An Extension Study to Evaluate the Sustainability of Clinical Benefits, Safety and Tolerability of Secukinumab in Patients With Active Ankylosing Spondylitis
Phase: PHASE3
Conditions: Spondylitis, Ankylosing
Sponsor: Novartis Pharmaceuticals

Clinical Development
Secukinumab (AIN457)
Clinical Trial Protocol CAIN457F2305E1 / NCT01863732
An extension study to evaluate the sustainability of clinical 
benefits, safety and tolerability of secukinumab in patients 
with active Ankylosing Spondylitis
Authors:
 
Document type:
Amended Protocol Version
EUDRACT number:
2013-001089-40
Version number:
01 (Clean)
Development phase:
III
Development status
Final
Release date:
31-Aug-2015
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
NCDS Template Version 03-Feb-2012

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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 1 .............................................................................................................................9
Amendment rationale ..........................................................................................................9
Changes to the protocol.....................................................................................................12
Protocol synopsis...............................................................................................................14
1
Introduction .......................................................................................................................16
1.1
Background............................................................................................................16
1.2
Purpose ..................................................................................................................17
2
Study objectives.................................................................................................................17
2.1
Primary objective...................................................................................................17
2.2
Secondary objectives .............................................................................................18
18
3
Investigational plan ...........................................................................................................18
3.1
Study design...........................................................................................................18
3.2
Rationale of study design.......................................................................................21
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....21
3.4
Rationale for choice of comparator .......................................................................22
3.5
Purpose and timing of interim analyses/design adaptations..................................22
3.6
Risks and benefits..................................................................................................22
4
Population..........................................................................................................................23
4.1
Inclusion criteria ....................................................................................................23
4.2
Exclusion criteria...................................................................................................23
5
Treatment...........................................................................................................................24
5.1
Protocol requested treatment .................................................................................24
5.1.1
Investigational treatment.......................................................................24
5.1.2
Additional study treatment....................................................................25
5.2
Treatment arms......................................................................................................25
5.3
Treatment assignment, randomization...................................................................25
5.4
Treatment blinding.................................................................................................25
5.5
Treating the subject................................................................................................26
5.5.1
Subject numbering ................................................................................26
5.5.2
Dispensing the investigational treatment ..............................................26

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5.5.3
Handling of study treatment..................................................................27
5.5.4
Instructions for prescribing and taking study treatment........................27
5.5.5
Permitted dose adjustments and interruptions of study treatment ........28
5.5.6
Rescue medication ................................................................................29
5.5.7
Concomitant treatment..........................................................................29
5.5.8
Prohibited Treatment.............................................................................30
5.5.9
Discontinuation of study treatment and premature subject 
withdrawal.............................................................................................30
5.5.10
Emergency breaking of treatment assignment ......................................32
5.5.11
Study completion and post-study treatment..........................................33
5.5.12
Early study termination.........................................................................33
6
Visit schedule and assessments .........................................................................................33
6.1
Information to be collected on screening failures..................................................42
6.2
Subject demographics/other baseline characteristics.............................................42
6.3
Treatment exposure and compliance .....................................................................42
6.4
Efficacy..................................................................................................................42
6.4.1
Assessment of SpondyloArthritis International Society criteria 
(ASAS)..................................................................................................42
44
45
 
45
45
46
46
46
47
6.4.10
Appropriateness of efficacy assessments..............................................47
6.5
Safety.....................................................................................................................47
6.5.1
Physical examination ............................................................................48
6.5.2
Vital signs..............................................................................................48
6.5.3
Height and weight .................................................................................48
6.5.4
Laboratory evaluations..........................................................................48
6.5.5
Electrocardiogram (ECG) .....................................................................49
6.5.6
Local tolerability (injection site reactions) ...........................................49
6.5.7
Pregnancy and assessments of fertility .................................................49
50
6.5.9
Appropriateness of safety measurements..............................................50

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50
.51
7
Safety monitoring..............................................................................................................51
7.1
Adverse events.......................................................................................................51
7.2
Serious adverse event reporting.............................................................................54
7.3
Pregnancy reporting...............................................................................................55
8
Data review and database management.............................................................................55
8.1
Site monitoring ......................................................................................................55
8.2
Data collection.......................................................................................................55
8.3
Database management and quality control............................................................56
8.4
Data Monitoring Committee..................................................................................56
8.5
Adjudication Committee........................................................................................56
9
Data analysis......................................................................................................................57
9.1
Analysis sets ..........................................................................................................57
9.2
Subject demographics and other baseline characteristics......................................57
9.3
Treatments .............................................................................................................57
9.3.1
Study Treatment....................................................................................57
9.3.2
Concomitant medication .......................................................................57
9.4
Analysis of the primary and key secondary variable(s).........................................58
9.4.1
Variable(s).............................................................................................58
9.4.2
Statistical model, hypothesis, and method of analysis..........................58
9.4.3
Handling of missing values/censoring/discontinuations.......................58
9.4.4
Supportive analyses...............................................................................58
9.5
Analysis of secondary 
 variables ..................................................58
9.5.1
Efficacy variables..................................................................................58
9.5.2
Safety variables .....................................................................................59
60
61
9.6
Interim analyses.....................................................................................................61
9.7
Sample size calculation..........................................................................................61
10 Ethical considerations........................................................................................................62
10.1
Regulatory and ethical compliance........................................................................62
10.2
Informed consent procedures.................................................................................62
10.3
Responsibilities of the investigator and IRB/IEC..................................................62
10.4
Publication of study protocol and results...............................................................63
11 Protocol adherence ............................................................................................................63

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11.1
Protocol Amendments ...........................................................................................63
12 References .........................................................................................................................63
13 Appendices ........................................................................................................................66
13.1
Appendix 1: Clinically notable laboratory values and vital signs .........................66
67
13.3
Appendix 3:  Modified New York criteria ............................................................68
13.4
Appendix 4:  Assessment of SpondyloArthritis International Society criteria 
(ASAS) ..................................................................................................................69
13.4.1
Bath Ankylosing Spondylitis Functional Index (BASFI).....................69
13.4.2
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........69
13.4.3
Bath Ankylosing Spondylitis Metrology Index (BASMI)....................70
72
73
List of tables
Table 5-1
Prohibited treatment..............................................................................30
Table 6-1
Assessment schedule - Part 1:  Week 104E1 to Week 156...................35
Table 6-2
Assessment schedule - Part 2:  Week 160 to Week 208 .......................37
Table 6-3
Assessment schedule - Part 3:  Week 212 to Week 260 and follow-
up visit F268..........................................................................................39
Table 13-1
Safety Analyses: Expanded Limits and Notable Criteria......................66
67
67
72
List of figures
Figure 0-1
Time course of ASAS 20 response (estimate and 95% confidence 
interval (CI)) using non-responder imputation by study and 
treatment up to Week 16 for CAIN457F2310 and CAIN457F2305 
(based on individual study results, FAS) ..............................................10
Figure 0-2
ASAS 20 response rate versus Cmin concentration at Week 16 
(Study CAIN457F2310)1,2,3 ..................................................................11
Figure 3-1
Core Study (AIN457F2305) Study Design...........................................19
Figure 3-2
Extension Study (AIN457F2305E1) Study Design ..............................21

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List of abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase
AS
Ankylosing Spondylitis
ASAS
Assessment of SpondyloArthritis International Society criteria
AST
Aspartate Aminotransferase
BASDI
Bath Ankylosing Spondylitis Disease Activity
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BMD
Bone Mineral Density
BME
Bone Marrow Edema
BSL
Baseline
CI
Confidence Interval
CPO
Country Pharma Organization
CRO
Contract Research Organization
DBL
Database Lock
DMARD
Disease Modifying Anti-Rheumatic Drug
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
GCP
Good Clinical Practice
GGT
Gamma Glutamyl Transferase
hCG
Human Chorionic Gonadotropin
HLA
Human Leukocyte Antigen
ICF
Informed Consent Form

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ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC/EC
Independent Ethics Committee
IFU
Instructions for Use
IL
Interleukin
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
i.v.
Intravenous(ly)
IVR
Interactive Voice Response
LLOQ
Lower Limit of Quantification
MRI
Magnetic Resonance Imaging
MTX
Methotrexate
NSAID
Non-Steroidal Anti-Inflammatory Drug
OPG
Osteoprotegerin
PFS
Prefilled Syringe
PoC
Proof of Concept
PsA
Psoriatic Arthritis
RA
Rheumatoid Arthritis
RANKL
Receptor Activator of Nuclear Factor Kappa-B Ligand
RDC
Remote Data Capture
SAE
Serious Adverse Event
s.c.
Subcutaneous(ly)
SpA
SpondyloArthritis
SUSAR
Suspected Unexpected Serious Adverse Reaction
TNF
Tumor Necrosis Factor
VAS
Visual Analog Scale

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Glossary of terms
Assessment
A procedure used to generate data required by the study
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
Enrollment
Point/time of subject entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Epoch (period)
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after treatment 
has ended.
Inadequate response to TNFα
Active disease despite stable treatment with anti-TNFα for at least 3 
months at an approved dose or for at least one dose in the case of lack of 
tolerance.
Investigational drug
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as approved drugs 
used outside of their indication/approved dosage or tested in a fixed 
combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage
Medication number
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system
Premature subject withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up)
Randomization number
A unique identifier assigned to each randomized subject, corresponding to 
a specific treatment arm assignment
Stop study participation
Point/time at which the subject came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later
Study drug/ treatment
Any single drug or combination of drugs administered to the subject as part 
of the required study procedures; includes investigational drug (s), active 
drug run-ins or background therapy 
Study/investigational treatment 
discontinuation
Point/time when subject permanently stops taking study/investigational 
treatment for any reason; may or may not also be the point/time of 
premature subject withdrawal
Subject Number 
A number assigned to each subject who enrolls into the study 
Variable
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points

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Amendment 1 
Amendment rationale
This protocol amendment is issued for the following reasons:
1. After approval and implementation of Amendment 1, all patients will receive study 
medication in an open-label fashion. The study medication for subjects on the 75 mg 
treatment arm will be re-evaluated for patients whose overall therapeutic response is 
not fully achieved with the current dose of 75 mg and may improve with a higher dose 
(150 mg s.c. every 4 weeks), as judged by the investigator at any time after 
implementation of Protocol Amendment 1. 
The 52-week efficacy data from the pivotal Phase 3 trial (CAIN457F2310) of 
secukinumab in active moderate to severe ankylosing spondylitis (AS) showed that 
secukinumab 150 mg s.c. provides robust, statistically significant, and clinically 
meaningful efficacy versus placebo in the treatment of AS when administered at 
Baseline (BSL), Weeks 1, 2, and 3, and every 4 weeks thereafter starting at Week 4, as 
reflected in an ASAS 20 response rate of approximately 60% at the Week 16 primary 
endpoint (Figure 0-1).  A higher dose intravenous (i.v.) loading regimen of 10 mg/kg 
at BSL, Weeks 2 and 4 administered in CAIN457F2305 did not provide any additional 
efficacy benefit to the 150 mg s.c. maintenance regimen, with a similar Week 16 
ASAS 20 response rate of approximately 60% in the 10 mg/kg - 150 mg arm. 
In contrast, the 75 mg s.c. dose was ineffective in that it failed to differentiate from 
placebo on the primary endpoint of ASAS 20 at Week 16 (Figure 0-1) and all 
secondary endpoints evaluated in a pre-defined hypothesis testing hierarchy in study 
CAIN457F2310, in which it was administered at BSL, Weeks 1, 2, and 3, and every 4 
weeks thereafter starting at Week 4.  The 75 mg s.c. loading and maintenance regimen 
demonstrated consistent and clinically meaningful dose separation from the 150 mg s.c. 
dose, with decreased treatment responses on the primary and nearly all secondary 
endpoints tested, including measures of disease signs and symptoms, physical function, 
and quality of life.  

