-91
60-110
13 yrs
104-137
60-91
60-110
14 yrs
106-140
60-92
60-110
15 yrs
107-142
61-93
60-110
16 yrs
108-145
63-94
60-110
17 yrs
108-147
64-97
60-110
18 yrs
108-147
64-97
60-100


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Table 13-2
Recommended dimensions for blood pressure cuff bladders
Width [cm]
Length [cm]
Maximum Arm 
Circumference 
[cm]*
Newborn
4
8
10
Infant
6
12
15
Child
9
18
22
Small adult
10
24
26
Adult
13
30
34
Large adult
16
38
44
*calculated so that the bladder can encircle even the largest arm by at least 80%
Source: Feld LG and Corey H (2007): Hypertension in childhood, Pediatric in Review 28: 
283-98


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14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Definition/threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert 
syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST > 3 × 
ULN and TBL > 2 × ULN [mainly conjugated fraction] 
without notable increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or 
vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver 
toxicity *
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at Investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at Investigator discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at Investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 


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Criteria
Actions required
Follow-up monitoring
up monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
at Investigator discretion)
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at Investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at Investigator discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice

Discontinue the study drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at Investigator discretion)


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Criteria
Actions required
Follow-up monitoring
Any AE potentially 
indicative of a liver 
toxicity*

Consider study drug interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.


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


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Appendix 4: Weight ranges: recommended maximum
sample blood volume per blood draw 
Recommended maximum blood collections are in accordance with the 2008 EU Commission 
Guideline on Ethical Considerations for Clinical Trials on Medicinal Products Conducted 
with the Pediatric Population.  As per the guideline, collections specified in the protocol do 
not exceed 3% of patients’ total blood volume during a 4-week period and/or 1% at any single 
visit.  Patients’ total blood volume is estimated at 80 to 90 mL/kg body weight; 3% is 2.4 mL 
blood per kg body weight, 1% is 0.8 mL blood per kg body weight.  The table below outlines 
the maximum allowable blood volume by weight category.  In order to stay within these limits, 
detailed instructions are provided by the Central Laboratory for all weight categories less than 
38 kg.  
Table 16-1
Weight range: Recommended maximum blood volume drawn per visit, 
and per 4 week period
Weight Range 
Category (kg)
Maximum Allowable Blood 
Volume Drawn / visit
(mL)
Maximum Allowable Blood 
Volume Drawn / 4 week period 
(mL)
7-10
5.6
16.8
>10-12
8.0
24.0
>12-14
9.6
28.8
>14-26
11.2
33.6
>26-38
20.8
62.4
>38
30.4
91.2
17
Appendix 5: Physician’s global assessment of disease 
activity (VAS)
The question text below will be shown to and will be answered by the physician.  The 
physician’s assessment should be made and recorded without viewing ANY of the patient’s 
assessments. The result of the physician’s assessment of the patient’s disease activity should 
be withheld from the patient / parents/guardian so as not to influence his/her own assessment.
The following is the text of the question, but does not represent the final formatting used in the 
study.
“Considering all the ways ERA/JPsA affects your patient, how would you rate his or her 
condition today?”
No disease activity 
0
Very severe disease activity 
100


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Appendix 6: Childhood Health Assessment Questionnaire 
(CHAQ)
The following does not represent the final formatting of the CHAQ used in the study.


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Appendix 7: ILAR classification criteria
Criteria
Exclusions
JPsA (MODIFIED)
Arthritis and psoriasis, or
arthritis with two or more of:
(a) Dactylitis
(b) Nail pitting or onycholysis
(c) Psoriasis in a first degree 
relative

Presence of IgM RF on 
at least 2 occasions at 
least 3 months apart

Presence of systemic 
JIA
ERA
Arthritis and enthesitis, or 
Arthritis or enthesitis with two or 
more of:
(a) Presence of or history of 
sacroiliac joint tenderness 
and/or inflammatory 
lumbosacral pain 
(b) HLA-B27 positivity
(c) Acute (symptomatic) anterior
uveitis
(d) History of ankylosing 
spondylitis, enthesitis related 
arthritis, sacroiliitis with 
inflammatory bowel disease, 
Reiter’s syndrome, or acute 
anterior uveitis in a first-
degree relative
(e) Onset of arthritis in a boy 
over the age of 6 years

Psoriasis or in first-
degree relative

Presence of IgM RF on 
at least 2 occasions 
more than 3 months 
apart

Presence of systemic 
JIA 
JPsA criteria (Petty et al 2004) have been modified by removal of the following 2 exclusions:   1)
Arthritis in a HLA-B27 positive male beginning after the 6th birthday and 2) diagnosis of ankylosing 
spondylitis, ERA, sacroiliitis with Inflammatory Bowel Disease (IBD), reactive arthritis (Reiter’s 
syndrome), or acute anterior uveitis, or a history of one of these disorders in a first-degree relative.


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Appendix 8: ACR definition of flare for JIA 
Both criteria 1 and 2 must be fulfilled to meet the definition of a disease flare.  Criteria 
changes described are relative to the End of Treatment Period 1 (Week 12 visit).
1. ≥ 30% worsening in at least 3 of the 6 ACR response variables 

Physician global assessment of overall disease activity 

Parent or patient global assessment of overall well-being 

Functional ability (CHAQ©) 

Number of joints with active arthritis

Number of joints with limited range of motion 

Index of inflammation: CRP
2. ≥ 30% improvement in no more than 1 of the 6 ACR response variables 
Contingencies:

if the Physician or Parent Global Assessment is one of the 3 response variables used to 
define flare, worsening of ≥ 20 mm (1-100mm visual analogue scale) must be present;

if the number of active joints or joints with limitation of motion is one of the 3 response 
variables used to define flare, worsening in ≥  2 joints must be present;

if CRP is one of the 3 response variables to define flare it must be above normal range.


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Appendix 9: ACR response criteria
The adapted ACR Pediatric 30/50/70/90/100 criteria will be used to determine efficacy
defined as improvement from baseline of at least 30/50/70/90/100% respectively in at least 3
of 6 components with no more than one component worsening more than 30% as defined in 
the ACR criteria.
The components are:

Physician’s Global Assessment of disease activity on a 0-100 mm VAS from 0 mm = no 
disease activity to 100 mm = very severe disease activity.

Parent’s or patient’s (if appropriate in age) Global Assessment of Subject’s overall well-
being on a 0-100 mm VAS from 0 mm= very well to 100 mm= very poor.

Functional ability: Childhood Health Assessment Questionnaire (CHAQ©)

Number of joints with active arthritis using the ACR definition (The ACR definition of 
active arthritis is any joint with swelling, or in the absence of swelling, limitation of 
motion accompanied by either pain on motion or tenderness not due to deformity)

Number of joints with limitation of motion

Laboratory measure of inflammation: CRP (mg/L)


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Appendix 10: Criteria for deﬁning clinical inactive disease
Criteria for deﬁning clinical inactive disease in ERA/JPsA
Inactive disease: 

No joints with active arthritis

CRP level within normal limits in the laboratory where tested or, if elevated, not 
attributable to ERA/JPsA

Physician’s global assessment of disease activity score of best possible on the scale 
used (i.e. best possible score is defined as 10 mm)

The absence of patient-reported morning stiffness attributable to JPsA or ERA lasting 
≥15 minutes 

No Uveitis
Adapted from Wallace CA, et al (2011). 


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SAP_001.pdf: 
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For business use only
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SAP
AIN457F2304
Clinical Development
CAIN457/Secukinumab/Cosentyx®
Clinical Trial Protocol CAIN457F2304 / NCT03031782
A three-part randomized, double-blind, placebo-controlled 
study to investigate the efficacy and safety of secukinumab 
treatment in Juvenile Idiopathic arthritis subtypes of 
psoriatic and enthesitis-related arthritis
Statistical Analysis Plan (SAP) Amendment 4
Author:
Statistician,
Statistician,
Document type:
SAP Documentation
Document status:
Final
Release date:
3-Dec-2020
Number of pages:
49
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Reason for update
Outcome for update
Section and title 
impacted (Current)
12-Mar-
2020
 
 
 
Protocol deviation 
period can’t be 
derived, since the 
date was not 
collected.
Protocol deviation summary is 
overall (not by treatment period).
2.3.1 Patient 
disposition
Novartis request to 
remove prohibited 
medication summary, 
since the analysis is 
not required.
Removed summary of prohibited 
medication. Also, updated 
medications are coded 
according to the Novartis Drug 
and Therapy Dictionary 
(NovDTD) and non-drug 
therapies are by MedDRA.
2.4.2 Prior and 
concomitant 
medications/therapies
Corrected typo.
Corrected ACZ to AIN457.
Updated plot from ‘cumulative 
probability to stay flare free’ to 
‘cumulative probability to flare’.
2.5.2 Statistical 
hypothesis, model, and 
method of analysis
Request from clinical 
team.
JIA ACR response plots added 
for TP1 and TP2. Also, mean 
percent improvement from 
baseline to Week 12 plot for JIA 
ACR core components other 
than CRP added. For CRP, use 
median percent change.
Also, added JADAS-27 and 
JADAS-71 change from baseline 
plots for TP1.
2.6 Analysis of 
secondary objectives
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Novartis programmer/ 
statistician request to 
remove, since the 
listing is not required. 
Removed sentence “For those 
subjects who received not the 
treatment randomized, i.e. who 
received erroneously the wrong 
2.8 Safety analyses


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Date
Reason for update
Outcome for update
Section and title 
impacted (Current)
treatment at least once, an 
additional adverse event (AE) 
listing will be prepared displaying 
which events occurred after the 
treatment errors.”
Updated per data 
collected.
The ratio “apolipoprotein B / 
apolipoprotein A1” can’t be 
derived since the components 
weren’t collected.
2.8.2 Laboratory data
AIN457 program level 
update, based on 
previous DMC 
feedback.
Vital signs notable criteria 
updated.
2.8.3 Vital signs
 
 
JADAS – corrected 
per reference papers.
 
