Conditions: Axial Psoratic Arthritis
Keywords: Assessment of spondyloarthritis international society ASAS axial Psoriatic Arthritis PsA Magnetic resonance imaging MRI
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 503
Healthy volunteers: no

Brief summary:
The purpose of this study is to demonstrate the efficacy and safety of secukinumab 150 mg or 300 mg in the management of axial manifestations in PsA patients who have failed to respond to at least 2 non-steroidal anti-inflammatory drugs (NSAIDs) over a 4-week period, according to assessment of spondyloarthritis international society (ASAS) recommendations for the treatment of axial spondyloarthritis (AxSpA).

Detailed description:
In the anlalysis (CSR), there are 498 patients, as 5 patients were mis-randomized, i.e. had randomization number but did never take study medication. So there were 498 participants, and not 503

Arms:
arm 1: Secukinumab dose amount 1 sc injection weekly for 4 weeks followed by Secukinumab dosage amount 1 sc injection every 4 weeks for remaining 44 weeks arm 2: Secukinumab dose amount 2 sc injection weekly for 4 weeks followed by Secukinumab dosage amount 2 sc injection every 4 weeks for remaining 44 weeks arm 3: Placebo sc injection weekly for 4 weeks and at week 8, followed by Secukinumab 150 mg or 300 mg sc injection every 4 week for remaining 40 weeks.

Interventions: intervention 1: Secukinumab intervention 2: Secukinumab and Placebo
Intervention descriptions: intervention 1: Anti IL-17a monoclonal antibody intervention 2: Placebo matching AIN457

Protocol document:
Prot_002.pdf: 
Clinical Development - Medical Affairs Region Europe
AIN457/Secukinumab
Protocol CAIN457F3302 / NCT02721966
MAXIMISE (Managing AXIal Manifestations in PsorIatic 
Arthritis with SEcukinumab), a randomized, double-blind, 
placebo-controlled, multicenter, 52-week study to assess 
the efficacy and safety of secukinumab 150 mg or 300 mg 
s.c. in patients with active psoriatic arthritis and axial
skeleton involvement who have inadequate response to 
non-steroidal anti-inflammatory drugs (NSAIDs)
Document type:
Amended Protocol Version Clean
EUDRACT number:
2016-000814-31
Version number:
Version 01
Clinical trial phase:
Phase 3b
Release date:
20-Jun-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment Rationale.......................................................................................................11
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................19
2.1
Primary objective...................................................................................................19
2.2
Key secondary objective........................................................................................19
2.3
Secondary objectives .............................................................................................19
20
3
Investigational plan ...........................................................................................................21
3.1
Study design...........................................................................................................21
3.2
Rationale for study design .....................................................................................24
3.3
Rationale for dose/regimen, route of administration and duration of treatment....24
3.4
Rationale for choice of comparator .......................................................................25
3.4.1
Rationale for re-randomization of patients ...........................................25
26
3.6
Risks and benefits..................................................................................................26
4
Population..........................................................................................................................26
4.1
Inclusion criteria ....................................................................................................27
4.2
Exclusion criteria...................................................................................................27
5
Treatment...........................................................................................................................30
5.1
Study treatment......................................................................................................30
5.1.1
Investigational and control drugs..........................................................30
5.1.2
Additional treatment..............................................................................30
5.2
Treatment arms ......................................................................................................32
5.3
Treatment assignment and randomization.............................................................32
5.4
Treatment blinding.................................................................................................33
5.5
Treating the patient................................................................................................33
5.5.1
Patient numbering .................................................................................34


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5.5.2
Dispensing the study drug.....................................................................34
5.5.3
Handling of study and additional treatment..........................................34
5.5.4
Instructions for prescribing and taking study treatment........................35
5.5.5
Permitted dose adjustments and interruptions of study treatment ........36
5.5.6
Rescue medication ................................................................................36
5.5.7
Concomitant medication .......................................................................37
5.5.8
Prohibited medication ...........................................................................37
5.5.9
Emergency breaking of assigned treatment code..................................38
5.6
Study completion and discontinuation...................................................................38
5.6.1
Study completion and post-study treatment..........................................38
5.6.2
Discontinuation of study treatment .......................................................38
5.6.3
Withdrawal of informed consent...........................................................39
5.6.4
Loss to follow-up ..................................................................................40
5.6.5
Early study termination by the sponsor.................................................40
6
Visit schedule and assessments .........................................................................................40
6.1
Information to be collected on screening failures..................................................47
6.2
Patient demographics/other baseline characteristics .............................................47
6.2.1
Demographic data .................................................................................47
6.2.2
Baseline characteristics .........................................................................48
6.2.3
Other baseline characteristics................................................................48
6.3
Treatment exposure and compliance .....................................................................49
6.4
Efficacy..................................................................................................................49
6.4.1
Assessment of spondyloarthritis international society..........................50
6.4.2
Spondyloarthritis research consortium of Canada – enthesitis index ...51
6.4.3
American college of rheumatology response........................................52
53
54
54
6.4.7
Appropriateness of efficacy assessments..............................................54
6.5
Safety.....................................................................................................................55
6.5.1
Physical examination ............................................................................55
6.5.2
Vital signs..............................................................................................55
6.5.3
Height and weight .................................................................................56
6.5.4
QuantiFERON TB-Gold test.................................................................56
6.5.5
Laboratory evaluations..........................................................................56
6.5.6
Electrocardiogram.................................................................................57


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6.5.7
Pregnancy and assessments of fertility .................................................57
6.5.8
Appropriateness of safety measurements..............................................58
6.6
Other assessments..................................................................................................58
6.6.1
Patient reported outcomes.....................................................................58
7
Safety monitoring ..............................................................................................................59
7.1
Adverse events.......................................................................................................59
7.2
Serious adverse events...........................................................................................61
7.2.1
Definition of SAE .................................................................................61
7.2.2
SAE reporting........................................................................................62
7.3
Liver safety monitoring .........................................................................................63
7.4
Renal safety monitoring.........................................................................................64
7.5
Reporting of study treatment errors including misuse/abuse ................................64
7.6
Pregnancy reporting...............................................................................................65
8
Data review and database management.............................................................................65
8.1
Site monitoring ......................................................................................................65
8.2
Data collection.......................................................................................................66
8.3
Database management and quality control............................................................66
8.4
Data monitoring committee ...................................................................................67
8.5
Adjudication committee.........................................................................................67
9
Data analysis......................................................................................................................67
9.1
Analysis sets ..........................................................................................................67
9.2
Patient demographics and other baseline characteristics.......................................68
9.2.1 Demographics and baseline characteristics ..................................................68
9.2.2 Medical history.............................................................................................68
9.3
Treatments .............................................................................................................68
9.3.1 Study treatment.............................................................................................68
9.3.2 Prior and concomitant medication................................................................68
9.4
Analysis of the primary and key secondary variable(s).........................................69
9.4.1
Variable.................................................................................................69
9.4.2
Statistical model, hypothesis, and method of analysis..........................69
9.4.3
Handling of missing values/censoring/discontinuations.......................70
9.4.4
Sensitivity analyses ...............................................................................71
9.5
Analysis of secondary variables ............................................................................71
9.5.1
Efficacy variables..................................................................................71
9.5.2
Testing strategy for secondary variables...............................................72
9.5.3
Safety variables .....................................................................................73


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9.5.4
Health-related quality of life .................................................................74
75
75
75
75
76
9.8
Sample size calculation..........................................................................................76
10 Ethical considerations........................................................................................................77
10.1
Regulatory and ethical compliance........................................................................77
10.2
Informed consent procedures.................................................................................77
10.3
Responsibilities of the investigator and IRB/IEC..................................................78
10.4
Publication of study protocol and results...............................................................78
10.5
Quality Control and Quality Assurance.................................................................78
11 Protocol adherence ............................................................................................................78
11.1
Protocol amendments.............................................................................................79
12 References .........................................................................................................................79
13 Appendix 1: Clinically notable laboratory values .............................................................83
14 Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ......................................................................................................................84
15 Appendix 3: Specific renal alert criteria and actions.........................................................86
16 Appendix 4: Classification criteria for psoriatic arthritis..................................................87
17 Appendix 5: Assessment of Spondyloarthritis International Society (ASAS) criteria......88
17.1
Bath ankylosing spondylitis functional index (BASFI).........................................88
17.2
Bath ankylosing spondylitis disease activity Index (BASDAI) ............................88
89
19 Appendix 7: Health assessment questionnaire – disability index (HAQ-DI©)..................91
20 Appendix 8: ASAS recommendations for collecting, analyzing and reporting NSAID 
intake .................................................................................................................................93
21 Appendix 9: American College of Rheumatology measures and criteria of response......94
List of tables
Table 5-1
Corticosteroids conversion table for the equivalence of 1 mg of 
cortisone................................................................................................31
Table 5-2
Prohibited medication ...........................................................................37
Table 6-1
Assessment schedule.............................................................................42
Table 6-2
Overview of study drug administration for Treatment Period 2...........47


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Table 6-3
Entheses sites comprising the total spondyloarthritis research 
consortium of Canada enthesitis index .................................................51
Table 6-4
Items of the ASAS health index............................................................59
Table 7-1
Treatment error types ............................................................................64
Table 13-1
Safety analyses: expanded limits and notable criteria...........................83
Table 14-1
Liver event and laboratory trigger definitions ......................................84
Table 14-2
Follow-up requirements for liver events and laboratory triggers..........84
Table 15-1
Specific renal alert criteria and actions .................................................86
89
89
90
Table 19-1
Coding for disability outcome dimension.............................................91
Table 20-1
ASAS-NSAID equivalent score............................................................93
List of figures
Figure 3-1
Study design..........................................................................................23
Figure 9-1
Testing strategy.....................................................................................70