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Figure 0-1
Time course of ASAS 20 response (estimate and 95% confidence interval 
(CI)) using non-responder imputation by study and treatment up to Week 16 
for CAIN457F2310 and CAIN457F2305 (based on individual study results, 
FAS)
As the i.v. loading regimen (10 mg/kg x 3 doses every 2 weeks) in CAIN457F2305 
resulted in similar drug exposure through Week 16 for both the 10 mg/kg-75 mg arm 
and the 10 mg/kg - 150 mg arm, the 10 mg/kg - 75 mg regimen was efficacious at 
Week 16 on the primary and all secondary endpoints. However, by Week 52, clinically 
meaningful dose-related differences in efficacy were apparent for higher hurdle clinical 
efficacy endpoints, including ASAS 40, ASAS partial remission, and BASDAI 50, 
which favored the 150 mg s.c. maintenance dose and demonstrated that the initial high 
exposure of the i.v. loading regimen cannot sustain optimal efficacy when followed by 
the 75 mg s.c. maintenance dose, as the 10 mg/kg - 75 mg regimen results in a lower 
treatment response over time on clinically relevant, higher hurdle efficacy endpoints.
In addition, pharmacokinetic analysis suggested that the 150 mg s.c. dose will provide 
greater benefit than the 75 mg s.c. dose because the 150 mg s.c. dose produces trough 
exposure levels at Week 16 of approximately 25 mcg/mL or higher, that are associated 
with approximately 60% probability of achieving an ASAS20 response, which was the 
maximal efficacy achieved with the doses tested in Phase 3 AS trials (Figure 0-2). In 
contrast, the lower dose of 75 mg s.c. was shown to lead to suboptimal exposure and 
decreased clinical benefit, as the mean exposure levels seen with the 75 mg s.c. dose are 
associated with an ASAS 20 response rate of approximately 40%. Thus, the 75 mg s.c. 

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dose would result in a 20% lower maximal ASAS 20 response rate compared to the 150 
mg s.c. dose on an absolute basis, which is a relative decrease in efficacy of 33%. 
Figure 0-2
ASAS 20 response rate versus Cmin concentration at Week 16 (Study 
CAIN457F2310)1,2,3                       
1The solid line and shaded area represent the mean and 95% CI from the 
logistic regression Emax model. 
2Black diamonds and whiskers represent mean and 95% CI of the observed 
response rates in each exposure subgroups.
3Boxplots (with mean, median, first and third quartile, minimum and maximum 
values) of observed concentrations at Week 16 are represented in the bottom 
panel for each dose level.
The safety results of studies CAIN457F2305 and CAIN457F2310, based collectively 
on 590 AS patients, demonstrated a safety profile for both the 150 mg s.c. and 75 mg 
s.c. doses that was consistent with that observed in the larger psoriasis clinical 
program, consisting of over 3430 patients.  In addition, there were no major dose-
related safety differences between the 150 mg s.c. or 75 mg s.c. doses, whether 
preceded by a subcutaneous (CAIN457F2310) or intravenous (CAIN457F2305) 
loading regimen, that suggest an unacceptable benefit-risk profile for secukinumab 
150 mg s.c. 
.

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Thus, given that the Phase 3 efficacy and safety results of the AS clinical program 
demonstrate that the proposed dose of secukinumab 150 mg s.c. provides the optimal 
benefit-risk assessment in AS, while the 75 mg s.c. dose is ineffective, the 75 mg s.c. 
dose arm will be re-evaluated in all on-going AS trials. The study medication for 
subjects on the 75 mg treatment arm should be escalated from 75 mg s.c. to 150 mg s.c. 
every 4 weeks for patients whose overall therapeutic response is not fully achieved
with the current dose of 75 mg and may improve with a higher dose, as judged by the 
investigator. The escalation of the study medication may be determined at any site 
visit. For patients escalated to 150 mg, no dose reduction can be performed at a later 
time point. 
2. Following the Week 52 DBL and interim analysis, based on the safety results of 
studies CAIN457F2305 and CAIN457F2310, the DMC review will no longer be 
required.
3. According to the CAIN457F2305E1 protocol exclusion criterion #6, women of child-
bearing potential, currently defined as all women physiologically capable of becoming 
pregnant and unwilling to use effective contraception during the study and for 16 
weeks after stopping treatment, should not be considered eligible for the study. 
However, there are approved secukinumab labels for the psoriasis indication that 
indicate a specific time window for the use of effective contraception after stopping 
treatment.  There is currently no evidence to indicate that a specific duration of post-
treatment contraception is required for patient safety. However, to align with these 
specifications in local prescribing information, protocol exclusion criterion #6 is 
changed to “Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using effective methods of 
contraception during the entire study or longer if required by locally approved 
prescribing information (e.g., 20 weeks in EU).” 
4.
 
 
5. The Risks and Benefits section was updated to reflect the currently available 
information as released in the Investigator’s Brochure.
None of the changes described in this amended protocol are due to evidence-based safety 
concerns.
At the time this amendment becomes effective, all the subjects would have been randomized 
in the study.
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 deletions and red underlined for insertions.
The wording of various sub-sections to “Study objectives” (Section 2), “Study design” 
(Section 3.1), “Risks and benefits” (Section 3.6), “Rationale of dose/regimen, route of 
administration and duration of treatment” (Section 3.3), “Exclusion criteria” (Section 4.2),
“Investigational treatment” (Section 5.1.1), “Treatment arms” (Section 5.2), “Treatment 

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blinding” (Section 5.4), “Permitted dose adjustments and interruptions of study treatment” 
(Section 5.5.5), “Efficacy” (Section 6.4), “Data Monitoring and Adjudication Committees” 
(Section 8.4) and “Data analysis” (Section 9) and have been amended to reflect the rationale 
given above.
Additionally, this protocol amendment includes the correction of typographical and 
formatting errors and minor editorial changes for increased clarity of the text. Consequently, a 
small number of changes were implemented throughout the protocol.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities as required.
The changes described in this amended protocol require IRBs/IECs approval prior to 
implementation.

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Protocol synopsis 
Protocol number
CAIN457F2305E1
Title
An extension study to evaluate the sustainability of clinical benefits, safety 
and tolerability of secukinumab in patients with active Ankylosing 
Spondylitis
Brief title
Study of sustainability of clinical benefits, safety and tolerability of 
secukinumab in patients with active Ankylosing Spondylitis 
Sponsor and Clinical 
Phase
Novartis
Phase III
Investigation type
Drug; Biologic
Study type
Interventional
Purpose and rationale
The purpose of this study is to obtain additional data on the sustainability 
of subject and clinical benefits, safety and tolerability during long-term 
treatment with secukinumab prefilled syringe (PFS) formulation.
Primary Objective(s) 
and Key Secondary 
Objective
To evaluate the sustainability of subject benefits as quantified by the 
ASAS20 (Assessment of SpondyloArthritis International Society criteria) in 
the whole study population during long-term treatment (Week 260) with 
secukinumab provided as prefilled syringes
Secondary Objectives
Objective 1:  To evaluate the sustainability of subject benefits in subjects 
with active AS as quantified by the ASAS40 response during long-term 
treatment with secukinumab
Objective 2:  To evaluate the overall safety and tolerability of secukinumab 
in subjects with active AS over time up to Week 260
Study design
The multicenter extension study uses a double-blind, double-dummy, 
parallel-group design during the first year after which the site personnel 
and subject will be unblinded, making it an open-label study the remaining 
2 years.
Population
The study population will consist of approximately 300 male and female 
subjects (≥18 years old at the time of consent) who completed the core 
study (CAIN457F2305) and who meet the inclusion/exclusion criteria.
Inclusion criteria
Subjects who completed the core study (CAIN457F2305)
Subjects who are deemed by the investigator to benefit from continued 
secukinumab therapy
Exclusion criteria
History of hypersensitivity to any of the study drugs or to drugs of similar 
chemical classes
Deemed by the investigator to not benefit from the study drug based on 
lack or improvement or worsening of their symptoms
Use of any investigational drug except for secukinumab during the core 
study
Investigational and 
reference therapy
Group 1:  secukinumab 75 mg 
Group 2:  secukinumab 150mg
After approval and implementation of Protocol Amendment 1, the study 
medication for subjects on the 75 mg treatment arm should be escalated 
from 75 mg s.c. to 150 mg s.c. every 4 weeks for patients whose overall 
therapeutic response is not fully achieved with the current dose of 75 mg 
and may improve with a higher dose, as judged by the investigator. The 

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escalation of the study medication may be determined at any site visit.
Efficacy assessments
Assessment of SpondyloArthritis International Society Criteria (ASAS)
 
 
Safety assessments
Evaluation of all AEs and SAEs including injection site reactions and 
laboratory assessments
ECG, physical examination, vital signs
Other assessments
Data analysis
The primary efficacy variable is the clinical response to treatment 
according to the ASAS20 over time up to Week 260. The analysis of the 
primary variable will be based on the FAS subjects and will be 
descriptively summarized for each treatment over time.
Key words
ankylosing spondylitis, AS, chronic inflammatory disease, inflammatory 
back pain, secukinumab, prefilled syringe (PFS), subcutaneous injection, 
arthritides, AIN457, AIN457F

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1
Introduction
1.1
Background
Ankylosing Spondylitis (AS) is a chronic inflammatory disease, which is mainly characterized 
by involvement of axial joints and bilateral sacroiliitis, but sometimes peripheral joints and 
extra-articular organs are involved as well. Associated extra-articular manifestations include 
acute anterior uveitis, cardiovascular and pulmonary abnormalities, neurologic sequelae, and 
both clinical and subclinical gastrointestinal findings. Decreased bone mineral density (BMD) 
is typical of extra-articular symptoms and many patients with AS have osteoporosis and 
consequent non-traumatic fractures in spite of their young age and gender (male). Generalized 
osteoporosis as well as regional osteopenia is common in AS with high incidence of 
osteoporosis or osteopenia, in spine (41–62%) and in femur (46–86%). The presence of the 
HLA-B27 antigen is strongly associated with AS: 90–95% of patients with AS who have 
European ancestry carry this marker.
It affects up to 1.1% of the population and is associated with significant morbidity and 
disability, and thus constitutes a major socioeconomic burden. 
The first-line drug treatments of mild AS are non-steroidal anti-inflammatory drugs (NSAIDs). 
Treatment of NSAIDs-refractory AS is hampered by the lack of efficacy of virtually all 
standard disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX). 
As an exception, peripheral arthritis associated with AS responds quite well to sulfasalazine. 
Tumor necrosis factor (TNF) blocking agents were successfully added to the armamentarium 
to treat AS (Braun 2002) and subsequently demonstrated prolonged efficacy up to three years 
of follow-up (Braun 2005). However, upon discontinuation of TNF blockers the disease 
relapses quickly (Baraliakos 2005), indicating that the inflammatory process may only be 
suppressed but not completely abolished. Results reported in the ASSERT study, the largest 
study ever conducted on Magnetic resonance Imaging (MRI) evaluation of spinal lesions in 
AS, demonstrated a near complete resolution of inflammatory lesions at the 24 week time 
point (Braun 2006). However, in other reports AS inflammatory bone lesions depicted by 
MRI did not completely disappear under TNF antagonist therapy over a six-month study 
period. The bone lesions persisted despite full clinical remission was achieved (Zochling 
2007). This observation suggests that the inflammatory process is still smoldering (Zochling 
2007). Similarly, residual bone marrow edema (BME) as determined by MRI may represent 
persistent inflammatory processes in rheumatoid arthritis (RA) patients (Brown 2006) and 
psoriatic arthritis (PsA) patients (Anandarajah 2008) despite clinical remission. A substantial 
level of BME and marrow inflammation must be present to be detectable in MRI (Appel 
2006), and the long-term structural consequences and thus the clinical significance of these 
subclinical chronic inflammatory processes in the bone have yet to be determined. 
Radiographic findings include syndesmophytes, with progression to total spinal fusion in
some cases. Radiographs of the sacroiliac joint often show sclerosis, erosion, and, eventually, 
fusion.
A variety of new drug classes have been investigated during the last years for the treatment of 
patients with AS (Kiltz 2012). Abatacept, IL-1 and IL-6 blockade seem to have no effect in 
patients with active AS disease. Although, promising results have been reported for 