 
 
 
 
Derivation of JADAS updated 
per reference papers.
 
 
 
 
 
 
 
 
 
 
22-Jun-
2020
Added clarification
Added clarification of when TP2 
will be considered complete.
1.1 Study design
Additional important 
stratification factor 
identified.
Primary 
 
updated to include MTX use at 
baseline as a stratification factor.
2.5.2 Statistical 
hypothesis, model, and 
method of analysis
 
4 Change to protocol 
specified analyses
5.2.1 Analysis of 
continuous data
 
 
 
 
 
 
 


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AIN457F2304
Date
Reason for update
Outcome for update
Section and title 
impacted (Current)
 
 
Required analysis 
updated.
Added percent change from 
baseline for JIA ACR core 
components.
Dropped all “Overall” tables for 
JIA ACR 30/50/70/90/100 and 
inactive disease status.
JIA ACR 30/50/70/90/100 line 
graph only for TP1 and not TP2 
or overall.
Added bar chart of JIA ACR 
30/50/70/90/100 response 
 
at the end of 
Treatment period 2 and 
corresponding table.
Removed descriptive statistics 
for each JIA ACR core 
component without LOCF.
2.6 Analysis of 
secondary objectives
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional analysis 
required.
Added analysis for 
Clinicaltrials.gov and EudraCT.
2.8.1 Adverse events 
(AEs)
Required analysis 
updated.
Cumulative events rate was 
replaced by flare-free rate.
Options ‘reduceout’ and ‘timelist’ 
added to the proc lifetest.
5.2.1.2 Kaplan-Meier 
analysis
13-Oct-
2020
 
 
 
 
 
 
 
 
 
 
 


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AIN457F2304
Date
Reason for update
Outcome for update
Section and title 
impacted (Current)
 
 
Consistent with SCS.
‘Entire study’ updated to ‘Entire 
treatment period’ throughout.
2.2 Analysis sets and 
treatment groups
2.8 Safety analysis
2.13 Summary of 
statistical analysis
Entire treatment 
period analysis 
added.
Added entire treatment period in 
the treatment groups description. 
2.2.1 Treatment groups
Remove wording 
about Rescue 
medication analysis, 
since not required. 
Added disposition for 
follow-up.
Remove wording about Rescue 
penalty medication analysis. 
Also, added disposition table for 
the follow-up period.
2.3.1 Patient 
disposition
Consistent with SCS.
Added duration of exposure 
(days) table for the entire 
treatment period.
2.4.1 Study treatment / 
compliance
Correct that MTX is 
not a stratification 
variable, but only 
another factor in the 
model.
MTX is not a stratification factor 
in the study, therefore, correct 
the description about MTX by 
removing it as a “stratification 
factor”.
2.5.2 Statistical 
hypothesis, model, and 
method of analysis
 
2.6.4 Analysis of 
secondary objectives
5.2.1 Analysis of 
continuous data
Consistent with SCS.
Added Treatment Period 3 in 
safety analysis. Also, replaced 
tables of exposure adjusted 
incidence of AEs during 
Treatment period 2 with tables
for the entire treatment period.
In Clinicaltrials.gov and EudraCT 
section Removed text about dry 
run and clarified 0-5%.
2.8.1 Adverse events 
(AEs)
2.8.2 Laboratory
Table 1-9 Summary of 
Safety analysis by 
treatment period and 
statistical method
Since, Cosentyx has 
been marketed the 
SPP is replaced by 
RMP.
Safety Profiling Plan (SPP) 
replaced by Risk Management 
plan (RMP). Location of Program 
Case Retrieval Sheet updated 
and note about primary and 
secondary system organ classes
updated.
2.8.5 Compound 
specific safety 
evaluation
In the CRF, if the 
patient has early 
discontinuation, it will 
state either “week 12” 
The early discontinuation week 
will be re-mapped to the next 
visit of last scheduled visit based 
on the assessments.
5.1 Visit Windows


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AIN457F2304
Date
Reason for update
Outcome for update
Section and title 
impacted (Current)
or “week 104” instead 
of the actual early 
discontinuation week. 
3-Dec-
2020
 
 
 
 
 
 
 
 
 
Criteria not required 
in protocol or 
standard.
Removed criteria ‘ALT or 
AST >8xULN & TBL >2xULN’.
2.8.2 Laboratory data
Overview of subjects 
with anti-drug 
antibodies table can 
be derived 
programmatically and 
reviewed by the 
medical writer.
For overview of subjects with 
anti-drug antibodies summary 
replaced text ‘will be provided as 
an in-text table by the medical 
writer’ with ‘ will be summarized’.
2.8.4
Immunogenicity
Clarification.
Minor update to SAS code to 
clarify timelist will also be 
produced at days 28, 56, 84, etc.
5.2.1.2 Kaplan-Meier 
analysis


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Table of contents
2.8.2 Laboratory data...............................................................................................6
2.8.4
Immunogenicity ......................................................................................6
5.2.1.2 Kaplan-Meier analysis.................................................................................6
Table of contents .................................................................................................................7
List of abbreviations............................................................................................................9
1
Introduction .......................................................................................................................11
1.1
Study design...........................................................................................................11
1.2
Study objectives and endpoints .............................................................................12
1.2.1
Primary objective ..................................................................................12
1.2.2
Secondary objectives.............................................................................12
12
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.2
Analysis sets and treatment groups........................................................................13
2.2.1
Treatment groups ..................................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................15
2.3.1
Patient disposition.................................................................................15
2.3.2
Background and demographic characteristics.......................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.4.1
Study treatment / compliance................................................................15
2.4.2
Prior and concomitant medications/therapies .......................................16
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................17
2.5.3
Handling of missing values/censoring/discontinuations.......................17
18
2.6
Analysis of secondary objectives...........................................................................18
19
2.8
Safety analyses.......................................................................................................20
2.8.1
Adverse events (AEs)............................................................................20
2.8.2
Laboratory data .....................................................................................22
2.8.3
Vital signs..............................................................................................24
2.8.4
Immunogenicity ....................................................................................25
2.8.5
Compound specific safety evaluation ...................................................25
2.9
Pharmacokinetic endpoints....................................................................................25


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26
2.11
 Efficacy Evaluation............................................26
26
2.11.2
Efficacy Evaluation...............................................................................27
2.12
Interim analysis......................................................................................................36
2.13
Summary of statistical analysis .............................................................................36
3
Sample size calculation .....................................................................................................41
4
Change to protocol specified analyses ..............................................................................41
5
Appendix ...........................................................................................................................42
5.1
Visit Windows .......................................................................................................42
5.2
Statistical methodology and assumptions..............................................................43
5.2.1
Analysis of continuous data ..................................................................43
5.2.2
Analysis of binary (and categorical) data..............................................46
5.2.3
Crude incidence estimates.....................................................................46
5.2.4
Exposure adjusted incidence rate estimates ..........................................47
6
Reference...........................................................................................................................48
PPD


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List of abbreviations
ACR
American College of Rheumatology 
AE
Adverse Event
AJC
Active joints count
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
BP
Blood pressure
CHAQ
Childhood Health Assessment Questionnaire
CMH
Cochran-Mantel-Haenszel
CRF
Case Report/Record Form (paper or electronic)
CRP
C-reactive Protein
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DBL
Database lock
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report/Record Form
ERA
Enthesitis-Related Arthritis
ESR
Erythrocyte sedimentation rate
 
FAS
Full analysis set
GGT
Gamma-glutamyl transferase
GPS
Global Programming and Statistics Environment
HDL
High-density lipoprotein
HGB
Hemoglobin
IGA
Investigators Global Assessment
IVR
Interactive Voice Response
JADAS
Juvenile Arthritis Disease Activity Score
JIA
Juvenile Idiopathic Arthritis
JPsA
Juvenile Psoriatic Arthritis
KM
Kaplan-Meier
LDL
Low-density lipoprotein
LFT
Liver function test 
LLN
Lower Limit of Normal
LLQ
Lower level of quantification
LOCF
Last Observation Carried Forward
LPLV
Last Patient Last Visit
MCP
Metacarpophalangeal 


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MedDRA
Medical dictionary for regulatory activities 
MTX
Methotrexate
NovDTD
Novartis Drug and Therapy Dictionary
OMU
Original measurement unit
PD
Protocol deviation
PDS
Programming Dataset Specification
PGA
Physician global assessment
PIP
Proximal interphalangeal 
PK
Pharmacokinetics
PsA
Psoriatic Arthritis
PRO
Patient Reported Outcome
PT
Preferred Term
RMP
Risk Management Plan
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
s.c.
Subcutaneous
SCS
Summary of clinical safety
SD
Standard deviation
SI
International standard
SJC
Swollen Joint Count
SMQ
Standardized MedDRA Query
SOC
System organ class
SPP
Safety Profiling Plan
TBL
Serum total bilirubin
TEAE
Treatment emergent adverse event
TFL
Tables, Figures and Listings
TG
Triglycerides
TJC
Tender Joint Count
TPx
Treatment Period x
ULN
Upper limit of normal
ULQ
Upper Level of Quantification
VAS
Visual Analogue Score