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List of abbreviations
ACR
American College of Rheumatology 
AE
Adverse event
ALP
Alkaline phosphatase
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
ANCOVA
Analysis of covariance
AS
Ankylosing spondylitis
ASAS
Assessment of spondyloarthritis international society
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
ATC
Anatomical therapeutic classification
AxPsA
Axial psoriatic arthritis (i.e. psoriatic arthritis with axial involvement)
BASDAI
Bath ankylosing spondylitis disease activity index
BASFI
Bath ankylosing spondylitis functional index
BASRI
Bath ankylosing spondylitis radiology index
bpm
Beats per minute
CASPAR
Classification criteria for psoriatic arthritis
CI
Confidence interval
COX
Cyclo-oxygenase
CPO
Country pharma organization
CRO
Contract research organization
CRF
Case report form
CQA
Compliance Quality Assurance
DAR
Drug administration record
DMARD(s)
Disease modifying anti-rheumatic drug(s)
eCRF
electronic case report/record form
ECG
Electrocardiogram
EDC
Electronic data capture
EMA/EMEA
European Medicines (Evaluation) Agency
EOS
End of study
EULAR
European league against rheumatism
FACIT-Fatigue©
Functional assessment of chronic illness therapy fatigue scale
FAS
Final analysis set
GCP
Good clinical practice
GGT/γGT
Gamma glutamyl transferase
GRAPPA
Group for research and assessment of psoriasis and psoriatic arthritis
HAQ-DI©
Health assessment questionnaire – disability index
hCG
human chorionic gonadotropin
HIV
Human immunodeficiency virus
HLA-B27
Human leukocyte antigen B27


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IB
Investigator brochure
IBP
Inflammatory back pain
ICH
International conference on harmonization of technical requirements for
registration of pharmaceuticals for human use
ICF
Informed consent form
IEC
Independent Ethics Committee
IFU
Instructions for use
IL
Interleukin
IN
Investigator notification
INR
International normalized ratio (for blood clotting time)
IRB
Institutional Review Board
IRT
Interactive response technology
i.v.
intravenous(ly)
LFT
Liver function test (raised serum transaminases and/or bilirubin levels)
LLN
Lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MRMM
Mixed-effects repeated measures model
MRI
Magnetic resonance imaging
m-SASSS
modified Stoke ankylosing spondylitis spinal score
MTX
Methotrexate
NSAID
Non-steroidal anti-inflammatory drug 
PCR
Protein-creatinine ratio
PFS
Prefilled syringe
PPD
Premature patient discontinuation
PRN
Pro re nata (as needed)
PRO
Patient reported outcome 
PsA
Psoriatic arthritis
PT
Prothrombin time
QFT
QuantiFERON tuberculosis gold test
QM
Quality management
RA
Rheumatoid arthritis
SAE
Serious adverse event 
s.c.
Subcutaneous(ly)
SDI
Standard disability index
SJC
Swollen joint count
SpA
Spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
SUSAR(s)
Suspected unexpected serious adverse reaction(s)
TB
Tuberculosis
TBL
Total bilirubin
TJC
Tender joint count


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TNF
Tumor necrosis factor
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
White blood cell


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Glossary of terms
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 patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol).
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.”
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense medication using an interactive response technology (IRT)
system.
Mis-randomization
A patient who is randomized to a treatment group, but did not receive any
study treatment.
Patient number
A number assigned to each patient who is screened for the study.
Period
The planned stage of the patient’s participation in the study. Each period
serves a purpose in the study as a whole. In this study, there is a
Screening period for determination of patient eligibility, Period 1, which is
a 12-week double-blind placebo-controlled period; and Period 2, which is
36-week double-blind active treatment period.
Premature patient 
withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned, unless the patient is followed for progression 
and/or survival.
Protocol
A written account of all the procedures to be followed in a trial, which 
describes all the administrative, documentation, analytical and clinical 
processes used in the trial.
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment.
Re-randomization
In this study, patients randomized to placebo at Baseline will be 
re-randomized (1:1 ratio) to secukinumab 150 mg or 300 mg at 
Week 12.
Re-screening
A patient who qualified for all or most eligibility criteria but could not be 
randomized within the Screening period can be considered for
re-screening only once.
Rescue medication
Any new therapeutic intervention or a significant change to ongoing
therapy made because a patient is experiencing either no benefit from
participation in the trial or worsening/ exacerbation of their disease.
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug, 
placebo or background therapy.
Study treatment 
discontinuation 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study.


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Amendment Rationale
 
 
It 
was decided not to perform the X-ray assessments in order to reduce the complexity of the 
study and to focus on the existing primary and secondary objectives. The Introduction 
(Section 1.1), the Study objectives and endpoints (Section 2.4), the Study design (Figure 3-1), 
the Visit schedule (Table 6-1) and assessments (Section 6.4), and the Data analysis (Section 
9.6) have been updated accordingly.  
Additionally, this protocol amendment includes the correction of typographical errors, 
formatting errors and editorial changes to increase clarity and consistency of the text. 
Consequently changes were incorporated directly in the protocol with track changes, even if 
not listed specifically in this section.
The first patient is planned to be recruited in the study on 30 September 2016.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
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.


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Protocol summary
Protocol 
number
CAIN457F3302
Title
MAXIMISE (Managing AXIal Manifestations in PsorIatic Arthritis with SEcukinumab), 
a randomized, double-blind, placebo-controlled, multicenter, 52-week study to assess 
the efficacy and safety of secukinumab 150 mg or 300 mg s.c. in patients with active 
psoriatic arthritis and axial skeleton involvement who have inadequate response to 
non-steroidal anti-inflammatory drugs (NSAIDs)
Brief title
Study of the efficacy and safety of secukinumab in patients with active psoriatic 
arthritis with axial skeleton involvement (AxPsA).
Sponsor and 
clinical phase
Novartis and Phase 3b
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to demonstrate the efficacy and safety of secukinumab 
150 mg or 300 mg in the management of axial manifestations in PsA patients who 
have failed to respond to at least 2 NSAIDs over a 4-week period, according to 
assessment of spondyloarthritis international society (ASAS) recommendations for the 
treatment of axial spondyloarthritis (AxSpA). In particular, the study will provide 
evidence on the ability of secukinumab 150 mg or 300 mg to improve clinical 
 
 outcomes in patients with AxPsA. 
Primary 
objective

To demonstrate that secukinumab 300 mg s.c. is superior to placebo in the 
achievement of ASAS 20 response at Week 12.
Key secondary 
objective

To demonstrate that secukinumab 150 mg s.c. is superior to placebo in the 
achievement of ASAS 20 response at Week 12 after superiority of 300 mg is 
established.
Secondary 
objectives

To evaluate secukinumab 300 mg s.c. versus placebo in the achievement of 
ASAS 40 at Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo in the achievement of 
ASAS 40 at Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo in the achievement of Bath 
ankylosing spondylitis disease activity index (BASDAI) 50 at Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo in the achievement of 
BASDAI 50 at Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo in the reduction of spinal 
pain measured by visual analog scale (VAS) at Week 12. 

To evaluate secukinumab 150 mg s.c. versus placebo in the reduction of spinal 
pain measured by VAS at Week 12. 

To evaluate secukinumab 300 mg s.c. versus placebo in achieving an 
improvement in Spondyloarthritis Research Consortium of Canada (SPARCC) 
enthesitis index at Week 12. 

To evaluate secukinumab 150 mg s.c. versus placebo in achieving an 
improvement in SPARCC enthesitis index at Week 12. 

To evaluate secukinumab 300 mg s.c. versus placebo in achieving an 
improvement in health assessment questionnaire disability index (HAQ-DI©) at 


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Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo in achieving an 
improvement in HAQ-DI© at Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo in achieving an 
improvement in the functional assessment of chronic illness therapy fatigue scale 
(FACIT-Fatigue©) at Week 12.

To evaluate secukinumab 150 mg versus placebo in achieving an improvement in 
the FACIT-Fatigue© at Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo in achieving an 
improvement in the ASAS health index at Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo in achieving an 
improvement in the ASAS health index at Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo based on the proportion of 
patients achieving an American College of Rheumatology (ACR) 20 response at 
Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo based on the proportion of 
patients achieving an ACR 20 response at Week 12.

To evaluate the safety and tolerability of secukinumab.


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Study design
This is a 52-week, randomized, double-blind, double-dummy, placebo-controlled, 
multicenter study to assess the efficacy of secukinumab 150 mg or 300 mg in patients 
with AxPsA who have had an inadequate response to 2 different NSAIDs. The study 
will consist of 2 treatment periods; a double-blind placebo-controlled period from 
Baseline to Week 12 followed by a double-blind secukinumab treatment period from 
Week 12 to Week 52.
Population
Male and female patients ≥18 years of age with PsA fulfilling the classification criteria
for psoriatic arthritis (CASPAR) and who are naïve to biologic treatment. Patients 
must have clinical signs of spinal involvement defined by presence of inflammatory 
back pain (IBP) with active disease defined by BASDAI score ≥4, spinal pain visual 
analog scale (VAS) ≥40 (0 to 100 mm scale) and inadequate response to at least
2 NSAIDs
over a 4-week period. Patients may continue pre-study NSAIDs, 
methotrexate (MTX) and corticosteroids from Baseline through to the end of study
(NSAID, MTX and corticosteroid doses must be stable from Baseline to Week 12).
Key inclusion 
criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1.
Patients must be able to understand and communicate with the investigator and 
comply with the requirements of the study and must provide a written, signed and 
dated informed consent before any assessment is performed.
2.
Male or non-pregnant, non-lactating female patients of at least 18 years of age.
3.
Diagnosis of PsA classified by CASPAR criteria.
4.
Active spinal disease defined by BASDAI score ≥4.
5.
Spinal pain as measured by VAS ≥40 at Baseline (0 to 100 mm scale).
6.
Inadequate response to at least 2 NSAIDs over a 4-week period (at least).
Key exclusion 
criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study: 
1.
Chest X-ray or chest MRI with evidence of ongoing infectious or malignant 
process obtained within 3 months prior to Screening and evaluated by a qualified 
physician.
2.
Patients taking high potency opioid analgesics (e.g. methadone, hydromorphone, 
morphine).
3.
History of exposure to other IL-17 or IL-23 inhibitor biologic drug(s).
4.
History of exposure to previous biologic disease modifying anti-rheumatic drug(s) 
(DMARD(s)) (tumor necrosis factor (TNF) blockers or ustekinumab).
5.
Current treatment with DMARD(s) other than MTX.
6.
Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
randomization.
7.
Patients regularly taking NSAIDs as part of their PsA therapy who are not on a 
stable dose for at least 2 weeks before study randomization.
8.
Patients regularly taking systemic corticosteroids as part of their PsA therapy who 