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thalidomide and apremilast, none of these new drugs have been shown to reach response rates 
compared to TNF-blockers.
Interleukin (IL)-17 antagonism by secukinumab represents a novel approach to interfere with 
the chronic inflammatory process by selectively targeting the predominant cytokine of the 
unique subset of helper T17 cells. Animal data suggest that IL-17 blockade reduces Receptor 
activator of nuclear factor kappa-B ligand (RANKL) dependent osteoclastogenesis upstream 
of TNF alpha (Koenders 2005). Emerging evidence suggests that IL-17 plays a role as an 
inflammatory mediator in patients with AS. Elevated levels of serum IL-17 and an increased 
number of circulating Th17 cells were detected in AS patients (Shen 2009). More IL-17 
producing cells were detected in the facet joints of patients with AS compared with those with 
osteoarthritis (Appel 2008). Serum sRANKL levels and sRANKL/ Osteoprotegerin (OPG) 
ratios are up-regulated in patients with AS and have relationship with BMD and radiological 
changes (Kim 2006). In a double-blind, placebo-controlled, multicenter, proof-of-concept 
study that investigated 30 patients with active AS, secukinumab demonstrated high efficacy, 
achieving ASAS20 (Assessment of SpondyloArthritis International Society Criteria) response 
rate at week 6 in approximately 60% of the patients. Moreover, IL-17A blockade with 
secukinumab reduced spinal inflammation in patients with AS as early as week 6, as detected 
by MRI (Baraliakos 2011). Sagittal magnetic resonance images of the spine including T1-
sequences and short-t inversion recovery-sequences performed showed a reduction of 
inflammation after 6 weeks, maintained up to Week 28. Early improvements were especially 
noted in patients with higher baseline MRI scores. This favorable response prompted the 
initiation of another ongoing, placebo-controlled, randomized trial to confirm the efficacy of 
secukinumab for the treatment of patients with active AS. 
As mentioned above and in the Baraliakos 2005 publication, disease relapse occurs once a 
TNF blocker has been discontinued; therefore, patients will likely remain on treatment 
indefinitely. Continuation of the pivotal core study is needed to demonstrate the sustainability 
of clinical benefits, and the long-term safety and tolerability required for managing the 
chronic nature of AS.
1.2
Purpose 
The proposed extension study CAIN457F2305E1 is designed as a 3-year extension to the 
phase III study CAIN457F2305. It aims to provide continuous treatment with secukinumab in 
prefilled syringes (PFS) for subjects who completed the phase III study CAIN457F2305, 
defined as the “core study”, to obtain additional data on the sustainability of subject and 
clinical benefits, safety and tolerability during long-term treatment.
2
Study objectives
2.1
Primary objective
To evaluate the sustainability of subject benefits as quantified by the ASAS20 (Assessment of 
SpondyloArthritis International Society criteria) in the whole study population during long-
term (Week 260) treatment with secukinumab 75 and 150 mg provided as prefilled syringes

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2.2
Secondary objectives
1. To evaluate the sustainability of subject benefits in subjects with active AS as quantified 
by the ASAS40 response during long-term treatment with secukinumab 75 or 150 mg
2. To evaluate the overall safety and tolerability of secukinumab in subjects with active AS 
over time up to Week 260
3
Investigational plan
3.1
Study design
Core Study (AIN457F2305) Study Design Summary
The AIN457F2305 core study used a double-blind, randomized, parallel-group, placebo-
controlled design. A screening period running 4 weeks before randomization was used to 
assess eligibility followed by a treatment period of 2 years (Week 0 through Week 104).

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At Week 16 (Visit 8), efficacy of secukinumab treatment was assessed based on the ASAS 20 
improvement criteria and subjects were classified as responders or non-responders.
The subjects were stratified according to being TNFα inhibitor incomplete responders (TNF-
IR) or TNFα inhibitor naïve subjects. Approximately 30% of subjects were TNF-IR to ensure 
a representative population for the assessment of efficacy and safety.
Figure 3-1
Core Study (AIN457F2305) Study Design
75mg  or 150mg AIN457 (1:1)
8
16
24
48
Week
-4 to BSL
32
40
56
100 104
52
4
NR
Escape treatment: 75mg  or 150mg AIN457 (1:1)
Group 2
AIN457 i.v. loading 
followed by 150mg s.c.
n = 116
NR
Randomization 
AIN457 administration (s.c.)
Placebo to AIN457 administration (s.c.)
Non-responder (not achieving ASAS 20)
AIN457 10 mg/kg administration (i.v.)
Placebo to AIN457 administration (i.v.)
Group 1
AIN457 i.v. loading 
followed by 75mg s.c.
n = 116
Group 3
Placebo i.v. 
followed by placebo s.c.
n = 116
F112
PE
Extension Study (AIN457F2305E1) Study Design
The multicenter extension study uses a double-blind, double-dummy, parallel-group design 
from Week 104E1 to Week 156 upon which the site personnel and subject will be unblinded, 
making it an open-label study through Week F268 (follow-up visit). All week numbers used 
in the extension study are relative to the randomization visit of the core study. This study will 
offer continuation of treatment for subjects completing the core study and who are deemed by 
the investigator to benefit from continued secukinumab therapy. The total combined duration 
of treatment for the core study and this extension study is five years.
At Week 104 of the core study, subjects eligible for the extension will complete the 
assessments associated with the core study visit per the core study protocol and will 
subsequently continue into the extension study on the same dose. A new Informed Consent 
must be signed before proceeding into the extension study. 

Group 1:  secukinumab 75 mg plus placebo 150 mg dosed every four weeks from Week 
104E1 through Week 152. Starting on Week 156 (after unblinding), only secukinumab 75 
mg will be dosed. 

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
Group 2:  secukinumab 150 mg plus placebo 75 mg dosed every four weeks from Week 
104E1 through Week 152.  Starting on Week 156 (after unblinding), only secukinumab 
150 mg will be dosed. 
The treatment will be offered in prefilled syringes (PFS) in the extension study. This is a 
change from the core study, which used s.c. injections prepared from lyophilisate. Subjects 
will be instructed in detail how to self-administer the s.c. injection using the PFS formulation. 
Each injection will be administered into an appropriate injection site of the body (thighs, arms, 
or abdomen). For the first 3 months of the study (through Week 116), all injections will be 
performed at the study site. Starting on Week 120, the subject is allowed to self-administer the 
study medication at home or continue to present at monthly intervals to the study site for 
injection administrations, based on the subject’s preference and the investigator’s judgment. 
Site staff will administer the injection to subjects who are not able or unwilling to self-
administer the PFS injection.
At Week 156 or after approval and implementation of Protocol Amendment 1, whichever 
occurs first, site personnel and the subject will be unblinded as to their current treatment 
regimen.  The subject will continue to receive the same dose of secukinumab and will no 
longer receive the placebo PFS. After approval and implementation of Protocol Amendment 1, 
the study medication for subjects on the 75 mg treatment arm should be escalated from 75 mg 
s.c. to 150 mg s.c. every 4 weeks for patients whose overall therapeutic response is not fully 
achieved with the current dose of 75 mg and may improve with a higher dose, as judged by 
the investigator. The escalation of the study medication may be determined at any site visit..
For patients escalated to secukinumab 150 mg s.c. every 4 weeks, no dose reduction can be 
performed and if the patient is unable to tolerate the 150 mg dose of secukinumab alternative 
treatment options should be considered only after discontinuation from the study (Section 
5.5.9).
Assessments for safety, efficacy, 
 will be performed according to the 
assessment schedule (Table 6-1, Table 6-2, Table 6-3).
A follow-up visit is to be done 12 weeks after the last study treatment administration for all 
subjects (regardless of whether they complete the entire study as planned or discontinue 
prematurely).
This long-term extension study extends the pivotal 2-year registration study CAIN457F2305 
by an additional 3 years and therefore may be affected by agency review or potential product 
approval considerations. Thus, the extension trial may be amended (via a future protocol 
amendment) based on clinical data analysis, Data Monitoring Committee recommendations, 
and/or on eventual agency recommendations for product usage in this indication.

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Figure 3-2
Extension Study (AIN457F2305E1) Study Design
3.2
Rationale of study design
This 3-year extension study will offer continuous secukinumab therapy to eligible subjects 
from the core study and will provide further long-term subject and clinical benefits, safety and 
tolerability data for two dosing regimens of secukinumab (75 and 150 mg s.c.). The study 
design is in line with other long-term studies in Ankylosing Spondylitis. The first year is 
blinded to protect the integrity of the data in the ongoing core study.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
The dosing regimen selected in this extension study is the same regimen used during the core 
study treatment period. The overall duration (2 year core and 3 year extension) of 5 years is 
based on the need for long-term treatment exposure in subjects suffering from a chronic 
illness such as Ankylosing Spondylitis in order to adequately evaluate the efficacy and safety 
profile of a new agent. The analysis of the 2 Phase III studies conducted in AS patients (see 
Rationale for Protocol Amendment 1) led to the conclusion that to increase the likelihood of 
maintaining a clinically meaningful response during the entire duration of the trial, the dose of 
secukinumab should be escalated from 75 mg s.c. every 4 weeks to 150 mg s.c. every 4 weeks 
for patients whose overall therapeutic response is not fully achieved and may improve with a 
higher dose, as judged by the investigator.
Bioequivalence between the secukinumab lyophilisate and prefilled syringe formulation has 
been established in study CAIN457A2106 in 150 healthy volunteers in which the 
pharmacokinetics, safety and tolerability of a prefilled syringe and the lyophilisate 
formulation were compared. The confidence intervals for geometric mean ratios of Cmax, 
Week
104  108  112  116 
256   260       F268
E1   E1
E1
Group 1
secukinumab 75 mg 
Group 2
secukinumab 150 mg 
Secukinumab administration (75 s.c.) via PFS
Secukinumab administration (150mg s.c.) via PFS
Start of extension phase
Dose switch to open-label 150 mg s.c.
(permitted at any site visit after 
implementation of Amendment 1)