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1
Introduction
Data will be analyzed by 
 according to this SAP and the data analysis section 9 of the 
amended clinical study protocol V02. The statistical methodology is described below and any 
deviations from the protocol are documented. Additional detailed information regarding the 
analysis methodology is contained in the Appendix section. The analysis plan for DMC will be 
prepared separately.
1.1
Study design
This is a double-blind, placebo-controlled, event-driven randomized withdrawal study to 
investigate the efficacy and safety of secukinumab treatment in the JIA categories of JPsA and 
ERA. The study is divided into 3 parts (plus a post-treatment follow-up period) consisting of 
open-label, single-arm active treatment in Treatment Periods 1 and 3 and a randomized, double-
blind, placebo controlled, event-driven withdrawal design in Treatment Period 2, as described 
below:
Treatment Period 1 (TP1): A maximum 8-week screening period is used to assess patient 
eligibility. All eligible patients will enter Treatment Period 1 to receive 12-weeks of open-label 
secukinumab at a dose predicted to achieve secukinumab serum levels equivalent to adults 
administered a 150 mg dose regimen. Secukinumab will be administered subcutaneously (s.c.) 
weekly for the first 4 weeks (Baseline, Weeks 1, 2, 3, 4) and then every 4 weeks thereafter. 
Clinical response (JIA ACR 30) will be assessed at Week 12. Responders will advance to 
Treatment Period 2 and non-responders must exit the trial (early termination visit and enter into 
the Post-treatment follow-up period).
Treatment Period 2 (TP2): Patients with a clinical response (JIA ACR30) at Week 12 will enter 
double-blind withdrawal Treatment Period 2 to be randomized 1:1 to either secukinumab or 
placebo on that visit. Treatment Period 2 is event driven and will close when 33 patients 
experience a disease flare as per JIA definition. If Treatment Period 2 is closed when a patient 
becomes eligible to enter Treatment Period 2, the patient will skip Treatment Period 2 and 
advance directly to Treatment Period 3. When the 33rd flare is observed, all investigators will 
be informed that Treatment Period 2 is closed and all remaining patients will enter Treatment 
Period 3 at their next scheduled visit. Because Treatment Period 2 is event driven, it is possible 
that a patient remains in Treatment Period 2 for the duration of the study (Week 104) before 33 
disease flares are observed. Such patients will complete the study without having entered 
Treatment Period 3. 
Treatment Period 3 (TP3): Patients experiencing a disease flare in Treatment Period 2 will 
immediately enter Treatment Period 3 to receive open label secukinumab every 4 weeks until 
total study duration of 104 weeks for that patient is achieved. Additionally, when Treatment 
Period 2 closes, all remaining patients in Treatment Period 2 will enter Treatment Period 3 at 
their next scheduled visit and all remaining Treatment Period 1 patients who become eligible 
to enter Treatment Period 2 will skip Treatment Period 2 and enter Treatment Period 3 directly. 
Consequently, the starting time point of Treatment Period 3 for each patient may be different. 
Post-treatment follow-up: All patients completing the study (Week 104) or who discontinue 
early will enter the Post-treatment follow-up period lasting 12 weeks from the last study drug 


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dose administration. Only patients who qualify and enter the secukinumab extension trial 
without interruption of treatment will not require this Post-treatment follow-up visit.
 
 
 
The primary endpoint analysis will be performed as part of the final analysis when all patients 
have completed Week 112 Visit in the post-treatment follow-up period, or entered into 
extension study after Week 104 Visit, or prematurely discontinued the study, whichever is 
later. 
1.2
Study objectives and endpoints
1.2.1
Primary objective
To demonstrate that the time to flare in Treatment Period 2 is longer with secukinumab for 
combined ERA and JPsA groups than with placebo.
1.2.2
Secondary objectives
1. To evaluate effect of secukinumab treatment for all patients and each JIA category in 
Treatment Period 1 up to Week 12 (end of Treatment period 1) with respect to:

JIA ACR 30/50/70/90/100 and inactive disease status 

Each JIA ACR core component 

Change from baseline Juvenile Arthritis Disease Activity Score (JADAS) score

Total enthesitis count

Total dactylitis count
2. To evaluate withdrawal effect of secukinumab treatment for all patients and each JIA 
category during and at the end of Treatment Period 2 with respect to:

JIA ACR 30/50/70/90/100 and inactive disease status 
3. To evaluate Pharmacokinetics (PK) of secukinumab and confirm the predicted dose in 
Treatment Period 1 
4. To evaluate the safety/tolerability and immunogenicity of Secukinumab


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2
Statistical methods
2.1
Data analysis general information
Summary statistics for continuous variables include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, and maximum. For binary or discrete variables, the 
absolute number of subjects in each category and relative frequencies will be provided. 
Unless otherwise specified, p-values will be presented as 2-sided p-values and the type I error 
rate (alpha) will be 5%.
Efficacy and safety data will be presented by treatment period and treatment groups.
2.2
Analysis sets and treatment groups
The following analysis sets will be used for the data analysis. 
Randomized set: The randomized set will be defined as all subjects who were randomized at 
the beginning of TP2. The subjects who participated in TP1 only or TP1 and TP3 only will not 
be included in the Randomized set. Unless otherwise specified, mis-randomized subjects (mis-
randomized in Interactive Voice Response (IVR)) will be excluded from the randomized set. 
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IVR for TP2 and to whom no randomized study medication was given. Mis-randomized 
patients will be considered as prematurely discontinued and completed treatment period 1. 


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The Full Analysis Set (FAS) for Treatment Period 1 (Full Analysis Set 1) will consist of all 
patients who received at least one dose of study drug in Treatment Period 1.
The FAS for Treatment Period 2 (Full Analysis Set 2) will consist of all randomized patients 
who received at least one dose of study drug in Treatment Period 2. Following the intent-to-
treat principle, patients will be analyzed according to the treatment they were assigned to at 
randomization in Treatment Period 2.
The FAS for Treatment Period 3 (Full Analysis Set 3) will consist of all patients who received 
at least one dose of study drug in Treatment Period 3.
The entire treatment period (overall) FAS consists of all subjects who received at least one dose 
of study drug in the study, this is equivalent to Full Analysis Set 1.
The Safety Set for Treatment Period 1 (Safety Set 1) will consist of all patients who received at 
least one dose of study drug in Treatment Period 1. 
The Safety Set for Treatment Period 2 (Safety Set 2) will consist of all patients who received at 
least one dose of study drug in Treatment Period 2.
The Safety Set for Treatment Period 3 (Safety Set 3) will consist of all patients who received at 
least one dose of study drug in Treatment Period 3.
Patients in Safety Set 1, 2 and 3 are analyzed according to treatment received. 
The entire treatment period (overall) Safety Set consists of all subjects who received at least 
one dose of study drug in the study, this is equivalent to Safety Set 1.
There is no Per-Protocol Analysis Set.
2.2.1
Treatment groups
The treatment groups in each treatment period are as follows:

TP1 - AIN457 

TP2 - AIN457, Placebo in TP2, total

TP3 - AIN457 (include those not randomized), Placebo in TP2, total

Entire treatment period (Overall) for efficacy data includes Treatment Period 1, 2 and 
3. Entire treatment period will use the same treatment groups as TP3.

Entire treatment period (Overall) for safety data includes Treatment Period 1, 2 and 3 
and Follow-up Period. Entire treatment period will use the same treatment groups as 
TP3.
AIN457 for entire treatment period refers to all subjects without taking any placebo (including 
subjects who did not enter Treatment Period 2 (TP2)) and Placebo refers to all subjects taking 
placebo in TP2. For entire treatment period (overall) and for Treatment Period 3 analysis; 
subjects with placebo in TP2 and AIN457 in TP3 will be included in the ‘Placebo in TP2’ and 
in the ‘Total’ columns and will not be included in the ‘AIN457’ column.


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2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Patient disposition will be presented by Treatment Period and treatment group, also the follow-
up disposition will be presented. The number of subjects screened will be presented. In addition, 
the reasons for screen failures will be provided. The number and percentage of subjects in the 
Safety Set who completed the study periods and who discontinued the study prematurely 
(including the reason for discontinuation) during or at end of each Treatment Period will be 
presented for each treatment period, each treatment group and all subjects.
For each protocol deviation (PD), the number and percentage of subjects for whom the PD 
applies will be tabulated by treatment group.
The number and percentage of patients in each analysis set will also be tabulated by treatment 
period and treatment group. 
2.3.2
Background and demographic characteristics
Background and disease characteristics at baseline will be summarized descriptively for the 
Safety Set 1 by the starting treatment (AIN457), and for the Safety Set 2 by the treatment 
according to randomization in TP2 and by JIA category (ERA and JPsA). 
Continuous variables will be summarized by mean, standard deviation, median, minimum, 
maximum, 25% and 75% quantiles, and number of patients with non-missing data. Categorical 
variables will be summarized by absolute frequencies and percentages. 
Relevant medical history/current medical conditions will be listed and summarized by primary 
system organ class (SOC) and preferred term of the MedDRA dictionary for the safety set in 
Treatment Period 1 and according to randomization in Treatment Period 2. 
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The exposure to study drug (number of injections) will be summarized by treatment group for 
the entire treatment period and duration of exposure (days) will be summarized by treatment 
group and treatment period, and by treatment group for the entire treatment period, both for the 
Safety Set.
Duration of exposure for the entire treatment period will be defined as the time from first dose 
of study medication to the last dose plus 84 days or last visit (including follow-up visits) 
whichever occurs earlier.