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are not on a stable dose ≤10 mg/day of prednisone or equivalent for at least 2 
weeks before randomization.
9.
Patients who are on MTX (≤25 mg/week) who are not on a stable dose for 
at least 4 weeks before randomization.
10. Patients on MTX who are not on folic acid supplementation at randomization.
11. Patients who are on DMARD(s) other than MTX who have not discontinued the 
DMARD(s) 4 weeks prior to the randomization visit, or 8 weeks prior to 
randomization for patients on leflunomide unless a cholestyramine washout has 
been performed (in which cases 4 weeks applies).
12. Active ongoing inflammatory diseases other than PsA (e.g. inflammatory bowel 
disease) that might confound the evaluation of the benefit of secukinumab 
therapy.
 
14. Any intramuscular or intravenous (i.v.) corticosteroid treatment within 4 weeks 
before randomization.
15. Previous treatment with any cell-depleting therapies including but not limited to 
anti-CD20, investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, 
anti-CD19).
Study 
treatment
Secukinumab 150 mg will be provided in 1 mL prefilled syringes (PFS) for s.c. 
injection. Secukinumab 300 mg will be provided as 2 PFS each containing 150 mg 
secukinumab. Secukinumab placebo will be provided in 1 mL PFS. 
At Baseline, all patients whose eligibility is confirmed will be randomized in a 1:1:1 
ratio to secukinumab 150 mg (Group 1), secukinumab 300 mg (Group 2) or placebo 
(Group 3). At Week 12, patients randomized to placebo at Baseline (i.e. Group 3) will 
be re-randomized in a 1:1 ratio to active treatment with secukinumab 150 mg or 
secukinumab 300 mg.
Group 1: secukinumab 150 mg 
Treatment Period 1

secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) at Baseline, 
Week 1, 2, 3 and 4, then 4 weeks later at Week 8
Treatment Period 2

secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) administered 
every 4 weeks from Week 12 to Week 52 (last dose on Week 48)
Group 2: secukinumab 300 mg
Treatment Period 1 

secukinumab 300 mg (2 × 1.0 mL PFS) administered at Baseline, Week 1, 2, 3 
and 4, then 4 weeks later at Week 8.
Treatment Period 2

secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from 
Week 12 to Week 52 (last dose on Week 48)
Group 3: placebo
Treatment Period 1

placebo (2 × 1.0 mL PFS) administered at Baseline, Week 1, 2, 3 and 4, then 4 
weeks later at Week 8.


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Treatment Period 2

secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) administered 
every 4 weeks from Week 12 to Week 52 (last dose on Week 48), OR

secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from Week 
12 to Week 52 (last dose on Week 48)
Patients will be allowed to continue background medications with MTX, NSAIDs and 
corticosteroids from Baseline until the end of study. The dose must be stable from 
Baseline to Week 12, and is recommended to continue at a stable dose from Week 12 
to Week 52/end of study.
In patients taking NSAIDs, the NSAID intake will be recorded according to ASAS 
recommendations up to Week 52.
Efficacy 
assessments

Assessment of spondyloarthritis international society (ASAS) responses 

Bath ankylosing spondylitis disease activity index (BASDAI)

Bath ankylosing spondylitis functional index (BASFI)

Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index

American College of Rheumatology 20 (ACR 20)

Spinal pain (VAS)
Key safety 
assessments

Evaluation of adverse events (AEs)/serious adverse events (SAEs)

Physical examination

Vital signs

Laboratory evaluations (hematology, clinical chemistry, urinalysis)
Other 
assessments
Patient reported outcomes (PROs):

Health assessment questionnaire – disability index (HAQ-DI©)

Functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue©)

ASAS health index
Note: The BASDAI, a PRO assessing disease activity, and BASFI, a PRO assessing 
functional limitation, which are part of ASAS are described under efficacy 
assessments
Data analysis
The primary endpoint in the study is ASAS20 at Week 12. The testing hierarchy tests
secukinumab treatments versus placebo for the primary endpoint at Week 12 for the 
full analysis population.
The statistical hypothesis for ASAS 20 being tested is that there is no difference in the 
proportion of patients fulfilling the ASAS 20 criteria at Week 12 in the secukinumab 
groups versus placebo group.
The primary analysis will be conducted via logistic regression with treatment and 
concomitant MTX intake status as factors. Odds ratios, 95% confidence interval (CI)
and p-values will be presented comparing each secukinumab group to placebo.
Key words
ASAS, PsA, axial, MRI


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1
Introduction
1.1
Background 
Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis, usually 
seronegative for rheumatoid factor, which can affect peripheral and/or axial joints. Axial PsA 
(AxPsA) is PsA involving the axial joints and ties PsA to the concept of spondyloarthritis 
(SpA) (Biagoni et al 2014). There is wide variability (25% to 70%) in the reported prevalence 
of axial involvement in PsA due to differences in the criteria used for defining AxPsA
(Gladmann et al 2007). AxPsA can affect the sacroiliac joints, as well as the lumbar, thoracic, 
and cervical spine. Some radiographic features of AxPsA are similar to those found in 
ankylosing spondylitis (AS) although patients with AS generally have more severe 
radiographic damage compared to AxPsA (Biagoni et al 2014). AxPsA may be distinguished 
from AS in terms of radiographic features of asymmetrical sacroiliitis, non-marginal and 
asymmetrical syndesmophytes, paravertebral ossification, and frequent involvement of the 
cervical spine (Biagoni et al 2014, Helliwell et al 1998). These distinguishing features of 
AxPsA mean there is a medical need to evaluate current treatment for PsA/AS in isolation for 
this sub-population.
Conventional X-ray scores used to assess spinal involvement in PsA, such as the Bath 
ankylosing spondylitis radiology index (BASRI) and the modified Stoke ankylosing 
spondylitis spinal score (m-SASSS), have been designed for AS and do not encompass some 
radiological features of AxPsA (Biagioni et al 2014, Lubrano et al 2009).
 
 
 
 
 
 
 
 
 
 
 
 
 
According to European League Against Rheumatism (EULAR) recommendations for the 
management of PsA with pharmacological therapies, non-steroidal anti-inflammatory drugs 
(NSAIDs) should be used as the first-line treatment in the majority of PsA patients (Gossec et 
al 2015). NSAIDs have been shown to be efficacious with regard to joint symptoms in 
patients with PsA but have not shown efficacy with regard to skin lesions. The latest 
GRAPPA treatment guidelines for axial disease (Coates et al 2016) are derived from 
diagnostic criteria, screening, monitoring and response to therapy in AS since these data are 


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not available for AxPsA. The guidelines recommend initiation of tumor necrosis factor (TNF)
inhibitors for patients with axial symptoms who have not responded to NSAIDs, 
physiotherapy, and sacroiliac injections (when appropriate). Disease modifying anti-rheumatic 
drug(s) (DMARDs) are not deemed effective in this population with no evidence available for
efficacy of sulfasalazine in axial disease within PsA or AS (Chen et al 2014). GRAPPA 
conditionally recommends NSAIDs for patients with an inadequate response to TNF 
inhibitors usually as an adjunct to further therapy on the basis of observational data for other 
disease domains (Coates et al 2016). The effectiveness of biologics in the treatment of AxPsA 
has been poorly assessed and so there is an unmet need for further clinical studies of biologics 
in patients with AxPsA.
The Assessment of SpondyloArthritis international Society (ASAS) has focused in the last 
years in defining measuring treatment response in clinical trials, and provided validated 
ASAS-endorsed response criteria for SpA. The ASAS response criteria are built on the basis 
of a core set of domains which includes function, pain, spinal mobility, patient global, 
peripheral joints and entheses, stiffness, fatigue and acute phase reactants (Sieper et al 2009). 
The primary endpoint of the present study is represented by the ASAS 20 improvement 
criteria which implies the improvement and no worsening of >20% and >1 unit on a scale of 
10 in at least 3 out of 4 domains (patient global, pain, function, inflammation). The secondary 
end points of the study are the ASAS 40, which implies the improvement and no worsening 
of >40% and >1 unit on a scale of 10 in the same domains of ASAS 20 response, the Bath 
ankylosing spondylitis disease activity index (BASDAI), which is a 6 questions tool providing
information on axial disease activity and the VAS assessments of Total Spine Pain which 
provides information on the severity of spinal pain as a general disease feature and 
specifically during the night.
In an observational study of patients with PsA with axial manifestations (Lubrano et al 2011), 
the effectiveness at 12 months of etanercept biologic therapy was assessed as per assessment 
of spondyloarthritis international society (ASAS) response criteria; 72% of patients had 
improvement in BASDAI, as well as in other outcome measures. In a Phase 3, 12-month 
study (Mc Innes et al 2013), the monoclonal antibody ustekinumab showed significant 
reduction in BASDAI 20 and 70 at the 45 mg dose and significant reduction in BASDAI 
20/50/70 levels at the 90 mg dose at Week 24. The proportion of ACR 20, ACR 50 and ACR 
70 responders in the ustekinumab groups was significantly greater than placebo for both the 
45 mg dose and 90 mg dose at Week 24, and responses were maintained until Week 52. 
Significantly greater ACR 20 responses with ustekinumab compared to placebo were 
observed as early as Week 8 (Mc Innes et al 2013).
Secukinumab (AIN457) is a high-affinity fully human monoclonal anti-human antibody that 
neutralizes interleukin (IL)-17A activity, which is approved in Europe (since Nov 2015) for 
the treatment of patients with active PsA (based on the pivotal Phase 3 trials in PsA: 
CAIN457F2306
(FUTURE 1;
Mease et al 2014)
and CAIN457F2312
(FUTURE 2;
Mc Innes et al 2015)) and patients with active AS (based on the pivotal Phase 3 trials in AS: 
CAIN457F2305 and CAIN457F2310 (MEASURE 1 and MEASURE 2; Baeten et al 2015)).
 