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AUClast and AUCinf for the two formulations were within the 0.8-1.25 boundaries and 
therefore, the prefilled syringe met the standard criteria for assuming bioequivalence. The use 
of the prefilled syringe was safe and well tolerated. Therefore, in study CAIN457F2305E1 it 
is considered appropriate to use secukinumab in prefilled syringes for the administration of 
secukinumab in the same dosing regimens as in the maintenance doses of the core study 
(CAIN457F2305) which used a lyophilisate formulation.
Subcutaneous injection through prefilled syringes (PFS) offers the option of self-
administration by the subject and is likely to provide a better treatment experience and added 
convenience. Subjects with chronic diseases who are able to self-inject their medication gain 
control of their treatment schedule and their treatment setting, thus allowing greater 
independence, better adherence, improved therapeutic outcomes and freedom in their social, 
domestic and professional lives resulting in economic benefits to both the subject and the 
healthcare system (Kivitz 2006; Chilton 2008). Self-injection may also offer psychological 
benefits over administration by healthcare professionals, including improved self-esteem 
(Hamm 2000).
3.4
Rationale for choice of comparator
There is no placebo or active control group in this study given the purpose and main 
objectives are to extend treatment of subjects who completed the core study. The use of two 
different doses of secukinumab (i.e. 75 and 150 mg) will allow comparison between the doses 
in terms of sustainability of clinical benefits, safety and tolerability.
3.5
Purpose and timing of interim analyses/design adaptations
Interim analyses on an approximately annual basis may be planned for purposes of 
publication as subjects continue treatment in this extension study. Additional analyses may be 
performed to support health authority interactions as necessary. Study design adaptations are 
not currently planned unless mandated by agency requests, Data Monitoring Committee 
recommendations or potential product approval considerations.
3.6
Risks and benefits
The risk to subjects in this trial will be minimized by compliance with the inclusion/exclusion 
criteria, close clinical monitoring, and extensive guidance for the investigators provided in the 
Investigator’s Brochure.
As of 12 Jul 2014, up to 10900 subjects have been enrolled into the secukinumab clinical 
program, of which over 8600 subjects have received secukinumab. Both Healthy subjects and 
patients have received secukinumab across various indications (plaque psoriasis, RA, AS, PsA, 
multiple sclerosis, uveitis, Crohn’s disease, dry eye, polymyalgia rheumatica) as single and /or 
multiple doses of 0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg s.c. Key results from the 
larger completed Phase II and III studies support a favorable benefit-risk profile for 
secukinumab in AS patients.
The risk profile of secukinumab in AS is informed by the safety experience from arthritides 
and psoriasis trials. In the dose-ranging RA trial CAIN457F2201 of 237 patients, the most 
common side effects were infections in about 20-30% of the patients, with most being mild to 
moderate. Gastrointestinal disorders were experienced by 8-12% of patients, skin rashes by 7-

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10%, joint muscle aches by 5-8%, and headaches by 1-3% of patients. However, these side 
effects were also seen in patients who received placebo.
Secukinumab has been studied most extensively in psoriasis, and side effects seen in psoriasis 
patients treated with secukinumab include upper respiratory tract infections (nasopharyngitis, 
rhinitis) (very common: in more than 1 in 10 patients); oral herpes, rhinorrhea, diarrhea and 
urticaria (common: in more than 1 in 100 but fewer than 1 in 10 patients); oral candidiasis, 
tinea pedis, neutropenia, and conjunctivitis (uncommon: in more than 1 in 1,000 but fewer 
than 1 in 100 patients). Hypersensitivity reactions to secukinumab, including urticaria and rare 
events of anaphylactic reaction, were also observed in clinical studies. Additionally, 
worsening of Crohn’s disease, in some cases serious, was seen in studies of Crohn’s disease 
and psoriasis, in patients receiving secukinumab or placebo. 
Taking into account the available safety data for the individual risks outlined in the 
Investigator’s Brochure, the expected risk profile of secukinumab from a mechanism of action 
perspective is anticipated to be similar or improved in comparison with approved cytokine 
targeting therapies. In some trials, infections were numerically higher in the secukinumab 
treatment groups than in the placebo cohorts although no dose-dependent increase in rates of 
serious infections was observed. This indicates that there does not appear to be a direct 
exposure-related effect on host defense. From the standpoint of the overall risk-benefit 
assessment, the current study with secukinumab is justified.
4
Population
It is estimated that approximately 279 to 316 (75-85%) subjects will enter this extension study 
from the core study.
4.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Subjects must have completed the core study
3. Subjects who are deemed by the investigator to benefit from continued secukinumab 
therapy
4.2
Exclusion criteria
Subjects 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 subjects.
1.
History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes
2.
Any subject who is deemed not to be benefiting from the study drug based upon lack of 
improvement or worsening of their symptoms
3.
Use of any investigational drug except for secukinumab during the core study
4.
Any subject taking other concomitant biologic immunomodulating agent(s) except 
secukinumab during the core study

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5.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test.
6.
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during the 
entire study or longer if required by locally approved prescribing information (e.g., 20 
weeks in EU). Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
NOTE:  Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential. 
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
Novartis will provide the following:

Investigational Treatment:

Secukinumab 75 mg/150 mg provided in 0.5 mL/1.0 mL PFS for s.c. injection

Secukinumab placebo provided in 0.5 mL/1.0 mL PFS for s.c. injection required for 
blinding
At extension study entry, subjects will be provided with detailed instructions and guidance on 
how to self-administer the s.c. injection using the PFS and following the Instructions for Use 

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(IFU). The investigational drug will be administered by the subject into the appropriate 
injection site of the body. Site staff will administer the injection to subjects who are not able 
or unwilling to self-administer the PFS injection.
Note:  The prefilled syringes do not need to be prepared at the site. The prefilled syringes are 
packed in double-blinded fashion for the double-blinded portion of the study and open-label 
fashion for the open-label portion. PFS are labeled as:

Blinded

AIN457 75mg/0.5ml/Placebo

AIN457 150mg/1ml/Placebo

Open-label

AIN457 75mg/0.5ml

AIN457 150mg/1ml
5.1.2
Additional study treatment
No additional treatment other than the investigational treatment is requested in this trial.
5.2
Treatment arms
All subjects will continue to receive the same dose of secukinumab they were receiving 
during the treatment period of the phase III core study. The two treatment groups are:

Group 1:  secukinumab 75 mg plus placebo 150 mg dosed every four weeks from Week 
104E1 through Week 152. Starting on Week 156 (after unblinding), only secukinumab 75 
mg will be dosed.

Group 2:  secukinumab 150 mg plus placebo 75 mg dose every four weeks from Week 
104E1 through Week 152. Starting on Week 156 (after unblinding), only secukinumab 
150 mg will be dosed.
After approval and implementation of the Protocol Amendment 1, the study medication for 
subjects on the 75 mg treatment arm should be escalated from 75 mg s.c. to 150 mg s.c. every 
4 weeks for patients whose overall therapeutic response is not fully achieved with the current 
dose of 75 mg and may improve with a higher dose, as judged by the investigator.
5.3
Treatment assignment, randomization
At Week 104 of the core study, all eligible and consenting subjects from the core study will be 
enrolled via Interactive Response Technology (IRT) and will continue to receive the same 
dose of secukinumab that they were receiving during the treatment period of the core study. 
The investigator or his/her delegate will contact IRT after confirming that the subject fulfills 
all the inclusion/exclusion criteria. IRT will then specify a unique medication number for the 
first package of investigational treatment to be dispensed to the subject.
5.4
Treatment blinding
This is a 3-year extension of a 2-year double-blind, double-dummy, randomized treatment 
trial. Subjects, investigator staff and persons performing the assessments will remain blinded 
to the identity of the treatment from the time of randomization in the core study until Week 

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156, or until approval and implementation of Protocol Amendment 1, whichever occurs first, 
using the following methods:  (1) Randomization data are kept strictly confidential until the 
time of unblinding and will not be accessible by anyone else involved in the study with the 
following exception:  bioanalyst, (2) The identity of the treatments will be concealed by the 
use of study treatments in form of prefilled syringes for s.c. injections, filled with 
secukinumab or placebo that are identical in appearance.
A double-dummy design is used because the identity of the study treatments (PFS) cannot be 
disguised due to their different volume forms (0.5 mL versus 1.0 mL)
The bioanalyst will have access to the randomization list to facilitate analysis of 
 
 samples to ensure appropriate sample dilution factors are applied, 
avoiding unnecessary repeat analyses.
Unblinding before Week 156 will only occur in the case of subject emergencies (see Section 
5.5.10). Subjects will be unblinded at Week 156, or after approval and implementation of 
Protocol Amendment 1, whichever occurs first, and will continue receiving the same 
secukinumab treatment open-label.
5.5
Treating the subject
5.5.1
Subject numbering
During the core study, each subject was uniquely identified by a Subject Number which was 
composed by the site number assigned by Novartis and a sequential number assigned by the 
investigator. Once assigned to a subject, the Subject Number will not be reused by another 
subject. This being an extension study, the subject numbers will remain the same as that of the 
core study; new subject numbers will not be assigned.
5.5.2
Dispensing the investigational treatment
The investigational treatment packaging has a label with a unique medication number which 
corresponds to one of the 2 treatment arms and a specific visit. Investigator staff will identify 
the investigational treatment package(s) to dispense to the subject by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the subject, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that subject’s unique subject number. 
After Week 116, if subjects opt for domiciliary treatment/home administrations (at protocol 
specified time points) then the investigator will dispense via IRT an appropriate number of 
investigational treatment packages for domiciliary administrations. The investigator will 
detach the outer part of the label and affix it to the source document (Drug Label Form).  
Detailed instructions on the self-administration of the study treatment will be described in the 
Instructions For Use (IFU) provided to each subject and made available to the site staff and 
investigator. These instructions should be reviewed in detail by the subject and the site 
personnel.

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5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. The investigator should educate the subject on how to 
properly store the study treatment if the subject is self-administering at home.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Subjects 
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.
5.5.4
Instructions for prescribing and taking study treatment
All study treatment (75 mg/150 mg secukinumab, and 0.5 mL/1.0 mL placebo) will be self-
administered subcutaneously by the subjects every four weeks throughout the study. The PFS 
will be provided by the site staff to the subject, who will self-administer the injections at the 
specified study time point. Site staff will administer the injection to those subjects who are not 
able to self-administer the PFS injection. Detailed instructions on the self-administration of 
the study treatment will be described in the Instructions For Use (IFU) and provided to each 
subject. It shall be recorded on the corresponding eCRF(s) whether the subject self-
administered the PFS or whether site staff or caregiver administered the PFS and whether it 
was administered at home or at the site.
The first study treatment administration will occur at Week 104E1 after the 
inclusion/exclusion criteria have been confirmed, all study scheduled assessments have been 
performed and the scheduled blood samples have been drawn. Through Week 116, all doses 
of study treatment will be self-administered by the subject at the study site under the 
supervision of a site staff member after the study assessments for the visit have been 
completed.  After Week 116, the subjects will be allowed to self-administer the PFS at home 
(see Domiciliary Administration below).
The trial-related safety and efficacy procedures will be conducted as indicated in Table 6-1,
Table 6-2, and Table 6-3. While at the site visits, subjects will be asked to refer to the IFU and 
to proceed with self-injection. At study visits requiring pre-dose blood samples (Table 6-1, 
Table 6-2, Table 6-3), the subject will self-administer study treatment only after the blood 
samples have been collected.