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2.4.2
Prior and concomitant medications/therapies
The number and percentage of patients taking concomitant medication  will be  summarized by 
Anatomical Therapeutic Chemical (ATC) class and preferred term according to the Novartis 
Drug and Therapy Dictionary (NovDTD). Separate summaries will be provided for therapies 
that ended prior to Treatment Period 1 (prior therapies) and that were active during Treatment 
Periods 1, 2 and 3 (concomitant therapies).
The Safety Set corresponding to the study Treatment Period summarized will be used.
Prior medications will be summarized in separate tables by one treatment group for TP1. 
Concomitant medications will be summarized by treatment groups for TP1, 2 and 3 separately 
and for all periods together.
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of study treatment 
and the date of within 84 days after last dose will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of subjects receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group.
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary efficacy endpoint will be time to disease flare event in Treatment Period 2, which 
is defined as the interval between the date of randomization to the date of first occurrence of 
disease flare event. The analysis of the primary efficacy endpoint will be based on the FAS 
Treatment Period 2.
All subjects who enter Treatment Period 2 will be followed until the sooner of either 
experiencing a disease flare or the end of Treatment Period 2 when at least 33 flare events are 
observed and treatment period 2 is completed. Subjects who have not experienced flare event 
at the end of Treatment Period 2 (as defined in Section 3.1 of the protocol) or discontinue 
prematurely from Treatment Period 2 before it closes for reasons other than experiencing a 
disease flare will be censored at the date of the last non-missing flare evaluation (i.e. flare=no 
evaluation) in Treatment Period 2.
For patients with disease flare, the time to event is computed as follows:
(date of disease flare – date of randomization + 1)
For patients with no disease flare or discontinued, the time to event is computed as follows:


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(date of last non-missing flare evaluation (i.e. flare=no) in Treatment Period 2 – date of 
randomization + 1)
and is considered as censored.
2.5.2
Statistical hypothesis, model, and method of analysis
The primary objective for Treatment Period 2 of the study is to show superiority of secukinumab 
over placebo regarding the primary variable in Treatment Period 2.
The following statistical hypothesis will be tested once the required number of flares has been 
observed and when the study has been stopped:
H0: 1-SAIN457(t) ≥ 1- SPla(t) 
HA: 1-SAIN457(t) < 1- SPla(t)
at each time point t, with SAIN457(t) and SPla(t) being the survivor functions in the secukinumab 
and placebo treatment group at time t.
The two treatment groups will be compared using a one-sided stratified Log-rank test with the 
stratification factor of JIA category (ERA or JPsA) and another factor MTX use at baseline (yes 
or no) at the 2.5% level of significance. Hazard ratios and their associated 95% confidence 
intervals will be estimated based on a Cox proportional hazards model with treatment and other 
factors as explanatory variables.
Kaplan-Meier estimates of the probability to experience a flare event will be calculated from 
the beginning of Treatment Period 2 along with 95% confidence intervals using Greenwood’s 
formula. The cumulative probability to flare will be plotted against time. 
The primary analysis will be based on the FAS for Treatment Period 2.
Specifically, a table of Survival analysis of time to flare in Treatment Period 2 will include 
randomized treatment, number of patients, number of events, Kaplan-Meier estimate of median 
of time to flare in days, Hazard ratio (95% Confidence interval) and p-value for the Stratified 
log-rank test. In addition, a figure of Kaplan-Meier estimates of the probability to flare by 
treatment in Treatment Period 2 will be drawn against days.
2.5.3
Handling of missing values/censoring/discontinuations
Missing data
All patients in Treatment Period 2 will have a value of time to flare either by having an event 
or being censored.
For the calculation of JIA ACR or flare, partially missing data for JIA ACR components will 
be imputed by Last Observation Carried Forward (LOCF). 
Missing data for other variables will not be imputed. Observed data except JIA ACR 
components will be used in all analysis.


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2.6
Analysis of secondary objectives
The analysis of secondary variables is descriptive only for FAS. Summary statistics will be 
presented. Summary statistics for continuous variables include N, mean, standard deviation, 
minimum, median, maximum, 25% and 75% quantiles, and number of patients with non-
missing data. Baseline, post-baseline and absolute change will be presented for all summary 
statistics. Percent change from baseline will be presented for JIA ACR core components. For 
binary or discrete variables, the number of subjects in each category and relative frequencies 
will be provided.
The following secondary efficacy endpoints will be analyzed by visit for all patients and each 
JIA category by descriptive statistics in Treatment Period 1:

JIA ACR 30/50/70/90/100 

Inactive disease status 

Each JIA ACR core component 

Change from baseline Juvenile Arthritis Disease Activity Score (JADAS) score

Total enthesitis count

Total dactylitis count
The following secondary efficacy endpoints will be analyzed by treatment and visit for all 
patients and each JIA category by descriptive statistics in Treatment Period 2:

JIA ACR 30/50/70/90/100 

Inactive disease status.
ACR pediatric response achieved in TP1 and TP2 will be summarized by descriptive statistics 
by treatment period, visit, and response criterion (30/50/70/90/100). ACR pediatric response 


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level achieved will also be plotted against visit for TP1. One figure (line graph) of JIA ACR 
30/50/70/90/100 and inactive disease responses over all visits in Treatment Period 1 will be 
plotted. 
A figure (bar chart) of JIA ACR 30/50/70/90/100 response and inactive disease at the end of 
Treatment period 2 will be plotted and the corresponding reference table will also be produced. 
The difference between treatment groups will be tested using the Cochran-Mantel-Haenszel 
(CMH) test, stratified by JIA category (ERA or JPsA) and another factor MTX use at baseline.
Mean percent improvement from baseline to Week 12 will be plotted for JIA ACR core 
components other than CRP. For CRP, median percent change will be presented due to the 
outliers of CRP values.
JADAS-27 and JADAS-71 change from baseline will also be plotted against visit for TP1.


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2.8
Safety analyses
The analysis of safety data by treatment may be provided for each Treatment Period separately 
and all periods combined, as appropriate. The analysis of safety data will be conducted on the 
Safety Set, which includes subjects who receive any study treatment. Safety analyses will be 
performed on treatment received or actual treatment as described below:
The actual treatment or treatment received for summaries of safety data will differ to the 
treatment assigned at randomization only if a subject received the wrong treatment during the 
entire treatment period.
The safety variables to be analyzed include Adverse events (AEs), clinical laboratory tests 
(hematology, chemistry and urinalysis), physical examination results, ECGs, and deaths. Safety 
variables are to be tabulated by descriptive statistics (n, mean, median, standard deviation, 
minimum, and maximum; or n and percent). No formal statistical testing is planned.
2.8.1
Adverse events (AEs)
The crude incidence of treatment emergent adverse events (TEAEs) (i.e. events started after the 
first dose of study treatment or events present prior to the first dose of study treatment but 
increased in severity based on preferred term and on or before last dose of study treatment + 84 
days) will be summarized by primary system organ class and preferred term. Confidence 
intervals for the crude rate will be derived as described in Section 5.2.3.1. In addition, exposure 
time-adjusted rates (incidence rate) including 95% confidence intervals by treatment will be 
provided for Treatment Period 2 (see Section 5.2.4.1) to adjust for differences in exposure. 


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Adverse events reported will be presented in descending frequency according to its incidence 
in secukinumab group starting from the most common event. Summaries (crude incidences only) 
will also be presented for AEs by severity and for study treatment related AEs. If a particular 
AE ‘severity’ is missing, this variable will be listed as missing and treated as missing in 
summaries. If a subject reported more than one adverse event with the same preferred term, the 
adverse event with the greatest severity will be presented. If a subject reported more than one 
adverse event within the same primary system organ class, the subject will be counted only 
once with the greatest severity at the system organ class level, where applicable.  
Separate summaries will be provided for adverse events suspected to be related to study drug, 
deaths, serious adverse events, and adverse events leading to discontinuation and adverse events 
leading to temporary dose interruption.
Adverse events will also be reported separately by Standardized MedDRA Query (SMQ) 
according to MedDRA. The MedDRA version used for reporting the study will be described in 
a footnote.
Non-treatment emergent adverse events will be listed.
Algorithms for date imputations will be provided in Programming Dataset Specification (PDS).
For serious adverse events (SAEs) occurred during screening a listing will be prepared for all 
subjects screened including screening failures.
The safety analyses that will be performed for treatment emergent AEs and on treatment labs, 
ECG and vital signs for each analysis period is described in Table 2-1.
Table 2-1
Overview of analyses on some safety endpoints
Analysis 
period
AEs & SAEs
AEs 
by 
severity
Study 
drug 
related AEs
AEs-SMQ
Risk
Notables for 
(vitals/
ECG), lab 
criteria
Treatment
Period 1
crude 
incidence
crude 
incidence
crude 
incidence
crude 
incidence
crude 
incidence
crude 
incidence
Treatment 
Period 2
crude 
incidence

crude 
incidence
crude 
incidence
crude 
incidence

crude 
incidence

crude 
incidence
Treatment 
Period 3
crude 
incidence
crude 
incidence
crude 
incidence
crude 
incidence
crude 
incidence
crude 
incidence
Entire 
treatment 
period
(TEAEs)
crude 
incidence
exposure 
adjusted 
incidence*
crude 
incidence
crude 
incidence
crude 
incidence
exposure 
adjusted 
incidence*
crude 
incidence
exposure 
adjusted 
incidence*
crude 
incidence
*Exposure adjusted incidence rates will be done for the following:

at the Primary SOC for AE analyses

at the Primary SOC and Preferred Term (PT) for SAE analyses 

at the Level 1 and PT for Risks and SMQ analyses


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Clinicaltrials.gov and EudraCT 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
X% (0-5 %, as appropriate) and on 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. 
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 will 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.
2.8.2
Laboratory data
The summary of lab data will only include on treatment data, which are defined as those lab 
assessments after the first dose of study treatment and on or before last dose + 84 days.
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, chemistry and urinalysis). In addition to the individual laboratory parameters the 
ratio “total cholesterol / HDL” will be derived and summarized.
For urinalysis, frequency tables will be presented.
Descriptive summary statistics for the change from baseline in Treatment Periods 1, 2 and 3 
will be presented. These descriptive summaries will be presented by laboratory test and 
treatment group. Change from baseline will only be summarized for subjects with both baseline 
and post baseline values and will be calculated as:
change from baseline = post baseline value – baseline value
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline, if appropriate for each study phase, will be analyzed analogously. 
In addition, shift tables will be provided for all parameters to compare a subject’s Week 12 
laboratory evaluation relative to the most extreme laboratory test value within treatment period 
2. For the shift tables, the normal laboratory ranges will be used to evaluate whether a particular 
laboratory test value was normal, low, high or “high and low” relative to whether or not the 
baseline value was normal, low, or high. These summaries will be presented by laboratory test 
and treatment group.
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-2: hemoglobin 
(HGB), platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin 
(TBL), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG).