 


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1.2
Purpose
The purpose of this study is to demonstrate the efficacy and safety of secukinumab 150 mg or 
300 mg in the management of axial manifestations in PsA patients who have failed to respond 
to at least 2 NSAIDs over a 4-week period, according to ASAS recommendations for the 
treatment of axial spondyloarthritis (AxSpA). In particular, the study will provide evidence on 
the ability of secukinumab 150 mg or 300 mg to improve clinical 
 outcomes 
in patients with AxPsA.
2
Study objectives and endpoints
2.1
Primary objective
To demonstrate that secukinumab 300 mg s.c. is superior to placebo in the achievement of 
ASAS 20 response at Week 12.
2.2
Key secondary objective
To demonstrate that secukinumab 150 mg s.c. is superior to placebo in the achievement of 
ASAS 20 response at Week 12 after superiority of 300 mg is established.
2.3
Secondary objectives

To evaluate secukinumab 300 mg s.c. versus placebo in the achievement of ASAS 40 at 
Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo in the achievement of ASAS 40 at 
Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo in the achievement of BASDAI 50 at 
Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo in the achievement of BASDAI 50 at 
Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo in the reduction of spinal pain 
measured by visual analog scale (VAS) at Week 12. 

To evaluate secukinumab 150 mg s.c. versus placebo in the reduction of spinal pain 
measured by VAS at Week 12. 


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
To evaluate secukinumab 300 mg s.c. versus placebo in achieving an improvement in 
Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index at Week 12. 

To evaluate secukinumab 150 mg s.c. versus placebo in achieving an improvement in 
SPARCC enthesitis index at Week 12. 

To evaluate secukinumab 300 mg s.c. versus placebo in achieving an improvement in 
health assessment questionnaire disability index (HAQ-DI©) at Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo in achieving an improvement in 
HAQ-DI© at Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo in achieving an improvement in the 
functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue©) at 
Week 12.

To evaluate secukinumab 150 mg versus placebo in achieving an improvement in the 
FACIT-Fatigue© at Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo in achieving an improvement in the 
ASAS health index at Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo in achieving an improvement in the 
ASAS health index at Week 12.

To evaluate secukinumab 300 mg s.c. versus placebo based on the proportion of patients 
achieving an ACR 20 response at Week 12.

To evaluate secukinumab 150 mg s.c. versus placebo based on the proportion of patients 
achieving an ACR 20 response at Week 12.

To evaluate the safety and tolerability of secukinumab.


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3
Investigational plan
3.1
Study design
This is a 52-week, randomized, double-blind, double-dummy, placebo-controlled, multicenter 
study to assess the efficacy of secukinumab 150 mg or 300 mg in patients with AxPsA who 
have had an inadequate response to NSAIDs. The study will consist of 2 treatment periods; a 
placebo-controlled period from Baseline to Week 12 followed by an active treatment period 
from Week 12 to Week 52.
Patient eligibility will be assessed during a maximally 8-week Screening period. At Baseline, 
all patients whose eligibility is confirmed will be randomized in a 1:1:1 ratio to secukinumab 
150 mg, secukinumab 300 mg or placebo as shown below. 
At Week 12, patients randomized to placebo at Baseline will be re-randomized (1:1) to active 
treatment with secukinumab 150 mg or secukinumab 300 mg. See Figure  3-1 for a schematic 
of the study design.
Group 1: secukinumab 150 mg 
Treatment Period 1

secukinumab 150 mg (1 × 1.0 mL prefilled syringes (PFS)) + placebo (1 × 1.0 mL PFS) at 
Baseline, Week 1, 2, 3 and 4, then 4 weeks later at Week 8.
Treatment Period 2


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
secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) administered every 
4 weeks from Week 12 to Week 52 (last dose on Week 48).
Group 2: secukinumab 300 mg
Treatment Period 1 

secukinumab 300 mg (2 × 1.0 mL PFS) administered at Baseline, Week 1, 2, 3 and 4, then 
4 weeks later at Week 8.
Treatment Period 2

secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from Week 12 to 
Week 52 (last dose on Week 48).
Group 3: placebo
Treatment Period 1

placebo (2 × 1.0 mL PFS) administered at Baseline, Week 1, 2, 3 and 4, then 4 weeks later 
at Week 8.
Treatment Period 2

secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) administered every 
4 weeks from Week 12 to Week 52 (last dose on Week 48), OR

secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from Week 12 to 
Week 52 (last dose on Week 48).


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Figure 3-1
Study design
* Randomization
** RE-randomization for placebo group
 PE = primary endpoint, SE = Secondary endpoints
During the study, patients will be required to self-administer secukinumab or placebo at the 
study site from Baseline to Week 12 (Treatment Period 1) and either at home or at the study 
center from Week 12 to end of study (last administration at Week 48) in Treatment Period 2 
(see Table 6-1 and Table 6-2 for the timing of study treatment administrations).
On each treatment day, 2 s.c. injections will be administered via PFSs. This is necessary to 
maintain the blind since secukinumab is supplied in 1.0 mL PFSs each containing 150 mg 
secukinumab i.e. secukinumab 150 mg is supplied as 1 PFS and secukinumab 300 mg as 
2 PFSs. Placebo to secukinumab is also available in 1.0 mL PFSs to match the active drug.
Patients will be allowed to continue background medications in accordance with the study 
inclusion/exclusion criteria (Section 4). In patients taking NSAIDs, the daily NSAID intake 
will be recorded according to ASAS recommendations (Appendix 8) up to Week 52.


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3.2
Rationale for study design
As described in Section 1, the latest GRAPPA treatment guidelines for axial disease (Coates 
et al 2016) are derived from diagnostic criteria, screening, monitoring and response to therapy 
in AS since these data are not available for AxPsA. The effectiveness of biologics in the 
treatment of AxPsA has been poorly assessed and so there is an unmet need for further 
clinical studies of biologics in patients with AxPsA in order to evaluate their efficacy in this 
population, which has its own distinct radiographic features.
To address unmet medical needs, this randomized, double-blind, double-dummy, parallel-
group 52-week study will evaluate the efficacy and safety of secukinumab 150 mg or 300 mg 
compared to placebo in patients with AxPsA. Specifically it will be performed only in patients 
who failed to respond to at least 2 NSAIDs over a 4 week period, which is in accordance with 
ASAS recommendations for the treatment of axial SpA as described in Section 1. The cut-off 
point (BASDAI score ≥4) for the definition of moderate to severe disease activity has been 
considered an appropriate criterion adopted from AS for axial disease in PsA. The study 
should provide evidence on the ability of secukinumab 150 mg or 300 mg to improve clinical 
 outcomes in AxPsA patients.
According to the Recommendations issued by the GRAPPA, in the absence of adequate 
studies in patients with AxPsA, criteria and outcome measures developed for AS have been 
accepted by consensus for use in AxPsA (Nash et al 2014). Therefore, the ASAS 20 
improvement criteria have been chosen as primary endpoint for the present study. Week 12 
was chosen to measure the primary endpoint to keep the exposure to placebo for patients in 
the control group to an acceptable level and still allowing patients in the verum groups to 
develop a stable treatment response.
The design used in this study is in alignment with Phase 3 trials of other biologics including 
secukinumab in this disease family and also in compliance with the European Medicines 
Agency (EMA) guidelines on PsA trials (EMA 2005). Treatment data up to 52 weeks is being 
generated to demonstrate long-term efficacy on signs, symptoms, structure, physical function 
and PROs, and to support the safety data in this population. 
The patient population is described in more detail in Section 4.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The dose (150 mg and 300 mg), dose regimen (weekly from Baseline to Week 3, monthly 
from Week 4 to Week 52), formulation (liquid in PFSs) and route of administration (s.c.) for
secukinumab used in this study are supported by the comprehensive PsA (including the 
pivotal Phase 3 CAIN457F2306 (Mease et al 2014) and CAIN457F2312 (Mc Innes et al 2015)
studies) and AS (including the pivotal Phase 3 CAIN457F2305 and CAIN457F2310 studies
(Baeten et al 2015)) clinical trial program that demonstrated the efficacy, tolerability and 
safety of secukinumab. Furthermore, secukinumab 150 mg and 300 mg are approved in 
Europe (since Nov 2015) for the treatment of PsA and AS.


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Overall, the Phase 3 studies in PsA (CAIN457F2306 (Mease et al 2014) and CAIN457F2312
(Mc Innes et al 2015) provided evidence that secukinumab 150 mg regimen is efficacious and 
demonstrates clinically meaningful improvement in all clinical domains of PsA. These 
domains include, signs and symptoms (both for arthritic and skin symptoms), structural 
damage, patient reported outcomes, physical function and quality of life. 
 