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All dosages prescribed and dispensed to the subject and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. Immediately before dispensing 
the package to the subject, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that subject’s unique 
subject number.
The investigator should promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 
safety and the validity of the study. The subject should be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
Administration
Single syringes will be packed in individual boxes. The site and patient should refer to the 
IFU for storage and handling instructions.
The study treatment solution should be injected subcutaneously into the arm, abdomen or 
thigh area. Each new injection should be given at least one inch from the previously used site. 
If the subject chooses the abdomen, a 2-inch area around the navel should be avoided. 
Investigational drug should not be injected into areas where the skin is tender, bruised, red, or 
hard or where subject has scars or stretch marks. Injection sites should be alternated to reduce 
the risk of reaction.
Used safety syringes should be disposed immediately after use in a sharps container or 
according to the regulatory needs of the respective countries.
Domiciliary administration
After Week 116, subjects will be allowed to self-administer the PFS at home when they are 
not visiting the site for any other trial-related procedures. Subjects will be allowed to self-
administer treatment at home (after Week 116) only if they have exhibited correct use for self-
administering the PFS at the site during the first 4 visits for treatment during the extension 
study. At such time points, if requested by the subject, a caregiver would also be allowed to 
administer the study medication. Optional site visits have been included in the assessment 
tables between the visits at which trial-related procedures are not to be conducted at the site. 
Subjects will be allowed to self-administer the PFS at home or to visit the site during the 
optional visits to self-administer the PFS under the supervision of the site staff. If the subject 
is not able or not confident to self-administer the PFS, he/she should visit the site every 4 
weeks during the treatment period and the site staff will administer the PFS.
Prior to self-administration at home, subjects should contact the investigator/site staff in the 
case they are experiencing any AE/SAEs or have any concerns.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments are not permitted until approval and implementation of 
Protocol Amendment 1. After approval and implementation of the Protocol Amendment 1, the 

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study medication for subjects on the 75 mg treatment arm should be escalated from 75 mg s.c. 
to 150 mg s.c. every 4 weeks for patients whose overall therapeutic response is not fully 
achieved with the current dose of 75 mg and may improve with a higher dose, as judged by 
the investigator. The escalation of the study medication may be determined at any site visit. 
For patients escalated to 150 mg, no dose reduction can be performed at a later time point.
Study treatment interruption is permitted only if, in the opinion of the investigator, a subject is 
deemed to be placed at a significant safety risk unless dosing is temporarily interrupted. In 
such cases, study treatment should be interrupted only during the time that this 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.
These changes must be recorded on the Dosage Administration Record CRF.
5.5.6
Rescue medication
Rescue medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a subject is experiencing either no benefit from participation in 
the trial or worsening/exacerbation of their disease. Serious consideration should be given to 
withdraw subjects who require significant amounts of rescue medication (see Section 5.5.8 for 
prohibited treatments).
Any use of rescue medication must be recorded in the Prior/Concomitant medications eCRF 
page.
5.5.7
Concomitant treatment
The investigator should instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the subject was enrolled into the study must be recorded (see Section 5.5.8
for prohibited treatments).
Guidelines for the use of specific medications are provided below:
Methotrexate (MTX)
Subjects taking MTX (7.5 – 25 mg/week) should be maintained on a stable dose throughout 
the study unless a change is deemed necessary by the investigator. Any change in dose should 
be recorded on the appropriate eCRF page.
Folic acid
Subjects on MTX must be taking folic acid supplementation while taking MTX during the 
trial to minimize the likelihood of MTX associated toxicity. Folic acid supplementation 
should not be taken on the same day as MTX intake.

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Sulfasalazine
Subjects taking Sulfasalazine (≤ 3 g/day) should be maintained on a stable dose throughout 
the study unless a change is deemed necessary by the investigator. Any change in dose should 
be recorded on the appropriate eCRF page.
Systemic corticosteroids
The dose and regimen of systemic corticosteroids (oral or intramuscular) may be modified as 
deemed appropriate and necessary and as per investigator’s judgment and subject need. Any 
change in the dose of systemic corticosteroids during the trial must be recorded on the 
corresponding eCRF page.
Intra-articular corticosteroids
As per investigator’s judgment and subject need, intra-articular corticosteroid injections can 
be performed. The total dose administered must be recorded on the corresponding eCRF page.
Non-steroidal anti-inflammatory drugs (NSAIDS)(COX-1 or COX-2 inhibitors) 
and acetaminophen/paracetamol
Changes to the NSAIDS intake regimen is permitted throughout the study.
Subjects taking NSAIDs, low strength opioids or paracetamol/acetaminophen PRN can 
continue to do so in the study; however, they have to refrain from any intake during at least 
the 24 hours before a visit with disease activity assessment.
Any change of the NSAID/paracetamol/acetaminophen treatment during the trial should be 
recorded on the corresponding eCRF page.
5.5.8
Prohibited Treatment
Use of the treatments displayed in Table 5-1 is NOT allowed during this extension study 
unless otherwise stated.
Table 5-1
Prohibited treatment
Medication
Action to be taken
Any other biologic agent (e.g. etanercept, infliximab, adalimumab, 
tocilizumab, rituximab, abatacept)*
Discontinue study treatment
Any other investigational treatment or participation in another 
interventional trial
Consult with Novartis study 
team
Live vaccines should not be given until 12 weeks after last study 
treatment administration
Interrupt study treatment 
*These agents fall under the category of biologic immunomodulators
5.5.9
Discontinuation of study treatment and premature subject 
withdrawal
Subjects may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.

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If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information. Study treatment must be discontinued. Even if the subject is not willing to 
come back for all assessments, every effort should be done to collect the scheduled x-ray 
assessments for this subject.
For subjects who discontinue study treatment a Dosage Administration Record eCRF should 
be completed, giving the date and primary reason for stopping study treatment. For subjects 
remaining in the trial, all Week 260 assessments  must be performed 4 weeks after last study 
treatment administration and a follow-up visit (F268) should be conducted 12 weeks after last 
study treatment administration (Table 6-1, Table 6-2, Table 6-3). Any unused study drug must 
be returned to the site.
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
5.5.9.1
Discontinuation of study treatment
The investigator should discontinue study treatment for a given subject and/or withdraw the 
subject from study if, on balance, he/she believes that continuation would be detrimental to 
the subject’s well-being.
Study treatment must be discontinued under the following circumstances:

Withdrawal of informed consent

Emergence of the following adverse events:

Any severe or serious adverse event that is not compatible with administration of 
study medication, including adverse events that require treatment with an 
unacceptable co-medication

Onset of lymphoproliferative disease or any malignancy except for treated basal cell 
carcinoma, treated actinic keratosis, treated in situ carcinoma of the cervix or non-
invasive malignant colon polyps which are being or have been removed.

Life-threatening infection

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).

Pregnancy

Use of any biologic immunomodulating agent except secukinumab

Any other protocol deviation that results in a significant risk to the subject’s safety
In case of undue safety risk for the subject, the subject should discontinue study treatment at 
the discretion of the investigator. 
In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given subject if, on balance, he/she thinks that continuation 
would be detrimental to the subject’s well-being.
For subjects who discontinue study treatment, a Dosage Administration Record eCRF should 
be completed giving the date and primary reason for stopping study treatment.

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The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently 
for any reason.
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
5.5.9.2
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent occurs when a subject does not want to continue participating in the 
study; that is, the subject does not want any further visits, assessments, or study-related 
contacts, and does not allow analysis of already obtained biologic material.
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information in the Withdrawal of Consent 
eCRF. Study treatment must be discontinued and no further assessments conducted. All 
biological material that has not been analyzed at the time of withdrawal must not be used. No 
further attempts to contact the subject are allowed.
5.5.9.3
Lost to follow-up
For subjects who are lost to follow-up (i.e. those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should
show "due diligence" by documenting in the source documents steps taken to contact the 
subject, e.g. dates of telephone calls, registered letters, etc.
5.5.9.4
Replacement
Subjects who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled subjects.
5.5.10
Emergency breaking of treatment assignment
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
subject safely and efficaciously. Most often, study drug discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the investigator contacts the system to break a treatment code for a subject, he/she must 
provide the requested subject identifying information and confirm the necessity to break the 
treatment code for the subject. The investigator will then receive details of the investigational 
drug treatment for the specified subject and a fax or email confirming this information. The 
system will automatically inform the Novartis monitor for the site and the Global Trial Lead 
(GTL) that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the subject how to contact 
his/her backup in cases of emergency when he/she is unavailable. The investigator will 
provide protocol number, study treatment name if available, subject number, and instructions 
for contacting the local Novartis CPO (or any entity to which it has delegate responsibility for 

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emergency code breaks) to the subject in case an emergency treatment code break is required 
at a time when the investigator and backup are unavailable.
In the case of emergency unblinding, the investigator should consult with the local Novartis 
CPO whether study medication should be discontinued.
In the case of accidental unblinding, subjects will not be replaced by an equal number of 
newly enrolled subjects.
5.5.11
Study completion and post-study treatment
A subject will be considered to have completed the study if he/she received treatment for 260 
weeks in the combined core study and extension study (last dose being administered at Week 
256) and upon completion of the scheduled study assessments and procedures up to and 
including Visit F268. 
Information on the subject’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the appropriate Study Phase Completion 
eCRF page.
A Study Phase Completion evaluation (associated with the last visit of the subject’s phase of 
the study: e.g. Week 156, Week 208 or Week 260) must also be performed when a subject 
prematurely withdraws from the study for whatever reason. In any case, the investigator or 
site staff must contact IRT as soon as possible to record the subject’s study completion (Visit 
F268) 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.
5.5.12
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible and treated for a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial.
6
Visit schedule and assessments
Table 6-1, Table 6-2, and Table 6-3 list all of the assessments and indicate with an “X” when 
the visits are performed. Subjects should be seen for all visits on the designated day or as 
close to it as possible. There should be at least 2 weeks between each study treatment 
administration.
Subjects who discontinue study treatment should also return 12 weeks after the last study drug 
administration for the assessments indicated by an asterisk (*) in Table 6-1, Table 6-2, and
Table 6-3. If they 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 or by sending 

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appropriate correspondence (i.e. certified letter) immediately. At this contact, the safety (e.g. 
potential occurrence of AE or SAE) and the primary reason for a subject’s premature 
withdrawal should be determined. Documentation of attempts to contact the subject should be 
recorded in the source documentation.
Order of assessments


All remaining study visit procedures (e.g. laboratory sample collection, vital signs, 
measurements etc.) must be completed prior to study treatment dosing

Contact IRT to register the subject visit

PFS medication boxes are made available to the subject who will then self-inject the study 
treatment under guidance and supervision, as necessary, of a site staff member

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Table 6-1
Assessment schedule - Part 1:  Week 104E1 to Week 156
Epoch
Treatment period 3
Week (relative to baseline of phase 
III study)
104E11
108E1
112E1
116
120
124
128
132
136
140
144
148
152
1569*
Optional Site Visit2
X
X
X
X
X
X
X
Obtain Informed consent
X
Inclusion/Exclusion criteria
X
Physical exam3
X
X
X
X
Weight
X
X
Vital signs
X
X
X
X
Hematology, blood chemistry, 
urinalysis
X
X
X
X
Urine pregnancy test
X
X
X
X
ECG
X
X
Administration of study treatment4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Conc. Medication/non-drug therapy
Update as necessary
Adverse events/SAE5
Update as necessary
Patient’s global assessment of 
disease activity (VAS)
X
X
X
X
Patient’s assessment of Spinal pain 
(VAS)
X
X
X
X

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Epoch
Treatment period 3
Week (relative to baseline of phase 
III study)
104E11
108E1
112E1
116
120
124
128
132
136
140
144
148
152
1569*
Lipids8
X
X
Cardiovascular panel
X
Treatment period 3 completion form
X
1 This visit corresponds to the Week 104 visit of the core study. Only those assessments which are unique to the extension study are mentioned here 
and the assessment carried out as part of Week 104 of the core study are not mentioned; however, those assessments need to be carried out as per 
core study protocol.
2 Optional visits – Week 120, 124, 132, 136, 144, 148, 152. At these optional visits only those subjects who are unable to self-administer the PFS 
injections at home will visit the site and site staff will supervise self-administration or administer the PFS injection for them. Other subjects who can 
self-administer the PFS injection can do so at home at these optional visits.
3 These assessments are source documentation only and will not be entered into the eCRF
4 The study treatment (PFS) has to be administered every 4 weeks. From Week 104E1 to 116, subjects will visit the site every 4 weeks for 
administering the PFS injection (by self or by site staff). After Week 116, at visits marked as optional visits, subjects can self-administer the study PFS 
at home or may visit the site to receive the PFS administration by site staff.
5 AEs/SAEs occurring after the subject has signed the informed consent must be captured on the appropriate eCRF page.
8 Sample must be obtained fasting.
9 Site staff and subjects will be unblinded. Subjects will no longer receive placebo PFS after unblinding.