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These summaries will be split into hematology and chemistry for study level reports and the 
pooled summary of clinical safety (SCS).
Table 2-2
CTCAE grades for laboratory parameters to be analyzed
CTCAE v4.0 Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
HGB 
decreased 
(Anemia)
<LLN – 100 g/L
<100 – 80 g/L
<80 g/L
Life-threatening 
consequences; urgent 
intervention indicated
Platelet count
decreased
<LLN – 75.0 x10e9 /L
<75.0 - 50.0 x10e9 /L
<50.0 – 25.0 x10e9 /L
<25.0 x 10e9 /L
White 
blood 
cell 
decreased
<LLN - 3.0 x 10e9 /L
<3.0 - 2.0 x 10e9 /L
<2.0 - 1.0 x 10e9 /L
<1.0 x 10e9 /L
Neutrophil 
count 
decreased
<LLN - 1.5 x 10e9 /L
<1.5 - 1.0 x 10e9 /L
<1.0 - 0.5 x 10e9 /L
<0.5 x 10e9 /L
Lymphocyte 
count 
decreased
<LLN - 0.8 x 10e9/L
<0.8 - 0.5 x 10e9 /L
<0.5 - 0.2 x 10e9 /L
<0.2 x 10e9 /L
Creatinine increased*
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN
>1.5 
-
3.0 
x 
baseline; >1.5 - 3.0 x 
ULN
>3.0 baseline; 
>3.0 - 6.0 x ULN
>6.0 x ULN
TBL increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALP increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Glucose 
increased 
(Hyperglycemia) 
>ULN - 8.9 mmol/L
>8.9 - 13.9 mmol/L
>13.9 - 27.8 mmol/L
>27.8 mmol/L
Glucose 
decreased 
(Hypoglycemia)
<LLN - 3.0 mmol/L
<3.0 - 2.2 mmol/L
<2.2 - 1.7 mmol/L
<1.7 mmol/L
Cholesterol high
>ULN - 7.75 mmol/L
>7.75 - 10.34 mmol/L
>10.34 - 12.92 mmol/L
>12.92 mmol/L
Hypertriglyceridemia
1.71 - 3.42 mmol/L
>3.42 - 5.7mmol/L
>5.7 - 11.4 mmol/L
>11.4 mmol/L
*Note: for “creatinine increased” the baseline criteria do not apply
The number and percentage of subjects with newly occurring or worsening CTCAE grades after 
baseline evaluation will be presented for Treatment Periods 1, 2 and 3, and entire treatment 
period.
Shift tables will be presented comparing Week 12 laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment period 2 analyzed. Subjects 
with abnormal laboratory values will be listed and values outside the normal ranges will be 
flagged.
Summaries for newly occurring or worsening clinically notable lipid abnormalities will also be 
provided cumulatively for each of the following parameters and categories:

HDL:
o
<=LLN
o
<0.8 x LLN

LDL, cholesterol, triglycerides:
o
>=ULN 
o
>1.5 x ULN 
o
>2.5 x ULN


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Newly occurring or worsening liver enzyme abnormalities will also be summarized based on 
the event criteria given in Table 2-3:
Table 2-3
Liver-related events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN; >10xULN, >20xULN
AST
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
ALT or AST
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
TBL
>1.5xULN, >2xULN, >3xULN,
ALP
>2xULN, >3xULN. >5xULN
(ALT or AST) & 
TBL
ALT or AST >3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN
ALP & TBL
ALP >3xULN & TBL >2xULN
ALP >5xULN & TBL >2xULN
(ALT or AST) & 
TBL & ALP
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law)
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or 
bile duct disease; ALP may also be increased in malignancy. FDA therefore terms 
Hy’s Law cases as indicators of pure hepatocellular injury. This does not mean that 
cases of ALT or AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result in 
severe DILI.
Notes:
1) In studies which enroll subjects with pre-existing liver disease, baseline LFT may be increased above 
ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the abnormality 
criteria
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN.
Individual subject data listings will be provided for subjects with abnormal laboratory data. 
Data of subjects with newly occurring or worsening liver enzyme abnormalities will be listed 
in an additional listing.
In addition, three individual subject data listings will be provided for liver events, laboratory 
values and viral serology, autoimmunity, imaging, pathology, drug abuse for patients with liver 
events.
The laboratory values below Lower Level of Quantification (LLQ) or above Upper Level of 
Quantification (ULQ) will be imputed as LLQ or ULQ, respectively. The numerical part of the 
reported result will be treated as the actual LLQ or ULQ. These laboratory values will be 
displayed in listings using the standard unit with the reported sign (“<” or “>”).
2.8.3
Vital signs
The summary of vital signs will only include on treatment data, which are defined as those vital 
sign measurements after the first dose of study treatment and on or before last dose + 84 days.
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed. These descriptive summaries will be 


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presented by vital sign and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are as follows.
Note: The age is the age at the time of the visit. It will be derived as follows:
Integer part of ((assessment date – imputed birth date) / 365.25)
Systolic blood pressure (mmHg):

High: >ULN and Increased >20 in change from baseline
Diastolic blood pressure (mmHg):

High: >ULN and Increased >20 in change from baseline
Pulse (bpm): 

High: >ULN and Increased >20 in change from baseline

Low: <LLN and Decreased >20 in change from baseline
Note: Only post-baseline values will be flagged as notable abnormalities
Table 2-4
Criteria for normal vital sign for pediatric patients
Age group
Systolic BP(mmHg)
Diastolic BP(mmHg)
Pulse (bpm)
2-5 years
76-120
45-80
55-120
6 -11 years
90-130
50-80
50-105
12-17 years
90-145
55-90
45-95
18 years and over
90-140
60-90
60-100
2.8.4
Immunogenicity
A listing of immunogenicity (anti-AIN457 antibodies) will be provided. Also, an overview of 
subjects with anti-drug antibodies will be summarized.
2.8.5
Compound specific safety evaluation
Safety topics of interest, such as risks defined in the Risk Management Plan (RMP) or topics of 
interest regarding signal detection or routine analysis are defined in the Program Case Retrieval 
Sheet that is stored in Global Programming and Statistics Environment (GPS).
The crude incidence and exposure-adjusted incidence rates for RMP risks will be summarized. 
In addition, listings will be provided presenting which subjects experienced which risk.
Important note: For the evaluation of risks primary and secondary system organ classes of the 
MedDRA dictionary will be considered.
2.9
Pharmacokinetic endpoints  
The following PK parameters will be determined: Cmin, Css. All completed subjects with 
quantifiable pharmacokinetic (PK) measurements of secukinumab will be included in the 


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pharmacokinetic data analysis. Serum concentrations will be expressed in mass per volume 
units. All concentrations below the limit of quantification as well as missing data will be labeled 
as such in the concentration data listings. PK concentrations will be summarized by Treatment 
Period, visit and treatment group. In addition to mean, standard deviation (SD), coefficient of 
variation (CV), median and quartiles, the geometric mean and geometric coefficient of variation 
(CV) and n(log) will be presented. The formula for deriving the geometric mean and CV (%) is
as following: 

CV (%) = (SD/mean)*100,

geometric mean=exp( (sum of log transformed data) / number of non-missing data points 
after log transformation),

geometric CV = sqrt( exp( variance of log-transformed data)-1)*100.
In addition, sample number, concentration, sample date, sample time at pre-dose and minutes 
pre-dose and elapsed time from first dose (in days) will be listed by treatment group.
Values below lower limit of quantification/below detection limit will be imputed by 0.


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2.11.2
Efficacy Evaluation
2.11.2.1 Description of efficacy variables
JIA ACR response criteria
Standard ACR pediatric Criteria (JIA ACR criteria) consist of 6 core components which will 
be assessed as scheduled in Table 6-1 of the protocol.  JIA ACR 30/50/70/90/100 are defined 
as 30%, 50%, 70%, 90% and 100% improvement from baseline respectively in a minimum of 
three variables in the core set with no more than one variable worsening more than 30% as 
defined in the ACR criteria.
The 6 core set variables are summarized below:

Physician global assessment of disease activity on a 0 - 100 mm VAS from 0 mm = no 
disease activity to 100 mm = very severe disease activity

Parent or patient’s (if appropriate in age) Global Assessment of Subject’s overall well-
being on a 0-100 mm VAS from 0 mm = very well to 100 mm = very poor.

Functional ability: Childhood Health Assessment Questionnaire (CHAQ©)
-
Within each of the 8 categories only the item indicating the most severe impairment 
will contribute to the category score (3 is the most severe, (Without any difficulty) = 0, 
(With some difficulty) = 1, (With much difficulty) = 2, (Unable to do) = 3).
-
If the patient indicates the need for an assistance from another person, or the use of an 
aid/device to perform a task, then the minimum score for the category is 2.
-
The score is set to 2 also if (Not Applicable) is chosen and the patient indicates the 
need for an assistance from another person or the use of an aid/device to perform a task.
-
CHAQ disability score has 8 category scores. The highest score for component 
questions within each category determines the score for that category and the final score is 
obtained by the average of the 8 category scores. (i.e. the range for CHAQ score is (0, 3)). 
CHAQ is set to missing if patients didn’t have the scores for all 8 categories. 