 
 
 
 
 
Pre-filled syringes have been selected for secukinumab s.c. administration in this study as 
these have been successfully used in the Phase 3 clinical studies in moderate-to-severe plaque 
psoriasis, as well as in the completed Phase 3 clinical studies for PsA (CAIN457F2306 and 
CAIN457F2312), which showed the use of PFSs was safe and well tolerated.
3.4
Rationale for choice of comparator
A placebo group is included in this study up to Week 12. Due to the nature of the disease and 
the primary outcome measure used (to demonstrate secukinumab 300 mg is superior to 
placebo in the achievement of ASAS 20 score at Week 12), a placebo group is necessary to 
obtain reliable efficacy measurements for comparison between the active treatment groups 
and placebo in a controlled fashion up to 12 weeks. The continuation of the placebo group up 
to Week 12 is supported from an ethical standpoint. Firstly, treatment duration of the placebo 
group is kept to a minimum and patients can continue to be treated with a range of 
concomitant treatments. Secondly, the regular assessments of disease activity ensures that 
patients experiencing worsening of their disease in any of the treatment groups can exit the 
study upon their own wish or based on the advice of the investigator at any time. In addition, 
the inclusion of a placebo group is in accordance with health authority guidelines, including 
(EMA 2006), and the parallel-group, placebo-controlled design is in alignment with Phase 3
trials of other biologics in this therapeutic domain as outlined in EMA guidelines (EMA 2006).
Furthermore, all patients randomized to the placebo group in this study will receive active 
treatment with secukinumab for up to 36 weeks (in Treatment Period 2).
3.4.1
Rationale for re-randomization of patients 
Patients randomized to placebo at Baseline will be re-randomized to active treatment with 
secukinumab 150 mg or 300 mg at Week 12 irrespective of achievement of ASAS 20. 
Re-randomization to secukinumab will afford patients an opportunity for prevention against 
further structural damage in the mid to longer term. Progression of structural damage, such as 
progression of bone erosion, has been reported to occur in spite of achievement of clinical
disease outcomes (Mease et al 2014, Mc Innes et al 2015).


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3.6
Risks and benefits 
Secukinumab is currently approved in Japan (since Dec-2014) for the treatment of PsA, as 
well as for the treatment of psoriasis vulgaris in adults not adequately responding to systemic 
therapies (except for biologics). Secukinumab is also approved in Europe (since Nov 2015) 
and the US (since Jan 2016) for the treatment of PsA and AS. Additionally, it is approved
in Europe (since Jan 2015), the US (since Jan 2015) and Canada (since Mar 2015) for the
treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic
therapy or phototherapy (US and Canada only).
As of July 2015, approximately 12 000 subjects have been enrolled in both completed and 
ongoing studies with secukinumab, with over 9 600 having received active drug at doses 
ranging from single and/or multiple doses of 0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg 
s.c. across various indications (including psoriasis, rheumatoid arthritis (RA), AS, PsA, 
multiple sclerosis and uveitis). Overall secukinumab was generally safe and well-tolerated.
The risk profile of secukinumab in AxPsA is informed by the safety experience from 
psoriasis and arthritides trials. 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). 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. Immunogenicity was low with secukinumab and did not 
correlate with hypersensitivity-related AEs or loss of efficacy in any of the indications studied 
to date.
The risk to patients in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring and extensive guidance to the investigators, provided in the current 
version of the Investigator’s Brochure.
4
Population
Male and female patients ≥18 years of age with PsA fulfilling the classification criteria for
PsA (classification criteria for psoriatic arthritis (CASPAR), see Appendix 4) and who are 
naïve to biologic treatment. Patients must report clinical signs of spinal involvement defined 
by presence of inflammatory back pain (IBP) with active disease defined by BASDAI score 
≥4, spinal pain VAS ≥40 (0 to 100 mm scale) and inadequate response to at least 2 NSAIDs 


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over 4 weeks period. Patients may continue pre-study NSAIDs, methotrexate (MTX) and 
corticosteroids at a stable dose from Baseline through to the end of study in accordance with 
the study entry criteria.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Patients must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must provide a written, signed and dated informed 
consent before any assessment is performed.
2. Male or non-pregnant, non-lactating female patients of at least 18 years of age.
3. Diagnosis of PsA classified by CASPAR criteria (Appendix 4). 
4. Active spinal disease defined by BASDAI score ≥4 (Section 6.4.1.5).
5. Spinal pain as measured by VAS ≥40 at Baseline (0 to 100 mm scale) (Section 6.4.1.2).
6. Inadequate response to at least 2 NSAIDs over a 4-week period (at least). 
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator in order to ensure that the study 
population will be representative of all eligible patients.
1. Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process, 
obtained within 3 months prior to Screening and evaluated by a qualified physician.
2. Patients taking high potency opioid analgesics (e.g. methadone, hydromorphone, 
morphine).
3. History of exposure to other IL-17 or IL-23 inhibitor biologic drug(s).
4. History of exposure to previous biologic DMARD(s) (TNF blockers or ustekinumab).
5. Current treatment with DMARD(s) other than MTX.
6. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
randomization.
7. Patients regularly taking NSAIDs as part of their PsA therapy who are not on a stable dose 
for at least 2 weeks before study randomization.
8. Patients regularly taking systemic corticosteroids as part of their PsA therapy who are not 
ona stable dose ≤10 mg/day of prednisone or equivalent for at least 2 weeks before 
randomization. 
9. Patients who are on MTX (≤25 mg/week) who are not on a stable dose for at least 
4 weeks before randomization.
10. Patients on MTX who are not on folic acid supplementation at randomization.
11. Patients who are on disease modifying anti-rheumatic drug(s) (DMARD(s)) other than 
MTX who have not discontinued the DMARD(s) 4 weeks prior to the randomization visit, 
or 8 weeks prior to randomization for patients on leflunomide unless a cholestyramine 
washout has been performed (in which cases 4 weeks applies).
12. Active ongoing inflammatory diseases other than PsA (e.g. inflammatory bowel disease) 
that might confound the evaluation of the benefit of secukinumab therapy.


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14. 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 human 
chorionic gonadotropin (hCG) laboratory test.
15. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant unless they use effective contraception during the study and longer if 
required by locally approved prescribing information (e.g. 20 weeks in the EU). Effective 
contraception is defined either as: 
a.
Barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicide (where available). Spermicides alone are not a barrier method of 
contraception and should not be used alone.
The following methods are more effective than the barrier method and are also 
acceptable: 
b. Total abstinence: When this is in line with the preferred and usual lifestyle of the 
patient (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception).
c.
Female sterilization: had a surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least 6 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.
d. Use of established oral, injected or implanted hormonal methods of contraception, 
intrauterine device or intrauterine system. In case of use of oral contraception women 
should have been stable on the same pill for a minimum of 12 weeks before taking 
study treatment.
e.
Male partner sterilization at least 6 months prior to Screening. For female patients on 
the study, the vasectomized male partner should be the sole partner for that patient.

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 6 months of 
spontaneous amenorrhea as defined by the central laboratory follicle stimulating 
hormone and/or estradiol levels.
16. History of an ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis 
infection as defined by a positive or indeterminate QuantiFERON tuberculosis (TB)-Gold 
test (QFT) at Screening. Patients with a positive test may participate in the study if further 
work up (according to local practice/guidelines) establishes conclusively that the patient
has no evidence of active tuberculosis. If presence of latent tuberculosis is established then 
treatment according to local country guidelines must be initiated. 
17. Use of any investigational drug and/or devices within 4 weeks before randomization or a 
period of 5 half-lives of the investigational drug, whichever is longer.
18. History of hypersensivity to the study drug or its excipient or to drugs of similar chemical 
classes.


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19. Any intramuscular or intravenous (i.v.) corticosteroid treatment within 4 weeks before 
randomization.
20. Previous treatment with any cell-depleting therapies including but not limited to 
anti-CD20, investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-
CD19).
21. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, 
cardiac, infectious or gastrointestinal conditions, which in the opinion of the investigator 
immunocompromises the patient and/or places the patient at unacceptable risk for 
participation in an immunomodulatory therapy. 
22. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥160/95 mmHg), congestive heart failure (New York Heart 
Association status of class III or IV), uncontrolled diabetes.
23. History of clinically significant liver disease or liver injury as indicated by abnormal liver 
function tests (LFTs), i.e. serum glutamic oxaloacetic transaminase (SGOT)/ aspartate 
aminotransferase (AST), serum glutamic pyruvic transaminase (SGPT)/ alanine
aminotransferase (ALT), alkaline phosphatase, or serum bilirubin. The investigator will be 
guided by the following criteria:
a.
Any single parameter must not exceed 2 × upper limit of normal (ULN). A single 
parameter elevated up to and including 2 × ULN should be re-checked once more as 
soon as possible, and in all cases, at least prior to enrollment/randomization, to rule 
out laboratory error. 
b. If the total bilirubin concentration is increased above 2 × ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. In any case, serum 
bilirubin should not exceed the value of 1.6 mg/dL (27 μmol/L).
24. History of renal trauma, glomerulonephritis, or patients with 1 kidney only, or a serum 
creatinine level exceeding 1.5 mg/dL (132.6 μmol/L).
25. Screening total WBC count < 3000/μL, or platelets < 1 00 000/μL or neutrophils 
< 1 500/μL or hemoglobin < 8.5 g/dL (85 g/L).
26. Active systemic infections during the last 2 weeks (exception: common cold) prior to 
randomization.
27. Past medical history record of or current infection with human immunodeficiency virus 
(HIV), hepatitis B or hepatitis C prior to baseline.
28. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for basal cell carcinoma or actinic 
keratosis that have been treated with no evidence of recurrence in the past 3 months, 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been 
removed).
29. Current severe progressive or uncontrolled disease, which in the judgment of the clinical
investigator renders the patient unsuitable for the trial. 
30. Any medical or psychiatric condition which, in the investigator’s opinion, would preclude 
the participant from adhering to the protocol or completing the study per protocol. 
31. History or evidence of ongoing alcohol or drug abuse within the last 6 months before 
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32. Plans for administration of live vaccines during the study period or within 6 weeks 
preceding randomization.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Novartis will supply the following:

Investigational treatment
Secukinumab 150 mg provided in 1.0 ml PFS

Placebo
Secukinumab placebo provided in a 1.0 ml PFS
The PFSs are packed in a double-blinded fashion. The study treatments will be labeled as 
follows:

AIN457 150 mg/1.0 ml/Placebo for dosing until Week 52.
For detailed instructions on the storage of the study treatments, please refer to Section 5.5.3.
5.1.2
Additional treatment
During this study, NSAIDs, MTX, and systemic corticosteroids are permitted as described in 
the sub-sections below as part of the routine medical care and will not be provided by 
Novartis.
Concomitant medications are described in Section 5.5.7 and prohibited medications are 
described in Section 5.5.8.
5.1.2.1
Non-steroidal anti-inflammatory drugs
Patients who are regularly taking NSAIDs (including cyclo-oxygenase 1 (COX-1) or 
cyclo-oxygenase 2 (COX-2) inhibitors) at Screening should be on stable dose for at least 
2 weeks before randomization to be eligible for inclusion in the study. 
Patients must refrain from any NSAID intake during at least 24 hours before a visit involving 
a disease activity assessment.
Patients are required to remain on a stable dose of NSAIDs from Baseline until Week 12.
After Week 12, it is recommended that the patient continues on the same stable dose of 
NSAIDs until Week 52.
The dose of NSAIDs during the study must be recorded on the corresponding electronic case 
report form (eCRF) page.


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5.1.2.2
Methotrexate
Patients who are taking MTX at Screening should be on a stable dose (≤25 mg/week) for at 
least 4 weeks before randomization to be eligible for inclusion in the study and apply folic 
acid supplement to avoid toxic effects. Patients are required to remain on a stable dose of 
MTX (≤25 mg/week) along with a folic acid supplement from Baseline until Week 12. The 
dose may be decreased only due to toxicity. After Week 12, it is recommended that the patient 
continues on the same stable dose of MTX until Week 52.
Folic acid supplementation is required so as to minimize the likelihood of MTX-associated 
toxicity.
The weekly dose of MTX should be taken more than 48 hours before any clinical laboratory 
evaluation.
The dose of MTX during the study must be recorded on the corresponding eCRF page.
5.1.2.3
Corticosteroids
Patients who received any intramuscular or intravenous corticosteroid within 4 weeks prior to 
randomization are NOT eligible to enter this study. Patients who are taking systemic 
corticosteroids at Screening should be on a stable dose ≤10 mg/day of prednisone for at least 
2 weeks before randomization to be eligible for inclusion in the study. The corticosteroids 
conversion table is presented in Table 5-1.
Patients are required to remain on a stable dose of systemic corticosteroids up to a maximum 
daily dosage of 10 mg prednisone equivalent from Baseline until Week 12. After Week 12, it 
is recommended that the patient continues on the same stable dose of corticosteroids until 
Week 52.
The dose of systemic corticosteroids during the study must be recorded on the corresponding 
eCRF page.
Table 5-1
Corticosteroids conversion table for the equivalence of 1 mg of 
cortisone
                                                                                                                                                                                       
Cortisone
1 mg
Prednisone, Prednisolone
0.2 mg
Methylprednisone, Triamcinolone
0.16 mg
Dexamethasone
0.03 mg
   Fludrocortisone
0.08 mg
Deflazacort
0.24 mg
Paramethasone
0.08 mg
Hydrocortisone, cortisol
0.8 mg
Sources: Asare 2007, Colburn 2012, Grover et al 2007, Liu et al 2013, Saviola et al. 2007, Shaikh et al 
2012.


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5.2
Treatment arms
At Baseline, all patients whose eligibility is confirmed will be randomized in a 1:1:1 ratio to 
secukinumab 150 mg (Group 1), secukinumab 300 mg (Group 2) or placebo (Group 3). At 
Week 12, patients randomized to placebo at Baseline (i.e. Group 3) will be re-randomized in a 
1:1 ratio to active treatment with secukinumab 150 mg or secukinumab 300 mg.
Group 1: secukinumab 150 mg 
Treatment Period 1

secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) at Baseline, Week 1, 
2, 3 and 4, then 4 weeks later at Week 8
Treatment Period 2

secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) administered every 
4 weeks from Week 12 to Week 52 (last dose on Week 48)
Group 2: secukinumab 300 mg
Treatment Period 1 

secukinumab 300 mg (2 × 1.0 mL PFS) administered at Baseline, Week 1, 2, 3 and 4, then 
4 weeks later at Week 8.
Treatment Period 2

secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from Week 12 to 
Week 52 (last dose on Week 48)
Group 3: placebo
Treatment Period 1

placebo (2 × 1.0 mL PFS) administered at Baseline, Week 1, 2, 3 and 4, then 4 weeks later 
at Week 8.
Treatment Period 2

secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) administered every 
4 weeks from Week 12 to Week 52 (last dose on Week 48), OR

secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from Week 12 to 
Week 52 (last dose on Week 48)
Patients will be allowed to continue background medications in accordance with the study 
inclusion/exclusion criteria. 
In patients taking NSAIDs, the NSAID intake will be recorded according to ASAS 
recommendations up to Week 12 (see Appendix 8). 
5.3
Treatment assignment and randomization
At Baseline, all eligible patients will be randomized via Interactive Response Technology 
(IRT) in a 1:1:1 ratio to one of the 3 treatment groups: Group 1 (secukinumab 150 mg),
Group 2 (secukinumab 300 mg), or Group 3 (placebo) as described in Section 5.2. The 
investigator or his/her delegate will contact the IRT after confirming that the patient fulfills all 
the inclusion/exclusion criteria. The IRT will assign a randomization number to the patient, 


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which will be used to link the patient to a treatment arm and will specify a unique medication 
number for the first package of study treatment to be dispensed to the patient. The 
randomization number will not be communicated to the caller.
The IRT will be programmed to allow study centers to be informed regarding which kits are 
for home administration versus study center administration. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the study drug(s).
At Week 12, patients in Group 3 will be re-randomized in a 1:1 ratio to secukinumab 150 mg 
or secukinumab 300 mg as also described in Section 5.2.
The randomization scheme for patients will be reviewed and approved by qualified 
randomization expert.
5.4
Treatment blinding
Patients, investigator staff, persons performing the assessments and data analysts will remain 
blinded to the identity of the treatment from the time of randomization until database lock, 
using the following methods: 
1. Randomization data are kept strictly confidential until the time of unblinding and will not 
be accessible by anyone else involved in the study with the exception of the bioanalyst. 
2. The identity of the treatments will be concealed by the use of study treatments in form of 
PFS for s.c. injection, filled with secukinumab or placebo that are identical in appearance.
As the primary endpoint analysis will be performed at Week 12, there will be a database lock 
after all patients have completed Week 12 assessments (Section 9.7). A selected Novartis 
clinical team will be unblinded to the Week 12 results. Summary results may be s hared 
internally and externally; however, individual unblinded patient data will not be disclosed. A 
final database lock will occur when all patients have completed the study.
 
 
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the study.
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.


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5.5.1
Patient numbering
Each patient is uniquely identified by a Patient Number which is composed by the study 
center number assigned by Novartis and a sequential number assigned by the investigator. 
Once assigned to a patient, the Patient Number will not be reused. 
Upon signing the informed consent form (ICF), the patient is assigned the next sequential 
number by the investigator. The investigator or his/her staff will contact the IRT and provide 
the requested identifying information for the patient to register them into the IRT. The site 
must select the case report form (CRF) book with a matching Patient Number from the 
electronic data capture (EDC) system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified that the patient was 
not treated. The reason for not being treated will be entered in the CRF.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the “3” treatment arms. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the patient, 
investigator staff will detach the outer part (tear-off part) of the label from the packaging and 
affix it to the source document (Drug Label Form) for that patient’s unique Patient Number. 
From Week 20, once the home study drug administration applies, patients will be expected to 
perform home drug administrations at the protocol specified time-points. For these cases, the 
Investigator will dispense, supported by the IRT system, an appropriate number of 
investigational treatment packages for home administrations. The patients will record details 
including the date of administration at home in a self-administration log and will return the 
used medication (if in compliance with local rules and guidelines) and medication packaging, 
together with the self-administration log, at their next visit to the study center. Patients will be 
asked to return all unused study drug and packaging at each scheduled study visit and by the 
very latest at the end of the study.
5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment
The study drug must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study drugs must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported following Novartis processes for 
instance to the respective Novartis country pharma organization (CPO) Quality Assurance.
The PFSs sealed in their outer box must be stored in a locked refrigerator between 2°C and 
8°C (36°F and 46°F) and must be carefully controlled in accordance with regulations 
governing investigational medicinal products, local regulations and in accordance with 