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Epoch
Treatment period 3
Week (relative to baseline of phase 
III study)
104E11
108E1
112E1
116
120
124
128
132
136
140
144
148
152
1569*
* For all subjects who discontinue or withdraw from the study, the investigator should ensure that the subject completes an end of treatment visit 
(corresponding to the last visit for the subject’s current period of treatment) 4 weeks after last study treatment and also return after an additional 8 
weeks for a final follow-up, F268 (12 weeks after last study treatment). The final visit should be performed before any new treatment is initiated.
Table 6-2
Assessment schedule - Part 2:  Week 160 to Week 208
Epoch
Treatment period 4
Week
160
164
168
172
176
180
184
188
192
196
200
204
208*
Optional Site Visit1
X
X
X
X
X
X
X
X
X
Physical exam2
X
X
X
X
Weight
X
X
Vital signs
X
X
X
X
Hematology, blood chemistry, 
urinalysis
X
X
X
X
Urine pregnancy test
X
X
X
X
ECG
X
X
Administration of study treatment3
X
X
X
X
X
X
X
X
X
X
X
X
X
Conc. Medication/non-drug therapy
Update as necessary
Adverse events/SAE4
Update as necessary
Patient’s global assessment of 
disease activity (VAS)
X
X
X
X
Patient’s assessment of spinal pain 
(VAS)
X
X
X
X

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Epoch
Treatment period 4
Week
160
164
168
172
176
180
184
188
192
196
200
204
208*
Lipids6
X
X
Cardiovascular panel
X
Treatment period 4 completion form
X
1 Optional visits – Week 160, 164, 172, 176, 184, 188, 196, 200, 204. At these optional visits only those subjects who are unable to self-administer the PFS 
injections at home will visit the site and site staff will supervise self-administration or administer the PFS injection for them. Other subjects who can self-
administer the PFS injection can do so at home at these optional visits.
2 These assessments are source documentation only and will not be entered into the eCRF
3 The study treatment (PFS) has to be administered every 4 weeks. From Week 104E1 to 116, subjects will visit the site every 4 weeks for administering the 
PFS injection (by self or by site staff). After Week 116, at visits marked as optional visits, subjects can self-administer the study PFS at home or may visit the 
site to receive the PFS administration by site staff.
4 AEs/SAEs occurring after the subject has signed the informed consent must be captured on the appropriate eCRF page.
6 Sample must be obtained fasting.
* For all subjects who discontinue or withdraw from the study, the investigator should ensure that the subject completes an end of treatment visit 
(corresponding to the last visit for the subject’s current period of treatment) 4 weeks after last study treatment and also return after an additional 8 weeks for a 
final follow-up, F268 (12 weeks after last study treatment). The final visit should be performed before any new treatment is initiated.

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Table 6-3
Assessment schedule - Part 3:  Week 212 to Week 260 and follow-up visit F268
Epoch
Treatment period 5
Week
212
216
220
224
228
232
236
240
244
248
252
256
260*
F268*
Optional Site Visit1
X
X
X
X
X
X
X
X
X
Physical exam2
X
X
X
X
Weight
X
X
Vital signs
X
X
X
X
Hematology, blood 
chemistry, urinalysis
X
X
X
X
Urine pregnancy test
X
X
X
X
ECG
X
X
Administration of 
study treatment3
X
X
X
X
X
X
X
X
X
X
X
X
Conc. 
Medication/non-drug 
therapy
Update as necessary
Adverse events/SAE4
Update as necessary
Patient’s global 
assessment of 
disease activity (VAS)
X
X
X
X
Patient’s assessment 
of spinal pain (VAS)
X
X
X
X

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Epoch
Treatment period 5
Week
212
216
220
224
228
232
236
240
244
248
252
256
260*
F268*
Lipids7
X
X
Cardiovascular panel
X
Treatment period 5 
completion form
X
Follow-up completion 
form
X
1 Optional visits – Week 212, 216, 224, 228, 236, 240, 248, 252, 256. At these optional visits only those subjects who are unable to self-administer 
the PFS injections at home will visit the site and site staff will supervise self-administration or administer the PFS injection for them. Other subjects 
who can self-administer the PFS injection can do so at home at these optional visits.
2 These assessments are source documentation only and will not be entered into the eCRF
3 The study treatment (PFS) has to be administered every 4 weeks. From Week 104E1 to 116, subjects will visit the site every 4 weeks for 

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Epoch
Treatment period 5
Week
212
216
220
224
228
232
236
240
244
248
252
256
260*
F268*
administering the PFS injection (by self or by site staff). After Week 116, at visits marked as optional visits, subjects can self-administer the study 
PFS at home or may visit the site to receive the PFS administration by site staff.
4 AEs/SAEs occurring after the subject has signed the informed consent must be captured on the appropriate eCRF page.
5 Only done in a sub-population at selected sites
7 Sample must be obtained fasting
* For all subjects who discontinue or withdraw from the study, the investigator should ensure that the subject completes an end of treatment visit 
(corresponding to the last visit for the subject’s current period of treatment) 4 weeks after last study treatment and also return after an additional 8 
weeks for a final follow-up, F268 (12 weeks after last study treatment). The final visit should be performed before any new treatment is initiated.

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6.1
Information to be collected on screening failures
Not applicable for this extension study.
6.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data collected on all subjects and recorded in 
the eCRF of the core study (CAIN457F2305) will be carried forward in this extension study 
(CAIN457F2305E1). Both the core study and the extension study data will be entered in the 
same database.
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 continuing or started during the 
study treatment period will be entered in the Prior/Concomitant medications or Significant 
non-drug therapies eCRF page for the core study.Compliance will be assessed by a Novartis 
monitor using information provided by the authorized site personnel.
6.4
Efficacy

Assessment of SpondyloArthritis International Society criteria (ASAS)


 
 
  

 
 




 


6.4.1
Assessment of SpondyloArthritis International Society criteria 
(ASAS)
The ASAS response measures consist of the following assessment domains (Sieper 2009):
Main ASAS domains:
1. Patient’s global assessment of disease activity measured on a VAS scale

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2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale
4. Inflammation represented by mean duration and severity of morning stiffness, represented 
by the average of the last 2 questions on the 6-question BASDAI as measured by VAS 
scale
Additional assessment domains:
5. Spinal mobility measured by BASMI (cervical rotation, maximal intermalleolar distance, 
spinal lateral flexion, lumbar flexion (modified Schober index), tragus-to-wall distance)
6. C reactive protein (acute phase reactant)
6.4.1.1
ASAS Response Criteria (ASAS 20)
The ASAS Response Criteria (ASAS 20) is defined as an improvement of at least 20% and 
absolute improvement of at least 10 units on a 0-100 mm scale in at least 3 assessment 
domains 1 to 4 and no worsening of more than 20% and 10 units on a 0-100 mm scale in the 
remaining unit.
6.4.1.2
ASAS Response Criteria (ASAS 40)
The ASAS Response Criteria (ASAS 40) is defined as an improvement of at least 40% and 
absolute improvement of at least 20 units on a 0-100 mm scale in at least 3 assessment 
domains 1 to 4 and no worsening at all in the remaining domain.
6.4.1.3
ASAS 5/6 improvement criteria
The ASAS 5/6 improvement criteria is an improvement of ≥ 20% in at least five of all six 
domains.
6.4.1.4
ASAS partial remission criteria
The ASAS partial remission criteria is defined as a value not above 2 units in each of the 
domains 1 to 4 on a scale of 10.
6.4.1.5
Patient’s global assessment of disease activity (VAS)
The patient’s global assessment of disease activity will be performed using a 100 mm visual 
analog scale (VAS) ranging from not severe to very severe, after the question "How active 
was your disease on average during the last week?”. 
6.4.1.6
Patient’s assessment of back pain intensity (VAS)
The patient’s assessment of back pain will be performed using a 100 mm VAS ranging from
no pain to unbearable pain, after the question “Based on your assessment, please indicate 
what is the amount of back pain at any time that you experienced during the last week?” and 
“Based on your assessment, please indicate what is the amount of back pain at night that you 
experienced during the last week?”.

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6.4.1.7
Bath Ankylosing Spondylitis Functional Index (BASFI)
The BASFI is a set of 10 questions designed to determine the degree of functional limitation 
in those subjects with AS. The ten questions were chosen with a major input from subjects 
with AS. The first 8 questions consider activities related to functional anatomy. The final 
2 questions assess the subjects’ ability to cope with everyday life. A 0 through 10 scale 
(captured as a continuous VAS) is used to answer the questions. The mean of the ten scales 
gives the BASFI score – a value between 0 and 10.
6.4.1.8
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem), which is used to answer 6 questions pertaining to the 5 major symptoms of AS:
1. Fatigue
2. Spinal pain
3. Joint pain / swelling
4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments)
5. Morning stiffness duration
6. Morning stiffness severity
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness is taken (questions 5 and 6). The resulting 0 to 10 score is added to the 
scores for questions 1 through 4. The resulting 0 to 50 score is divided by 5 to give a final 0 –
10 BASDAI score. Scores of 4 or greater suggest suboptimal control of disease, and subjects 
with scores of 4 or greater are usually good candidates for either a change in their medical 
therapy or for enrollment in clinical trials evaluating new drug therapies directed at AS. 
BASDAI is a quick and simple index taking between 30 seconds and 2 minutes to complete.
6.4.1.9
BASDAI 50
BASDAI 50 response is defined as at least a 50% improvement (decrease) in total BASDAI 
score, as compared to the baseline total BASDAI score (Braun 2003; Rudwaleit 2004).

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6.4.10
Appropriateness of efficacy assessments 
The efficacy outcome measures used in this study are the standard measures used across all 
AS trials and are required for filing.
This study involves exposure to radiation from x-rays of the cervical and lumbar spine. The 
radiation exposure by these procedures is not necessary for medical care but is intended for 
research purposes only.
The amount of cumulative annual radiation in this study is about 3.42 mSv for the x-ray 
procedures and is based on effective doses for various diagnostic radiological procedures 
reported in literature (Mettler 2008). This exposure is comparable to the natural radiation an 
average person receives in one year. The radiation between 3 mSv and 50 mSv is considered 
‘minimal’ (Stabin 2009). Therefore, the radiation exposure in this study involves minimal risk 
and is necessary to obtain the research information desired.
6.5
Safety

Physical examination

Vital signs

Height and weight

Electrocardiogram

Local tolerability (injection site reactions)

Laboratory evaluations (hematology, clinical chemistry, lipid panel, urinalysis)

Pregnancy and assessment of fertility
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.

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6.5.1
Physical examination
A physical examination will be performed at scheduled visits as indicated in Table 6-1, Table 
6-2, and Table 6-3. 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 systems.
Information for all physical examination must be included in the source documentation at the 
study site. Significant findings that are present before signing the ICF must be included in the 
relevant medical history eCRF. Significant findings made after signing the ICF which meet 
the definition of an AE must be recorded in the Adverse Event 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.
6.5.3
Height and weight
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing) (both without shoes) will be 
measured. The baseline height from the core study will be used in this trial. Therefore, height 
will not be collected in this trial
If possible, body weight assessments should be performed by the same study site staff 
member using the same scale throughout the study.
6.5.4
Laboratory evaluations
A central laboratory will be used in this study. All laboratory tests should be conducted at the 
central laboratory except for 
 urinalysis/urine pregnancy tests. Details on the 
collection, 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.
6.5.4.1
Hematology
Hemoglobin, platelet, red blood cell (RBC), white blood cell (WBC) and different white 
blood cell counts will be measured at scheduled visits.
6.5.4.2
Clinical chemistry
Serum chemistries will include glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, 
total protein, albumin, and uric acid.