Number of active joints using the ACR definition (The ACR definition of active arthritis 
is any joint with swelling or in the absence of swelling, limitation of motion accompanied 
by either pain on motion or tenderness not due to deformity), so three types of data will be 
collected and used for deriving number of active joints: Swelling, Pain, and Limitation of 
motion.

Number of joints with limited range of motion

Laboratory measure of inflammation: CRP (mg/L)
-   CRP local lab value will be standardized according to Appendix 5.3.
Note for CRP variable: in case at the Baseline visit the CRP is within the normal limit, then 
improvement or worsening in this variable that remains within the normal range at the study 
visit for which response is being calculated cannot contribute as one of the 6 parameters of 
either improvement or worsening.
The respective response variables listed above will be used by 
 
 to determine ACR Pediatric response, responder 
status at Week 12, and flare occurrence in Treatment Period 2. These results will be 


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communicated to the investigator prior to the patient leaving the study site. Additionally, 
these components will be used to determine JADAS and inactive disease status (Wallace et al. 
2011) as part of secondary 
 analyses.
ACR definition of flare for JIA 
Both criteria 1 and 2 must be fulfilled to meet the definition of a disease flare.  Criteria changes 
described are relative to the End of Treatment Period 1 (Week 12 visit).
1. ≥ 30% worsening in at least 3 of the 6 ACR response variables 

Physician global assessment of overall disease activity 

Parent or patient global assessment of overall well-being 

Functional ability (CHAQ©) 

Number of joints with active arthritis

Number of joints with limited range of motion 

Index of inflammation: CRP
2. ≥ 30% improvement in no more than 1 of the 6 ACR response variables 
Contingencies:

if the Physician or Parent Global Assessment is one of the 3 response variables used 
to define flare, then worsening of ≥ 20 mm (1-100mm visual analogue scale) must be 
present

if the number of active joints or joints with limitation of motion is one of the 3 
response variables used to define flare, then worsening in ≥ 2 joints must be present

if CRP is used to define flare, then CRP must be >10 mg/L
Note for CRP: in case at Week 12 visit the CRP is within the normal limit, then worsening in 
the value at the study visit for which flare is being calculated must be above the upper limit of 
normal and at least 30% higher than the Week12 visit value to count as worsening in that 
parameter for the definition of flare. CRP must change from normal to abnormal or from 
abnormal to a higher value in order to be considered for the Flare.
ACR Components
Tender joint count and swollen joint count 
The number of joints with active arthritis at each visit will be determined by applying the ACR 
definition to the number of joints with swelling, tenderness and limited range of motion at each 
scheduled visit for all patients throughout the study. The ACR definition of active arthritis is 
any joint with swelling or, in the absence of swelling, limitation of motion accompanied by 
either pain on motion or tenderness not due to deformity.  The active joint count will therefore 
range from 0 to 73.


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Tender 75 joint count (TJC)
The following 75 joints will be scored as either tender or not tender:   

Temporomandibular joints: 2 

Sternoclavicular joints: 2 

Acromioclavicular joints: 2 

Shoulders: 2 

Elbows: 2 

Wrists: 2

Hands: 
o
distal interphalangeal 
o
10 proximal interphalangeal 
o
10 metacarpophalangeal  

Hip: 2 

Knee: 2

Ankle: 2

Subtalar joints: 2

Intertarsal joints: 2

Feet: 
o
10 metatarsophalangeal joints 
o
10 toes 

Cervical spine is assessed as a single joint

Thoracic spine is assessed as a single joint

Lumbar spine is assessed as a single joint

Sacroiliac joints: 2
Joint tenderness is to be scored as present or absent.  For there to be consistency between the 
joint assessments, it is strongly recommended that the same evaluator perform these 
assessments at all visits.
Swollen joint count (SJC)
A total of 68 joints are to be scored as either swollen or not swollen. The same 75 joints assessed 
for tenderness will also be assessed for swelling excluding the cervical spine, thoracic spine, 
lumbar spine, 2 hips and 2 sacroiliac joints.
For there to be consistency between the joint assessments, it is strongly recommended that the 
same evaluator perform these assessments at all visits.
Joint counts with limitation of motion
A total of 69 joints will be assessed for limitation of motion at each scheduled visit for all 
patients throughout the study.  The same 75 joints assessed for tenderness (see Section 6.4.8 of 


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the protocol) will also be assessed for limitation of motion excluding the 2 sternoclavicular, 2 
acromioclavicular joints as well as the 2 sacroiliac joints. 
Parent’s/patient’s Global Assessment of subject’s overall well-being (VAS)
The parent’s or patient’s global assessment of the patient’s overall well-being will be assessed 
on the VAS that is part of the CHAQ©. The VAS scale ranges from 0-100 mm, from very well 
(0 mm) to very poor (100 mm). 
Scores on the 100 mm linear scale will be measured to the nearest millimeter from the left.
Physician’s global assessment of PsA disease activity
The physician will rate the patient’s current condition on a 0-100 mm VAS (see Appendix 5 of 
the protocol), ranging from no disease activity (0 mm) to very severe disease activity (100 mm), 
at each scheduled visit for all patients throughout the study.
Scores on the 100 mm linear scale will be measured to the nearest millimeter from the left. To 
enhance objectivity, the physician must not be aware of the specific parent’s or patient’s global 
assessment of patient’s overall well-being, when performing his own assessment on that patient.
Childhood Health Assessment Questionnaire (CHAQ©)
The Childhood Health Assessment Questionnaire, CHAQ© (see Appendix 6 of the protocol),
will be used to assess physical ability and functional status of patients as well as quality of life. 
The disability dimension consists of multiple choice and VAS items concerning difficulty in 
performing eight common activities of daily living; dressing and grooming, arising, eating, 
walking, reaching, personal hygiene, gripping and activities. Subjects choose from four 
response categories, ranging from ‘without any difficulty’ to ‘unable to do’. 
This questionnaire should be completed by the parent (or, for patients 18 years and older, the 
questionnaire will be completed together by both the patient and parent) according to schedule 
in Table 6-1 of the protocol. The CHAQ© will be completed only in a validated version of the 
instrument in the language understandable to the parent and/or patient.
C-reactive protein (CRP)
Blood for this assessment will be obtained in order to identify the presence of inflammation, to 
determine its severity, and to monitor response to treatment. 
  
Total dactylitis count
The dactylitis count is the number of fingers and toes presenting with dactylitis, with a range of 
0-20. 


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Total enthesitis count
The following 16 entheseal sites will be assessed for the presence or absence of tenderness 
(enthesitis) on each side of the body:

Anterior Entheses: Greater trochanter of the Femur; Medial condyle of the femur; Lateral 
condyle of the femur

Posterior Entheses: Greater tuberosity of humerus; medial epicondyle of humerus; lateral 
epicondyle of humerus, Achilles tendon; and calcaneal insertion of the plantar fascia.


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Juvenile Arthritis Disease Activity Score (JADAS)
The Juvenile Arthritis Disease Activity Score (JADAS) is a composite disease activity score 
developed and validated for juvenile idiopathic arthritis (JIA). JADAS consists of four 
components: physician global assessment of disease activity on a 10 cm VAS (0=no activity, 
10=maximum activity); parent/patient global assessment of well-being on a 10 cm VAS 
(0=very well, 10=very poor); number of joints with active disease; and an inflammatory marker 
(ESR) (Consolaro, 2009).
The 
JADAS-27 
includes 
the 
following 
joints: 
cervical 
spine, 
elbows, 
wrists, 
metacarpophalangeal joints (MCP) (from first to third), proximal interphalangeal (PIP) joints, 
hips, knees, and ankles. 
The JADAS-71 includes the following joints: cervical spine,
temporomandibular, 
sternoclavicular, acromioclavicular, shoulder, elbow, wrist, MCP, PIP, Distal interphalangeal, 
hip, knee, ankle, subtalar, tarsometatarsal – replaced by intertarsal in our study, 
metatarsophalangeal, foot interphalangeal.
The JADAS is calculated as the simple linear sum of the scores of its 4 components, which 
yields a global score of 0–57, 0–101 for the JADAS-27 and JADAS-71 respectively.


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JADAS-CRP is adapted by substituting ESR with CRP as the inflammatory marker (Nordal 
2012). CRP is truncated to a 0–10 scale according to the following formula: (CRP (mg/l) −
10)/10, similar to the truncated ESR used in JADAS. Before calculation, CRP values <10 mg/l 
will be converted to 10 and CRP values >110 mg/l will be converted to 110.
The following formula to calculate the JADAS27 using CRP (mg/L) will be used:
JADAS27-CRP = (27 AJC)* + Physician Global Assessment of Disease Activity (0-10cm) + 
Parent’s or Patient’s Global Assessment of Patient’s overall well-being (0-10cm) + CRP 
(standardized in mg/dl unit (=CRP/10).
27 AJC=Active joints count based on 27 joints list (see Table 2-7 below)
The following formula to calculate the JADAS71 using CRP (mg/L) will be used:
JADAS71-CRP = (71 AJC)* + Physician Global Assessment of Disease Activity (0-10cm) + 
Parent’s or Patient’s Global Assessment of Patient’s overall well-being (0-10cm) + CRP 
(standardized in mg/dl unit (=CRP/10).
71 AJC=Active joints count based on 71 joints list (see Table 2-7 below)
The corresponding score will be calculated only when all components are available.
Table 2-7
Joints Identification for Disease Activity Scores and Indexes
*Table: Joints index
In CRF
Side
71-joint
27-joint
Cervical spine
Yes
+
+
Temporomandibular
Yes
R/L
+
–
Sternoclavicular
Yes
R/L
+
–
Acromioclavicular
Yes
R/L
+
–
Shoulder
Yes
R/L
+
–
Elbow
Yes
R/L
+
+
Wrist
Yes
R/L
+
+
Metacarpophalangeal (MCP)
1
Yes
R/L
+
+
2
Yes
R/L
+
+
3
Yes
R/L
+
+
4
Yes
R/L
+
–
5
Yes
R/L
+
–
Proximal interphalangeal (PIP)
1
Yes
R/L
+
+
2
Yes
R/L
+
+
3
Yes
R/L
+
+
4
Yes
R/L
+
+
5
Yes
R/L
+
+
Distal interphalangeal
2
Yes
R/L
+
–
3
Yes
R/L
+
–