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instructions from the Novartis Drug Supply Management or Novartis Drug Supply Chain or 
corresponding service providers. The study drug should be protected from light and must not 
be frozen.
Study drug labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study drug but no information about the 
patient except for the patient number / medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
drug in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging latest at the end of the study or at the time 
of discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study drug, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis associate or sponsor designee or to the 
Novartis address provided in the investigator folder at each site.
5.5.3.2
Handling of additional treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Patients will self-administer secukinumab 150 mg (1 × 150 mg PFS and 1 × placebo PFS), 
secukinumab 300 mg (2 × 150 mg PFSs) or placebo (2 × placebo PFS) by s.c. injection of 
1 mL each. The dosing frequency will be either weekly or every 4 weeks in accordance with 
the administration schedule (Table 6-1 and Table 6-2). The last dose administration will occur 
at Week 48.
Patients will receive instructions and training from study center staff on how to 
self-administer the study drug. The injections up to Week 16 and the subsequent ones 
occurring during a visit will be done by the patient (or caregiver) at the study center, under the 
supervision of the Investigator or study staff (i.e. at Baseline, Weeks 1, 2, 3, 4, and 8 during 
Treatment Period 1; and Week 12, 16, 24, 32, 40 and 48 during Treatment Period 2).
The patient will be instructed on the use of secukinumab via review of instructions for use 
(IFU) for secukinumab PFSs (PFS-IFU). At subsequent visits, the Investigator/qualified study 
center staff will observe the self-administration of secukinumab at the clinic. The injections 
not occurring during a study center visit will be done by eligible patients (or caregiver) at their 
home (Week 20, 28, 36 and 44 during Treatment Period 2). 
All dosages prescribed and dispensed to the patient during the study must be recorded in the 
eCRF.
The patient will document all doses and dates of self-administration at home in a 
self-administration log. Patients are required to return the self-administration log at every visit 
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The Investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the Investigator if he/she 
is unable for any reason to take the study drug as prescribed.
At the beginning of the study, the Investigator/qualified study center staff will determine if 
self-administration is appropriate for the patient, e.g. manual dexterity, ability to follow the 
secukinumab PFS-IFU. If a patient requires a caregiver to administer study drug, the caregiver 
should be trained by the Investigator/qualified study center staff. If a caregiver is not available 
at a particular visit or the patient is having problems with self-administration, the 
Investigator/qualified study center staff may administer the study drug to the patient. However, 
all patients should be trained sufficiently and be comfortable with the study drug self-
administration before the first home administration visit. Patients should be instructed to 
contact the Investigator site staff in case of any issue during study drug home administration.
Records of study drug kits assigned to the patient during the study must be documented.
At each visit, all study assessments, including the completion of PROs, should be completed 
prior to self-injection of the study drug.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Study drug dose adjustments are not permitted. Study drug interruption should be avoided 
with the following exceptions:
Study drug interruption is only permitted if, in the opinion of the investigator, a pa tient 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.
These changes must be recorded on the appropriate CRF page.
5.5.6
Rescue medication
Please refer to Section 5.1.2 for details of the additional treatments (MTX, NSAIDs, and 
corticosteroids) permitted for use alongside secukinumab in this study.
Rescue medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a patient is experiencing either no benefit from participation in 
the trial or a worsening/exacerbation of their disease. Rescue medication must not be used 
before completion of Week 52 assessments. Please see Section 5.5.7 and Section 5.5.8 for 
details on concomitant and prohibited medication for this study. 
If prohibited treatments (as described in Section 5.5.8) are administered prior to completion of 
the Week 52 visit, patients will be discontinued from the study treatment but can continue 
with the study visit assessments until at least Week 12 (i.e. time of primary analysis).
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5.5.7
Concomitant medication
Please refer to Section 5.1.2 for details of the additional treatments (MTX, NSAIDs, and 
corticosteroids) permitted for use alongside secukinumab in this study.
All patients should have had adequate therapeutic trial of (or inadequate therapeutic effect 
with) at least two NSAIDs; defined as at least two NSAIDs over a 4-week period in a total at 
maximum recommended dose unless contraindicated (van der Heijde et al 2011) and keep 
NSAID treatment on a stable dose during the study. 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-2 is NOT allowed after the start of the washout 
period. Live vaccines should not be given until 12 weeks after last study treatment 
administration.
Table 5-2
Prohibited medication
Prohibited medication
Washout period
(before randomization)
Biological immunomodulating agents
Never
Unstable dose of MTX 
4 weeks
Other DMARD (except MTX)
4 weeks
Leflunomide 
8 weeks
Leflunomide with cholestyramine washout 
4 weeks
Unstable dose of NSAIDs (COX1 or COX2 inhibitors) 
2 weeks
Analgesics other than NSAIDs, paracetamol/acetaminophen and
low strength opioids PRN
2 weeks
Systemic corticosteroids > 10 mg prednisone equivalent* 
2 weeks
Unstable dose of systemic corticosteroids ≤10 mg prednisone 
equivalent 
2 weeks
Intra-articular injections 
4 weeks
Intramuscular or intravenous corticosteroid treatment
4 weeks
Any investigational treatment or participation in any interventional
Trial
4 weeks or 5 half-lives 
(whichever is longer)
Live vaccines
6 weeks
Abbreviations: COX = cyclo-oxygenase, DMARD = disease modifying anti-rheumatic drug, 
MTX = methotrexate, NSAIDs = non-steroidal anti-inflammatory drugs, PRN = pro re nata (as needed); 
* See details about corticosteroid management in Section 5.1.2.3.


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5.5.9
Emergency breaking of assigned treatment code
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the investigator contacts the system to break a treatment code for a patient, he/she must 
provide the requested patient identifying information and confirm the necessity to break the 
treatment code for the patient. The investigator will then receive details of the investigational 
drug treatment for the specified patient and a fax or email confirming this information. The 
system will automatically inform the Novartis monitor for the site and the Regional Trial 
Leader (or designee) 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 patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The investigator will 
provide protocol number CAIN457F3302, study drug name if available, patient number, and 
instructions for contacting the local Novartis CPO (or any entity to which it has delegated 
responsibility for emergency code breaks) to the patient in case an emergency unblinding is 
required at a time when the investigator and backup are unavailable.
Study drug must be discontinued after emergency unblinding.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
Study completion is defined as all patients who have been enrolled at Baseline and completed 
the study as described in the protocol.
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
Patients who successfully complete the current study may be given the opportunity to enter an 
extension study. If an extension study is agreed on, it will be described in a separate extension 
study protocol.
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator.
Patients may voluntarily discontinue from the study for any reason at any time. They may be 
considered discontinued if they state an intention to withdraw, fail to return for visits, or 
become lost to follow-up for any other reason.
Study treatment must be discontinued if the investigator determines that continuation of study 
treatment would result in a significant safety risk for a patient.
The following circumstances require study treatment discontinuation:

Withdrawal of informed consent


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
Emergence of the following AEs:

Any severe AE or SAE that is not compatible with administration of study medication, 
including AEs that require treatment with an unacceptable concomitant medication.

Onset of lymphoproliferative disease or any malignancy, except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or non-
invasive malignant colon polyps which are being or have been removed.

Life-threatening infection.

Severe hypersensitivity reaction or anaphylactic reaction.

Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the patient 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 protocol deviation that results in a significant risk to the patient’s safety.
In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given patient if there is a lack of improvement or worsening 
of their symptoms, or if on balance, he/she thinks that continuation would be detrimental to 
the patient’s well-being. 
For patients who discontinue study treatment the CRF should be completed, giving the date 
and primary reason for stopping study treatment.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because the treatment code has been broken, please refer 
to Section 5.5.9.
Efficacy and safety will be assessed in detail at every study visit, and patients who are deemed 
not to be benefiting from the study treatment based upon safety and efficacy assessments by 
the investigator or for any reason on their own accord will be free to discontinue participation 
in the study at any time.
Patients who prematurely discontinue the study should return and complete assessments 
associated with Week 52 visit (4 weeks after the last study treatment, see Table 6-1) and any 
Adverse Events that are treatment emergent should be reported until 12 weeks after last study 
treatment. The final visit should be performed before any new treatment is initiated.
Patients who prematurely withdraw from the study will not be replaced.
5.6.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore, and

Does not want any further visits or assessments, and

Does not want any further study related contacts, and


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
Does not allow analysis of already obtained biologic material.
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in Table 6-
1.
5.6.4
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
During the study, the assessments must be performed as indicated in Table 6-1.
Patients must be seen for all visits on the designated day, or as closely as possible to the 
original planned visit.

For visits scheduled through Week 4, the study treatment should not be administered less 
than 3 days after the previous administration.

For visits scheduled after Week 4, the study treatment should not be administered less than 
14 days after the previous administration.
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Patients who prematurely discontinue the study for any reason should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the final visit will be 
performed. At this final visit, all dispensed investigational product should be reconciled and 
the adverse event (AE) and concomitant medications reconciled on the CRF. If patients refuse 
to return for these assessments or are unable to do so, every effort should be made to contact 
them or a knowledgeable informant by telephone to determine the reason. Documentation of 
attempts to contact the patient should be recorded in the source documentation.
No study assessment will be performed unless patients sign the ICF. Once patient signs the 
ICF, he will be screened for eligibility criteria. Screening will be flexible in terms of the time 
required to washout prior antirheumatic and other medications and will have a duration of up 
to 8 weeks.
During the Screening Visit, initial assessments will be performed as outlined in Table 6-1.
The duration of the washout period will be determined at the Screening Visit. Note: All 
patients evaluated at Screening (Visit 1) for eligibility should not be screen failed on the basis 
of a medication requiring washout, unless the patient will be unable to complete the washout 
in the appropriate time frame before randomization. Patients should be seen for all visits to 
perform the scheduled assessments on the designated day, or as close to is as possible, i.e., not 
exceeding recommended visit window outlined in Table 6-1 and Table 6-2.
If patients do not have a chest X-ray obtained within 3 months preceding the Screening Visit, 
a chest X-ray should be performed. In order to minimize unnecessary exposure to radiation, 
the chest X-ray should only be performed after confirming that the patient meets all 
inclusion/exclusion criteria. In some sites selected by Novartis, the X-ray assessment may be 
replaced by MRI assessment.