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6.5.4.3
Lipid panel
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
cholesterol and triglycerides will be measured from a fasting blood sample.
6.5.4.4
Cardiovascular panel
A cardiovascular profile including lipoprotein (a), apolipoprotein B-100, apolipoprotein A-1, 
and adiponectin will be measured from a blood sample.
6.5.4.5
Urinalysis
Dipsticks will be provided by the central laboratory to the sites for local urinalysis 
assessments. The urinalysis results for standard parameters such as protein, glucose, blood 
and WBCs will be recorded in the appropriate eCRF page.
6.5.5
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as indicated in Table 6-1, Table 6-2, and Table 6-3. 
All ECGs must be performed on the ECG machines provided for the study.
All ECGs will be independently reviewed. Instructions for the collection and transmission of 
the ECGs to the independent reviewer will be provided in the ECG investigator manual.
Clinically relevant abnormalities should be recorded on the relevant medical history/Current 
medical conditions eCRF page for the baseline ECG. 
Clinically relevant abnormalities noted after the baseline ECG should be reported as AE 
(Section 7).
6.5.6
Local tolerability (injection site reactions)
The local tolerability at the site of the s.c. injection of the study treatment will be assessed in 
case of any local reaction, until the reaction has disappeared.
The assessment of pain, redness, swelling, induration, hemorrhage and itching will be 
performed by a physician and will be recorded on the Adverse Events eCRF, including the 
severity (mild, moderate, severe) and the duration.
6.5.7
Pregnancy and assessments of fertility
Secukinumab should not be given to pregnant women; therefore effective method of birth 
control must be used for women of child-bearing potential (see exclusion criteria definitions, 
Section 4.2).
All women who are not surgically sterile when enrolling into the study will have local urine 
pregnancy tests as indicated in Table 6-1, Table 6-2, and Table 6-3. A positive urine 
pregnancy test requires immediate interruption of study medication until serum β-hCG is 
performed and found to be negative. If positive, the subject must be discontinued from the 
trial.

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6.5.9
Appropriateness of safety measurements
The safety measures used in this study are reliable and relevant standard measures for a 
biologic in AS. 

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7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 

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clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms 

they are considered clinically significant 

they require therapy 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information:

the severity grade [mild, moderate, severe]

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)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.

whether it constitutes a serious adverse event (SAE) 

action taken regarding study treatment 

whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)

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An SAE is any adverse event (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for (specify what it includes):

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); investigational treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
medication given; non-drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the investigational study 
treatment, the interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed.
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.

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7.2
Serious adverse event reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 12 weeks following the last administration of study 
treatment or 30 days after the subject has stopped study participation must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after this 
period should only be reported to Novartis if the investigator suspects a causal relationship to 
study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form or the electronic Serious Adverse 
Event Form within the OC/RDC system (where available). The Investigator must assess the 
relationship to each specific component of the study treatment (if the study treatment consists 
of several components). 
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of awareness of the SAE to the local Novartis Drug Safety and Epidemiology 
Department.  The telephone and fax number of the contact persons in the local department of 
Drug Safety and Epidemiology, specific to the site, are listed in the investigator folder 
provided to each site.  The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a 
follow-up to a previously reported SAE  
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing SAE. These data will automatically be submitted to Novartis Drug Safety & 
Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first. 
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 

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7.3
Pregnancy reporting
To ensure subject safety, each pregnancy occurring while the subject is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.
Any SAE experienced during pregnancy must be reported on the SAE Report 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 CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of subject 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the 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 
subjects 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 
.

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the data entered into the electronic Case Report Forms are complete and accurate. After DBL, 
the investigator will receive copies of the subject data for archiving at the investigational site. 
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. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will 
make the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). Novartis Data Management staff will perform a 
reconciliation of the data entered into the eCRF versus what is received from the central 
laboratory. At a minimum this reconciliation will include header reconciliation, visit window 
checks, duplicate record checks, out of range checks as defined by the Clinical Trial Team 
and checks to address missing laboratory data.
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Data about all study drug(s) dispensed to the subject and all dosage changes will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, 
who will also manage the database. The database will be sent electronically to Novartis (or a 
designated CRO).
8.4
Data Monitoring Committee
An independent data monitoring committee (DMC) reviewed the safety data of this trial at 
regular intervals. Details regarding the DMC process are available in relevant secukinumab 
DMC charters. Following the Week 52 DBL and interim analysis, the DMC review will no 
longer be required.
8.5
Adjudication Committee
An independent adjudication committee will be used to monitor specific safety events, 
including but potentially not limited to clinically significant cardio- and cerebro-vascular 
events. The events will be blindly reviewed and adjudicated as they occur during the conduct 
of the trial.
Details regarding the adjudication process will be available in relevant secukinumab 
Adjudication Committee charters.

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9
Data analysis 
Summary statistics for continuous variables will generally include the number of subjects (N), 
minimum, lower quartile, mean, median, upper quartile, and maximum. For categorical or 
binary variables, the number and percent of subject in each category will be presented. The 
95% confidence intervals will be provided to evaluate the treatment efficacy.
Data will be presented by a combination of the ‘original’ and ‘switch’ treatment groups. 
These treatment groups represent the treatment combinations the subjects experience over the 
course of the entire trial in case of re-randomization and dose escalation.
Note that the treatment groups for a subject may differ depending on the time period of the 
analysis and whether one assesses the subject for efficacy or safety.
9.1
Analysis sets
The following analysis sets will be used in this study:
Full analysis set (FAS): The FAS will be comprised of all subjects enrolled in the study.
Safety set: The safety set includes all subjects enrolled in the study who took at least 1 dose 
of study treatment during the study.
9.2
Subject demographics and other baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and for all subjects enrolled in the study.  The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects.
9.3
Treatments
9.3.1
Study Treatment
The analysis of study treatment data will be based on the safety set. The duration of exposure 
to study treatment will also be summarized by treatment group. In addition, the number and 
percentage of subjects with cumulative exposure levels will be presented.
9.3.2
Concomitant medication
Concomitant medications will be summarized by treatment group. Any medication given at 
least once between the start of the first dose in this extension trial and the date of the last 
study visit in the extension study will be a concomitant medication, including those which 
were started before Week 104E1 and continued into the extension study 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 medical surgeries and procedures will be summarized by primary system organ 
class and MedDRA preferred term.

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The number and percentage of subjects receiving concomitant rheumatoid arthritis therapy 
will be presented by treatment group as well as the reasons for stopping their therapies 
(primary lack of efficacy, secondary lack of efficacy, lack of tolerability, other) and the total 
duration of exposure to rheumatoid arthritis therapies previously.
9.4
Analysis of the primary and key secondary variable(s)
9.4.1
Variable(s)
The primary efficacy variable is the clinical response to treatment according to the ASAS20 
over time up to Week 260. The analysis of the primary variable will be based on the FAS 
subjects.
9.4.2
Statistical model, hypothesis, and method of analysis
No formal hypotheses are proposed for this study. The proportion of subjects meeting the 
ASAS20 will be descriptively summarized for each treatment over time. Treatment efficacy 
will be assessed by providing the 95% confidence interval of treatment response according to 
the ASAS criteria. No statistical comparison is expected to be performed between treatment 
groups.
9.4.3
Handling of missing values/censoring/discontinuations
Efficacy data will be presented using all available data at the given time point of analysis.
Additionally, under the assumption of missing at random, multiple imputation by treatment 
may be performed for baseline weight as well as for all baseline and post-baseline efficacy 
variables of interest during the trial.
9.4.4
Supportive analyses
Sensitivity analysis may be performed to assess the robustness of missing data handling. 
These may include multiple imputation for ASAS20.
9.5
Analysis of secondary 
 variables
9.5.1
Efficacy variables
For binary variables, the proportion of responders will be summarized over analysis visits. For 
continuous variables, the change from baseline (of core) will be presented. The 95% 
confidence intervals will be provided to evaluate the long-term treatment efficacy of the 
secondary binary variables of interest. Summary statistics for continuous variables include 
mean, standard deviation, minimum, lower quartile, median, upper quartile and maximum.
Secondary variables include:

The proportion of subjects achieving ASAS40

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No statistical comparisons between any of the treatment groups (75 mg treatment arm and 150 
mg treatment arm including patients who escalated from 75 mg s.c. to 150 mg s.c. every 4 
weeks)will be provided for the analysis of the secondary 
 variables.
9.5.2
Safety variables
Adverse events
Treatment emergent adverse events (events started after the first dose of study treatment in the 
extension or events present prior to the first dose of study treatment in core study but 
increased in severity based on preferred term and within 84 days after last dose of 
secukinumab) will be summarized. 
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects having any AE, having an AE in each primary system organ class and having each 
individual AE (preferred term). Summaries will also be presented for AEs by severity and for 
study treatment related AEs. 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. Serious adverse events will also be summarized. 
The incidence of AEs will be presented per 100 subject years of exposure. 
Separate summaries will be provided for death, serious adverse event, other significant 
adverse events leading to discontinuation and adverse events leading to dose adjustment 
(including study treatment discontinuation).
A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, will be presented.
When adjudication is required of major cardiovascular adverse events, a summary of those 
types of events as reported by the investigator and confirmed by adjudication will be provided.

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Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from baseline will only 
be summarized for subjects with both baseline of core study and post baseline values. 
For each parameter, the maximum change from baseline within each study period will be 
evaluated analogously. 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was 
normal, low, or high for each visit value relative to whether or not the baseline value was 
normal, low, or high. These summaries will be presented by laboratory test and treatment 
group. Shifts will be presented by visit as well as for most extreme values post-baseline.
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values.
ECG
Summary statistics will be presented for ECG variables by visit and treatment group. 
Qualitative changes will be summarized.

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9.6
Interim analyses
Interim analyses may be planned in order to support regulatory filing and for purposes of 
publication after subjects complete additional years of treatment in this extension study. 
Additional analyses may be performed to support heath authority interactions, as necessary.
9.7
Sample size calculation
It is estimated that approximately 75% to 85% of subjects enrolled in the core study will 
complete the entire treatment period and be eligible for entry into the extension study, which 
is equivalent to about 279 to 316 subjects.

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10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the subject. 
In cases where the subject’s representative gives consent, the subject should be informed 
about the study to the extent possible given his/her understanding. If the subject is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the subject source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.

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10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted.
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Under no circumstances should an investigator collect additional data 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs. 
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
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. Only 
amendments that are required for subject safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any subject 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations.
12
References
References are available upon request
Anandarajah AP, Schwarz EM, Totterman S, et al. (2008) The effect of etanercept on 
osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic 
arthritis. Ann Rheum Dis; 67:296-301.
Appel H, Kuhne M, Spiekermann S, et al. (2006) Immunohistologic analysis of zygaphyseal 
joints in patients with ankylosing spondylitis. Arthritis Rheum; 54:2845-51.
Appel H, Heydrich R, Loddenkemper C, et al. (2008) In situ detection of IL-17 secreting cells 
in the bone marrow of facet joints obtained from patients with ankylosing spondylitis. 
Arthritis Rheum; 58 (Suppl):S351.