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In CRF
Side
71-joint
27-joint
4
Yes
R/L
+
–
5
Yes
R/L
+
–
Hip
Yes
R/L
+
+
Knee
Yes
R/L
+
+
Ankle
Yes
R/L
+
+
Subtalar
Yes
R/L
+
–
Tarsometatarsal
INTERTARSAL
R/L
+
–
Metatarsophalangeal
1
Yes
R/L
+
–
2
Yes
R/L
+
–
3
Yes
R/L
+
–
4
Yes
R/L
+
–
5
Yes
R/L
+
–
Foot interphalangeal (Toe)
1
Yes
R/L
+
–
2
Yes
R/L
+
–
3
Yes
R/L
+
–
4
Yes
R/L
+
–
5
Yes
R/L
+
–


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Inactive Disease status
Clinical inactive disease definition is adapted from the ACR criteria of Wallace et al 2011. All 
must be met:

No joints with active arthritis 

No uveitis

CRP value within normal limits for the laboratory where tested or, if elevated, not 
attributable to JIA

Physician’s global assessment of disease activity score ≤ 10mm 

Duration of morning stiffness attributable to JIA ≤15 min
 
 
2.12
Interim analysis
No interim analysis will be performed, see section 4 ‘Change to protocol specified analysis’ for 
details.
will perform on behalf of Novartis final  analysis when the study is completed.
2.13
Summary of statistical analysis 
Table 2-8 is a summary of efficacy analysis in this study by treatment period and statistical 
method used.
Table 2-8
Summary of efficacy analysis by treatment period and statistical 
method
TP1
TP2
TP3
Entire treatment 
period 
(overall)/across 
period
Statistical 
Method: 
descriptive 
statistics?
Treatment 
group
AIN
AIN, 
placebo
AIN, placebo, 
total 
AIN, placebo
Disposition/
Number (%) of 
patients in the 
analysis sets
X
X
X
Screening period 
and overall 
Y
Demographics 
and background 
characteristics 
at baseline
X 
X
Y
exposure to 
study drug
X
X
X
X
Y


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TP1
TP2
TP3
Entire treatment 
period 
(overall)/across 
period
Statistical 
Method: 
descriptive 
statistics?
Prior 
medications
X
Concomitant 
medications
X
X
X
X
Y
Time to flare
X
Survival 
analysis
JIA ACR 
30/50/70/90/100
X
X
Only one figure 
and one table for 
subjects who 
flared on TP2, 
which combine 
all ACR pediatric 
responses (JIA 
ACR 
30/50/70/90/100)
Only one table 
and one figure 
for  all subjects 
randomized to 
AIN457 group in 
TP2 for overall 
study, which 
combine all ACR 
pediatric 
responses (JIA 
ACR 
30/50/70/90/100)
Y
Inactive disease 
status
X
X
Y
JIA ACR core 
component
X
X
Y
Change from 
baseline in 
JADAS score
X
X
Y
Total enthesitis 
count
X
X
Y
Total dactylitis 
count
X
X
Y


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TP1
TP2
TP3
Entire treatment 
period 
(overall)/across 
period
Statistical 
Method: 
descriptive 
statistics?
JADAS, VAS 
and CHAQ
Period 2 and the 
end of study
PK
X
X
X
Y


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Table 2-9
Summary of Safety analysis by treatment period and statistical 
method
TP1
TP2
TP3
Entire 
treatment 
period 
(overall)/across 
period
Statistical 
Method: 
descriptive 
statistics?
Treatment 
group
AIN
AIN, placebo
AIN, placebo, 
total 
AIN:TP1+TP2,
TP1+TP2+TP3
TP1+TP3,
TP1 
Any subject 
taking only AIN
Placebo:
TP1+TP2,
TP1+TP2+TP3
Any subject 
taking placebo 
at any time
total
Hematology: 
Change from 
baseline by 
parameter, visit 
and treatment
X
X
X
X
Y
Clinical Blood 
chemistry: 
Change from 
baseline by 
parameter, visit 
and treatment
X 
X
X
X
Y
Hematology: 
Notable 
abnormality 
newly occurring 
by treatment
X
X
X
X
Y
Chemistry: 
Notable 
abnormality 
newly occurring 
by treatment
X
X
X
X
Y
Hematology: 
Shift table from 
week 12 in part 
2 by parameter 
and treatment
X
Y
Chemistry: Shift 
table from week 
12 in part 2 by 
parameter and 
treatment
X
Y


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TP1
TP2
TP3
Entire 
treatment 
period 
(overall)/across 
period
Statistical 
Method: 
descriptive 
statistics?
Vital 
signs/weight: 
Change from 
baseline by 
parameter, 
treatment and 
visit
X
X
X
X
Y
Vital signs: 
Notable 
abnormality 
newly occurring 
by parameter 
and treatment
X
X
X
X
Y
ECG: Changes 
from baseline 
by treatment
week 12
week 52 
week 104 
X
Y
Adverse events 
by primary 
system organ 
class, preferred 
term and 
treatment    
X
X
X
X
Y
Adverse events 
by primary 
system organ 
class, preferred 
term, maximum 
severity and 
treatment
X
X
X
X
Y
Serious 
adverse events 
by primary 
system organ 
class, preferred 
term and 
treatment    
X
X
X
X
Y
Adverse events 
causing study 
drug 
discontinuation 
by primary 
system organ 
class, preferred 
term and 
treatment    
X
X
X
X
Y
Deaths by 
primary system 
organ class, 
X
X
X
X
Y


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TP1
TP2
TP3
Entire 
treatment 
period 
(overall)/across 
period
Statistical 
Method: 
descriptive 
statistics?
preferred term 
and treatment
3
Sample size calculation
It is assumed that the Flare-free time follows an exponential distribution with a constant 
hazard ratio.
The hazard ratio of flare events for the secukinumab group relative to placebo group is 
estimated to be 0.32 in Treatment Period 2. The hazard ratio of 0.32 was used to establish the 
sample size necessary in Treatment Period 2 and consequently Treatment Period 1 (derived 
from the median time to disease flare for ETANERCEPT and placebo in Lovell et. al. 2000).  
With the hazard ratio assumed to be 0.32, 33 flares are necessary to detect a statistically 
significant difference between secukinumab and placebo assuming 90% power and a 1-sided 
significance level of 0.025.  No data is available to estimate the placebo hazard rate beyond 6-
months.  Given that uncertainty and a maximum 21-month follow-up in Treatment Period 2, 
the total sample size necessary to achieve 33 flares in Treatment Period 2 is estimated to be at 
least 60 and at most 80 patients.  Assuming approximately 70% to 85% of patients respond in 
Treatment Period 1, the estimated minimum number of patients treated in Treatment Period 1 
is between 70 and 86. Under the assumption of 12 months of accrual duration, the total 
maximum expected study duration is 33 months. The expected number of flare events is 12 
and 21 respectively for secukinumab and placebo group in Treatment Period 2.
4
Change to protocol specified analyses
 
Prior and concomitant therapies will be reported based on the Safety Set (instead of FAS 
specified in the protocol), since Safety Set is the standard analysis set for reporting prior and 
concomitant therapies.
Vital signs criteria for notable abnormalities in Table 2-4 was updated as per AIN457 program 
level update, based on previous DMC feedback.
 
 


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5
Appendix
5.1
Visit Windows
For early discontinuation visits in the CRF, it states either “week 12” (for discontinuation in 
period 1) or “week 104” (for discontinuation in period 2 or 3) instead of the actual study week, 
so the early discontinuation visit will be re-mapped to the next scheduled assessment week 
based on the patients available visit. Different parameters have different assessment schedules, 
so the early discontinuation visit will be re-mapped for different parameters according to each 
parameter’s assessment schedule. The follow-up visit “week 112” will be analyzed as follow-
up and not re-mapped to any study week.


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5.2
Statistical methodology and assumptions
5.2.1
Analysis of continuous data
5.2.1.1
Summary statistics for continuous data
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, maximum) will be provided for continuous data by study treatment period, visit 
and treatment group. 
Minimum and maximum will be presented to the same number of decimal places as the raw 
data, mean, median to one additional decimal place, and standard deviation to two additional 
decimal places.
5.2.1.2
Kaplan-Meier analysis
The SAS procedure PROC LIFETEST is used to obtain Kaplan-Meier estimates of the 
proportion of patients with disease flare. 
• The Kaplan-Meier estimate for the cumulative flare-free rate along with the corresponding 
95% confidence interval, using Greenwood’s formula to compute the estimate of the standard 
error, at specific time points,
•median (95% confidence interval) and the estimate of the event rate at the end of the Treatment 
Period 2 will be provided. 
The SAS procedure PROC LIFETEST will be used to obtain Kaplan-Meier estimates of the 
time to event variables.
The Kaplan-Meier estimate will be derived along with the corresponding 95% confidence 
interval, using Greenwood’s formula to compute the estimate and the standard error, at specific 
time points,
The format of the SAS code is as follows:
proc lifetest data=<input_dataset> method=km outsurv=<output_dataset> reduceout
timelist=(1 to xxx by 28) timelist=(28 to xxx by 28);
  strata <treatment>;
  time <time variable>*<censor variable>(1);
run;
Explanations of the variables used and some SAS options:

The time variable contains the calculated time to event values (time to last efficacy 
evaluation (i.e. flare=no evaluation in TP2) for lack of efficacy).