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Baraliakos X, Braun J, Baeten D, et al. (2011) Interleukin-17A blockade with secukinumab 
reduces spinal inflammation in patient with ankylosing spondylitis as early as week 6, as 
detected by magnetic resonance imaging. Arthritis Rheum; 63:S972.
Baraliakos X, Landewe R, Hermann K-G, et al. (2005) Inflammation in ankylosing 
spondylitis: a systematic description of the extent and frequency of acute spinal changes using 
magnetic resonance imaging. Ann Rheum Dis; 64:730-734.
Braun J, Baraliakos X, Golder W, et al. (2003) Magnetic Resonance Imaging Examinations of 
the Spine in Patients with Ankylosing Spondylitis, Before and After Successful Therapy with 
Infliximab. Arthritis Rheum; 48:1126-1136.
Braun J, Baraliakos X, Brandt J, et al. (2005) Persistent clinical response to the anti-TNF-
alpha antibody infliximab in patients with ankylosing spondylitis over 3 years. Rheumatology; 
44:670-6.
Braun J, Brandt J, Listing J, et al. (2002) Treatment of ankylosing spondylitis with infliximab. 
A randomized controlled multicenter trial. Lancet; 359:1187-93.
Braun J, Pham T, Sieper J, et al. (2003) International ASAS consensus statement for the use 
of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis; 
62:817-824.
Braun J, Landewé R, Hermann K-G, et al. (2006) Major reduction in spinal inflammation in 
patients with ankylosing spoindylitis after treatment with infliximab. Arthritis Rheum; 
54:1646-52.
Brown AK, Quinn MA, Karim Z, et al. (2006) Presence of significant synovitis in rheumatoid 
arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: 
evidence from an imaging study may explain structural progression. Arthritis Rheum; 
54:3761-73.
Cella DF, Tulsky DS, Gray G et al. (1993) The Functional Assessment of Cancer Therapy 
(FACT) scale: Development and validation of the general measure. Journal of Clinical 
Oncology; 11(3):570-579.
Chilton F, Collett RA. (2008) Treatment choices, preferences and decision-making by patients 
with rheumatoid arthritis. Musculoskeletal Care.; 6:1–14.
Gladman DD (2007) Axial disease in psoriatic arthritis. Curr Rheumatol Rep; 9:455-60.
Hamm R, Patel B, Whittlestone T, Persad R(2000) Patient self-injection: a new approach to 
administering luteinizing hormone-releasing hormone analogues. BJU Int; 86:840-842. 
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al. (2003) Assessment of enthesitis 
in ankylosing spondylitis. Ann Rheum Dis; 62:127-32.
Kiltz U, Heldmann F, Baraliakos X, Braun J. (2012) Treatment of ankylosing spondylitis in 
patients refractory to TNF-inhibition: are there alternatives? Current Opinion in 
Rheumatology; 24(3):252–260.
Kim HR, Lee SH, Kim HY, et al. (2006) Elevated serum levels of soluble receptor activator 
of nuclear factors-kappaB ligand (sRANKL) and reduced bone mineral density in patients 
with ankylosing spondylitis. Rheumatology; 45(10):1197-200.

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Kivitz A, Cohen S, Dowd JE, et al.(2006) Clinical assessment of pain, tolerability, and 
preference of an autoinjection pen versus a prefilled syringe for patient self-administration of 
the fully human, monoclonal antibody adalimumab: the TOUCH trial. Clin Ther; 28:1619–
1629.
Koenders MI, Lubberts E, Oppers_Walgreen B, et al. (2005) Blocking of interleukin-17 
during reactivation of experimental arthritis prevents joint inflammation and bone erosion by 
decreasing RANKL and interleukin-1. Am J Pathol; 167:141-9.
Lukas C, Braun J, van der Heijde D, et al. (2007) Scoring inflammatory activity of the spine 
by magnetic resonance imaging in ankylosing spondylitis: a multireader experiment. J 
Rheumatol; 34(4):862-70.
Lukas C, Landewé R, Sieper J, (2009) Development of an ASAS-endorsed disease activity 
score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis.; 68(1):18-24.
Machado PM, Landewé RB, van der Heijde DM (2011) Endorsement of definitions of disease 
activity states and improvement scores for the Ankylosing Spondylitis Disease Activity Score: 
results from OMERACT 10. J Rheum; 38(7):1502-1506.
Mettler FA Jr, Huda W, Yoshizumi TT, et al. (2008) Effective doses in radiology and 
diagnostic nuclear medicine: a catalog. Radiology; 248(1):254-63.
Rudwaleit M, Listing J, Brandt J, et al. (2004). Prediction of a major clinical response 
(BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum 
Dis; 63(6):665-70.
Shen H, Goodall JC, Hill Gaston JS. (2009) Frequency and phenotype of peripheral blood 
Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum; 60:1647–1656.
Sieper J, Rudwaleit M, Baraliakos X,(2009)The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis.; 
68 Suppl 2:ii1-44.
Stabin M, RADAR medical procedure radiation dose calculator and consent language 
generator; http://www.doseinfo-radar.com/RADARDoseRiskCalc.html.
Ware J, Kosinki M, Gandeck B. (1993) SF-36 Health Survey manual and interpretation guide. 
Boston: The Health Institute, New England Medical Center.
Ware J, Kosinki M, Gandeck B. (1994) SF-36 Health Survey manual and interpretation guide. 
Update. Boston: The Health Institute, New England Medical Center.
Yellen SB, Cella DF, Webster K, et al. (1997) Measuring Fatigue and Other Anemia-Related 
Symptoms with the Functional Assessment of Cancer Therapy (FACT) Measurement System. 
Journal of Pain and Symptom Management; 13:63-74.
Zochling J, Baraliakos X, Hermann KG, et al. (2007) Magnetic resonance imaging in 
ankylosing spondylitis. Curr Opin Rheumatol; 19:346-50

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13
Appendices
13.1
Appendix 1: Clinically notable laboratory values and vital signs
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests.
Clinically notable values will be forwarded to Novartis at the same time that they are sent to 
investigators.
Table 13-1
Safety Analyses: Expanded Limits and Notable Criteria
Final Harmonization
Notable Criteria
Laboratory Variable
Standard Units
SI Units
LIVER FUNCTION AND RELATED VARIABLES
SGOT (AST)
>3 x ULN
>3 x ULN
SGPT (ALT)
>3 x ULN
>3 x ULN
Bilirubin
>2 x ULN
>2 x ULN
Alkaline phosphatase
>2.5 x ULN
>2.5 x ULN
RENAL FUNCTION, METABOLIC AND ELECTROLYTE VARIABLES
Creatinine (serum)
>2 x ULN
>2 x ULN
HEMATOLOGY VARIABLES
Hemoglobin:
≥20 g/L decrease from baseline
Platelet count:
<100x10E9/L
White blood cell count: <0.8 x LLN
Neutrophils:
<0.9 x LLN

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13.3
Appendix 3:  Modified New York criteria
Clinical criteria

Low back pain and stiffness for more than 3 months that improves with exercise, but is not 
relieved by rest

Limitation of motion of the lumbar spine in the sagittal and frontal planes

Limitation of chest expansion relative to normal values correlated for age and sex
Radiological criterion

Sacroiliitis grade ≥ 2 bilaterally or grade 3-4 unilaterally
Definite AS if the radiological criterion is associated with at least one clinical criterion

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13.4
Appendix 4:  Assessment of SpondyloArthritis International 
Society criteria (ASAS)
The ASAS response measures consist of the following assessment domains (Sieper 2009):
Main ASAS domains:
1. Patient’s global assessment of disease activity measured on a VAS scale
2. Patient’s assessment of back pain represented by either total or nocturnal pain scores, both 
measured on a VAS scale
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale
4. Morning stiffness represented by the average of the last 2 questions on the 6-question 
BASDAI regarding morning stiffness as measured by VAS scales
Additional assessment domains:
5.
 
6.
13.4.1
Bath Ankylosing Spondylitis Functional Index (BASFI)
The BASFI is a set of 10 questions designed to determine the degree of functional limitation 
in those subjects with AS. The ten questions were chosen with a major input from subjects 
with AS. The first 8 questions consider activities related to functional anatomy. The final 2 
questions assess the subject’s ability to cope with everyday life. A 10cm visual analog scale is 
used to answer the questions. The mean of the ten scales gives the BASFI score – a value 
between 0 and 10.
13.4.2
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to 
the 5 major symptoms of AS:
1. How would you describe the overall level of fatigue/tiredness you have experienced?
2. How would you describe the overall level of AS neck, back or hip pain you have had?
3. How would you describe the overall level of pain/swelling in joints other than neck, back, 
hips you have had?
4. How would you describe the overall level of discomfort you have had from any areas 
tender to touch or pressure?
5. How would you describe the overall level of morning stiffness you have had from the 
time you wake up?
6. How long does your morning stiffness last from the time you wake up?
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness (questions 5 and 6) is taken.  The resulting 0 to 10 number is added to the 
scores from questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 to 10 
BASDAI score. Scores of 4 or greater suggest suboptimal control of disease, and subjects 

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with scores of 4 or greater are usually good candidates for either a change in their medical 
therapy or for enrollment in clinical trials evaluating new drug therapies directed at 
Ankylosing Spondylitis. BASDAI is a quick and simple index, taking between 30 seconds and 
2 minutes to complete.
13.4.3
Bath Ankylosing Spondylitis Metrology Index (BASMI)
Cervical rotation
Cervical rotation is measured twice with the subject supine on plinth, head in neutral position, 
forehead horizontal (if necessary head on pillow or foam block to allow this, must be 
documented for future reassessments). Gravity goniometer placed centrally on the forehead. 
Subject rotates head as far as possible to the left, keeping shoulders still, ensure no neck 
flexion or side flexion occurs and the angle between the sagittal plane and the new plane after 
rotation is recorded. The better reading of the two is recorded. The same is repeated for the 
right side. Record the mean of the better reading from the right side and the better reading 
from the left side.
Tragus to wall distance
Tragus to wall distance is measured twice with the subject’s heels and back rested against the 
wall. The chin should be at usual carrying level and the subject takes maximal effort to touch 
the head against the wall. The distance between the tragus and the wall is assessed and the 
better of the two assessments is to be reported.
Spinal lateral flexion (lumbar lateral flexion)
Subject stands with heels and buttocks touching the wall, knees straight, shoulders back, 
hands by the side. The subject is then asked to bend to the right side as far as possible without 
lifting the left foot/heel or flexing the right knee, and maintaining a straight posture with heels, 
buttocks, and shoulders against the wall. The distance from the third fingertip to the floor 
when subject bends to the side, is subtracted from the distance when subject stands upright. 
The better of two tries is recorded. The maneuver is repeated on the left side. Record the mean 
of the better reading from the right side and the better reading from the left side.
Lumbar flexion (modified Schober index)
Set marks in upright position 5 cm below and 10 cm above lumbosacral junction (spinal 
section of a line joining the dimples of Venus). Measure distraction of the marks when the 
subject bends forward as far as possible, keeping the knees straight. The better of two tries is 
recorded.
Maximal intermalleolar distance
Subject is lying down with the legs separated as far as possible with knees straight and toes 
pointed upwards. Alternatively, the subject stands and separates the legts as far as possible. 
The distance between medial malleoli is measured and the better of the two measurements is 
recorded.

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Chest expansion
Chest expansion is measured with the subject hands resting on or behind the head. The 
measurement is taken at the fourth intercostal level anteriorly. The difference between 
maximal inspiration and expiration in cm is recorded twice and the better of the two 
measurements is reported.
Occiput-to-wall distance
Occiput to wall distance is measured twice with the subject’s heels and back rested against the 
wall. The chin should be at usual carrying level and the subject takes maximal effort to touch 
the head against the wall. The distance between the occiput and the wall is assessed and the 
better of the two assessments is to be reported.

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