For the censoring variable, the value 1 indicates censoring. That is, the values of the time 
variable are considered censored if the corresponding values of the censoring variable are 
1; otherwise, if the censoring variable equals 0, they are considered as event times.
SAS OUTPUT DATASET:


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
outsurv; contains the product-limit survival estimates (from which the cumulative event 
rates will be extracted by taking Estimated Survival Function if necessary). Additionally, 
95% confidence intervals based on Greenwood’s formula will be provided.
Stratified log-rank test
Log-rank tests will be computed, adjusted for the stratification variable of JIA category, and 
another factor MTX use at baseline. The test statistics are computed by pooling the statistics for 
treatment over the strata.
proc lifetest data=<input_dataset> method=km notable;
strata < var> / group=<treatment>;
time <time variable>*<censor variable>(1);
run;
The p-value obtained by fitting this model is two-sided. In order to obtain the one-sided p-
value, the p-value obtained by the SAS procedure above will be divided by two, provided that 
the estimated effect is in the hypothesized direction. If the estimated effect is in the other 
direction, then the p-value will be calculated as 1 – [p-value/2].
5.2.1.3
Cox’s proportional hazards model
Differences between treatment groups in time to event variables will be analyzed using Cox’s 
proportional hazards regression model with treatment group and stratification factor (JIA 
categories (ERA and JPsA) and another factor MTX use at baseline (Yes/No)) as explanatory 
variables. Hazard ratios and their associated 95% confidence intervals will be estimated. This 
analysis will be performed using SAS PROC PHREG with options of TIES=BRESLOW (which 
is the default) and RISKLIMITS. The format of the SAS code is as follows:
proc phreg data=<input_dataset>;
  model <time variable>*<censor>(1)=<treatment> <covariates> /
  ties=breslow rl;
run;
The hazard ratio and its corresponding 95% confidence interval will be computed using the 
above model. The p-value obtained by fitting this model is two-sided. In order to obtain the 
one-sided p-value, the p-value obtained by the SAS procedure above will be divided by two, 
provided that the estimated effect is in the hypothesized direction. If the estimated effect is in 
the other direction the p-value is calculated as 1 – [p-value/2].


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Univariate models and a multivariate model are fitted to explore the effect on time to flare of 
treatment, of the stratification variables (JIA category) and another factor MTX use at 
baseline. The format of the SAS code is as follows:
proc phreg data=<input_dataset>;
  model <time variable>*<censor>(1)=<explanatory variable(s)> /
  ties=breslow rl;
run;
The proportionality of the hazard function will be tested in all the univariate models and in the 
final multivariate model (cf. below “Checking of model assumptions”).
Checking of model assumptions 
The assumption of proportionality of the hazard function(s) over time will be tested using a Cox 
proportional hazards regression model which includes treatment and a time-dependent 
explanatory variable created through the interaction between the response variable (time to 
event) and treatment:
proc phreg data=<input_dataset>;
  model <time variable>*<censor>(1)=<treatment> <covariates> treat_time 
                                     <covariate1_time, ...>;
  treat_time = <treatment>*log(<time variable>);
  <covariate1>_time = <covariate1>*log(<time variable>);
  <covariate2>_time = <covariate2>*log(<time variable>);
     /* add interaction terms for all covariates in the model */
  proportionality_test: test treat_time, <covariate1>_time,
                        <covariate2>_time; 
run;
In addition, a graphical method will be used for checking the proportional hazards assumption. 
A plot of log-log survivor function versus time for each of the treatments will be used, using 
PROC LIFETEST as described in section Kaplan-Meier analysis, above. Approximate 
parallelism between the curves for the treatment groups would have provided supportive 
evidence of the proportional hazards assumption.


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5.2.2
Analysis of binary (and categorical) data
5.2.2.1
Summary statistics for binary and categorical data
Summary statistics for discrete variables will be presented in contingency tables and will 
include count and frequency in each category. If applicable, confidence intervals will be derived 
as well based on the score method including continuity correction [Newcombe (1998)]:
With z as (1-alpha/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-
alpha/2)), n as total number of subjects (i.e. number of subjects in the denominator), and p
as estimated crude incidence (number of subjects with event / n ) it is 
p
q

1
Then the lower limit is























2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
and the upper limit is























2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
.
In addition, if L > p then L = p and if U < p then U = p.
5.2.3
Crude incidence estimates 
5.2.3.1
Crude incidence and 100*(1-α)% confidence interval
For n subjects, each at risk to experience a certain event with probability π, the crude incidence 
is estimated as p=x/n, where x is the number of subjects with the event.
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the 
relative frequency based on the score method including continuity correction [Newcombe 
(1998)]. 
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/2), n
as total number of subjects (i.e. number of subjects in the denominator), and p as estimated 
crude incidence (number of subjects with event / n ) it is 
p
q

1
.
Then the lower limit is























2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
and the upper limit is


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






















2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
.
In addition, if L > p then L = p and if U < p then U = p.
5.2.4
Exposure adjusted incidence rate estimates
5.2.4.1
Exposure adjusted incidence rate and 100*(1-α)% confidence interval
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 



n
j
jt
T
1
and D is the number of subjects with 
at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson 
variable with parameter θT and observed value D can be obtained based on Garwood (1936), 
from which an exact 100*(1-α)% confidence interval for D/T will be derived as follows (Sahai, 
1993; Ulm, 1990):
Lower confidence limit   
T
c
L
D
2,2
/
5.0


for D>0, 0 otherwise,
Upper confidence limit 
T
c
U
D 2
2,2
/
1
5.0




where
k
c ,

is the αth quantile of the Chi-square distribution with k degrees of freedom.
5.2.4.2
CRP Normalization Procedure
All CRP values referred to in this SAP constitute a STANDARDIZED CRP value to a 
NORMAL RANGE of 0 – 10 mg/L as per protocol (e.g. CRP value 20 mg/L normal value 0-
20 mg/L will be transformed to 10 mg/L, nv 0-10 mg L) as follows: 
For the adapted ACR pediatric response, flare calculation, and for all instances in which CRP 
is necessary, the value coming from the local laboratory will be used. Local CRP will be 
standardized according to the following formula as per Ruperto (2005).
Standardization of laboratory tests: the CRP test results will be standardized based on the 
normal values provided by each local laboratory. All values will be converted to the 
international standard (SI) unit system (Laposata 1992), according to the following formulas:
xref= [(rangeref × xref100) / 100] + minref, 
where 


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
xref= value in the SI system, 

range ref= normal range of the SI system, and 

minref= minimum value in the SI system;
And 
xref100= [(xi – min OMU) / rangeOMU] × 100, where 

xi= value in the original measurement unit (OMU), 

range OMU= normal range of the OMU, and 

min OMU= minimum value of the OMU. 
For the purposes of the trial CRP will be normalized and the following normal range used:
xref= normalized value, 

range ref=  normalized range of = 0 - 10 mg/dL, 

minref= minimum value = 0 mg/L;
For example, a CRP level of 2.5 mg/dl (OMU normal values 0.1–0.5 mg/dl) will be converted 
to 60 mg/L (Novartis normal values 0-10 mg/L).
xref= [(rangeref × xref100) / 100] + minref, 
xref100= [(xi – min OMU) / rangeOMU] × 100
xref100= [(2.5 – 0.1) / 0.4] × 100 = 600 
xref= [(10 × 600) / 100] + 0 = 60 mg/L
6
Reference

Brunner HI, Ruperto N, Tzaribachev N, et al (2018) Subcutaneous golimumab for 
children with active polyarticular-course juvenile idiopathic arthritis: results of a 
multicentre, double-blind, randomized withdrawal trial. Ann Rheum Dis; 77:21–29.

Consolaro A, Ruperto N, Bazso A, et al (2009) Development and validation of a 
composite disease activity score for juvenile idiopathic arthritis. Arthritis Rheum; 
61(5):658-66

Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–
453.

Laposata M. SI unit conversion guide. Boston: NEJM books; 1992.

Lovell DJ, Giannini EH, REIFF A, et al (2000) Etanercept in Children with Polyarticular 
Juvenile Rheumatoid Arthritis. The New England Journal of Medicine 2000; volume 
342 (11) 763-69

Newcombe RG (1998) Two-sided confidence intervals for the single proportion: 
comparison of seven methods. Statistics in Medicine; 17: 857-872.


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
Nordal EB, Zak M, Bernston L, et al (2012) Validity and predictive ability of the 
juvenile arthritis disease activity score based on CRP versus ESR in a Nordic 
population-based setting. Ann Rheum Dis.71(7):1122-7.

Ramanan AV, Whitworth P, Baildam EM (2003) Use of methotrexate in juvenile 
idiopathic arthritis. Arch Dis Child; 88:197–200.
 
 
 

Sahai H, Khurshid Anwer (1993). Confidence intervals for the mean of a poisson 
distribution: a review. Biom J, 35 (7); 857-867
 
 

Ulm K (1990). A simple method to calculate the confidence interval of a standard 
mortality ratio. American Journal of Epidemiology, 131(2); 373-375
 
  

Wallace CA, Giannini EH, Huang B, et al (2011) American College of Rheumatology 
provisional criteria for defining clinical inactive disease in select categories of juvenile 
idiopathic arthritis. Arthritis Care Res 63:929-936.

Weiss PF, Colbert RA.2 Xiao R et al. (2014) Development and Retrospective Validation 
of the Juvenile Spondyloarthritis Disease Activity Index. Arthritis Care & Research: 
66(12): 1775–1782.