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Table 6-1
Assessment schedule
Scr Bsl
Double-blind placebo-
controlled period
(last dose at Week 8)
Double-blind active treatment 
period
(last dose at Week 48)
USV**
Comments
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
EOS/ 
PPD*
* Patients who prematurely discontinue during the 
treatment period should return for assessments 
associated with the Week 52 visit (i.e. 4 weeks after the 
last study treatment).
**Unscheduled visits – assessments at the discretion of 
the investigator
Week
-8
0
1
2
3
4
8
12
16 24
32
40
48
52
Recommended visit 
window (days)
± 2 ± 2 ± 2 ± 2 ± 5 ± 2 ± 5 ± 5 ± 5
± 5
± 5
± 5
Obtain informed consent 
X
Inclusion & exclusion criteria
X
X
Randomization via IRT
X
X#
# At Visit 8, all patients receiving placebo will be re-
randomized to receive 150 mg secukinumab or 300 mg 
secukinumab in a 1:1 ratio
IRT contact such as for 
registration or drug supply 
including home 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration at 
the study center 
X
X
X
X
X
X
X
X
X
X
X
X
Please refer Table 6-2 to for timing of home 
administrations. 
Demography
X
Relevant medical 
history/current medical 
condition
X
X
Wash out 
evaluations/instructions
S
Smoking history 
X


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Scr Bsl
Double-blind placebo-
controlled period
(last dose at Week 8)
Double-blind active treatment 
period
(last dose at Week 48)
USV**
Comments
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
EOS/ 
PPD*
* Patients who prematurely discontinue during the 
treatment period should return for assessments 
associated with the Week 52 visit (i.e. 4 weeks after the 
last study treatment).
**Unscheduled visits – assessments at the discretion of 
the investigator
Week
-8
0
1
2
3
4
8
12
16 24
32
40
48
52
Recommended visit 
window (days)
± 2 ± 2 ± 2 ± 2 ± 5 ± 2 ± 5 ± 5 ± 5
± 5
± 5
± 5
Cardiovascular medical 
history
X
AxPsA medical history and 
previous therapies
X
X
CASPAR criteria
X
X
Physical examination
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
These assessments are source documentation only and 
will not be entered into the CRF.
Height
X
X
Weight
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
QuantiFERON TB-Gold test
X
X
Chest X-ray/MRI 
(for study inclusion)
S
S
If patients do not have a chest X-ray available within 3 
months of Screening, an X-ray should be performed after 
it is certain the patient meets inclusion/exclusion criteria 
in order to minimize unnecessary exposure to X-ray 
radiation. In some sites selected by Novartis, the X-ray 
assessment may be replaced by chest MRI assessment.
Safety laboratory (clinical 
chemistry, hematology, 
urinalysis)
X
X
X
X
X
X
X
Dipsticks will be provided by the central laboratory to the 
sites for local urinalysis assessments
Samples must be obtained fasting.


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Scr Bsl
Double-blind placebo-
controlled period
(last dose at Week 8)
Double-blind active treatment 
period
(last dose at Week 48)
USV**
Comments
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
EOS/ 
PPD*
* Patients who prematurely discontinue during the 
treatment period should return for assessments 
associated with the Week 52 visit (i.e. 4 weeks after the 
last study treatment).
**Unscheduled visits – assessments at the discretion of 
the investigator
Week
-8
0
1
2
3
4
8
12
16 24
32
40
48
52
Recommended visit 
window (days)
± 2 ± 2 ± 2 ± 2 ± 5 ± 2 ± 5 ± 5 ± 5
± 5
± 5
± 5
Lipid lab panel
X
X
X
X
Samples must be obtained fasting. 
Cardiovascular lab panel
X
X
X
X
Electrocardiogram
X
X
X
X
Serum pregnancy test
X
X
Urine pregnancy test
X
X
X
X
X
X
X
Hepatitis B, C or HIV 
serology (only in countries 
where required)
S
Hepatitis B and/or hepatitis C and/or HIV serology testing 
to be performed during screening period only if required 
as per local medical practice or local regulations prior to 
initiation of therapy. These assessments will be 
documented in source records only and will not be 
entered into the eCRF
BASFI
X
X
X
X
X
X
X
X
X
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spinal pain VAS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s global assessment 
of disease activity (VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient's assessment of PsA 
pain (VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Scr Bsl
Double-blind placebo-
controlled period
(last dose at Week 8)
Double-blind active treatment 
period
(last dose at Week 48)
USV**
Comments
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
EOS/ 
PPD*
* Patients who prematurely discontinue during the 
treatment period should return for assessments 
associated with the Week 52 visit (i.e. 4 weeks after the 
last study treatment).
**Unscheduled visits – assessments at the discretion of 
the investigator
Week
-8
0
1
2
3
4
8
12
16 24
32
40
48
52
Recommended visit 
window (days)
± 2 ± 2 ± 2 ± 2 ± 5 ± 2 ± 5 ± 5 ± 5
± 5
± 5
± 5
Physician’s global 
assessment of disease 
activity (VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SPARCC enthesitis index
X
X
X
X
X
X
X
X
X
X
X
78 tender joint count
X
X
X
X
X
X
X
X
X
X
X
76 swollen joint count
X
X
X
X
X
X
X
X
X
X
X
FACIT-Fatigue©
X
X
X
X
X
X
X
X
HAQ-DI©
X
X
X
X
X
X
X
X
X
X
X
ASAS health index
X
X
X
X
X
X
X
X
Prior/concomitant 
medication/non-drug therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs/SAEs (including 
injection site reactions)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs/SAEs occurring after the patient has signed the 
informed consent must be captured on the appropriate 
eCRF page. Any AEs that are treatment emergent should 
be reported until 12 weeks after last study treatment.
Check self-administration log 
S
S
S
S
S
S
Patients must return the self-administration log along with 
all dispensed PFS and drug packaging at every visit, if 
applicable.


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Scr Bsl
Double-blind placebo-
controlled period
(last dose at Week 8)
Double-blind active treatment 
period
(last dose at Week 48)
USV**
Comments
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
EOS/ 
PPD*
* Patients who prematurely discontinue during the 
treatment period should return for assessments 
associated with the Week 52 visit (i.e. 4 weeks after the 
last study treatment).
**Unscheduled visits – assessments at the discretion of 
the investigator
Week
-8
0
1
2
3
4
8
12
16 24
32
40
48
52
Recommended visit 
window (days)
± 2 ± 2 ± 2 ± 2 ± 5 ± 2 ± 5 ± 5 ± 5
± 5
± 5
± 5
Treatment completion form
X
AE = adverse event, ASAS = assessment of spondyloarthritis international society, AxPsA = axial psoriatic arthritis (i.e. psoriatic arthritis with axial involvement), 
BASDAI = Bath ankylosing spondylitis disease activity index, BASFI = Bath ankylosing spondylitis functional index, CASPAR = classification criteria for psoriatic arthritis, 
FACIT-Fatigue© = functional assessment of chronic illness therapy fatigue scale, HAQ-DI© = health assessment questionnaire – disability index, 
 
, IRT = interactive response technology,
, PFS = prefilled syringe, PPD =
premature patient discontinuation, SAE = serious adverse event, SPARCC = Spondyloarthritis Research Consortium of Canada, VAS = visual analog scale
X = assessment to be recorded on clinical database, S = assessment to be recorded on source documentation only


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Table 6-2
Overview of study drug administration for Treatment Period 2
Study Visit
8
9
10
11
12
13
14
Week
12
16
20
24
28
32
36
40
44
48
52
Recommended visit 
window (days)
± 2
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
± 5
Study drug 
administration
All Groups
S
S
H
S
H
S
H
S
H
S
Abbreviations: H = home administration; S = administration at study center
6.1
Information to be collected on screening failures
All patients who have signed informed consent but not entered into the next period will have 
the study completion page for the Screening period, demographics, inclusion/exclusion, and 
serious adverse event (SAE) data collected. Adverse events that are not SAEs will be
followed by the investigator and collected only in the source data.
All patients who have signed informed consent but discontinue prior to first intake of study 
drug on Day 0 (Baseline Visit) are considered to be screen failures. If a patient discontinues
prior to or at Day 0, the reason for screen failure will be entered on the appropriate eCRF page.
For details on completing the eCRF please refer to the CRF completion guideline. In brief the 
Screening information such as the visit date, information on demography, informed consent, 
and the inclusion/exclusion criteria, must be completed. The AE eCRF should be completed 
for any AEs that occurred during the Screening period. Information on withdrawal of consent 
must be completed if consent has been withdrawn during the Screening period. The Death 
eCRF should be completed in the case of death during the Screening period.
For all patients who sign the informed consent and enter into the next period of the study, all 
AEs occurring after the informed consent is signed will be recorded on the AE eCRF page.
At the discretion of Investigators, abnormal test findings if judged clinically significant should 
be recorded after informed consent signature on the AE eCRF page.
6.2
Patient demographics/other baseline characteristics
All Baseline assessments should be performed prior to first study drug administration. These 
may occur during the Screening period or at the Baseline Visit depending on the assessment
(Table 6-1).
6.2.1
Demographic data
Patient demographic data to be collected on all patients include: date of birth, sex, race, 
ethnicity, height, weight, child-bearing potential (for females only), and source of patient
referral.


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6.2.2
Baseline characteristics
6.2.2.1
Psoriatic arthritis history
Patient’s disease history will be collected at the Screening Visit. The information to be 
collected and entered as “AxPsA history” and “prior AxPsA therapies” includes the following:

Date of first diagnosis of AxPsA prior to the Baseline Visit (by a rheumatologist)

Date of first signs and symptoms of AxPsA

Previous treatments of AxPsA and the reason for discontinuation.
6.2.2.2
Smoking history
The current and/or previous use of tobacco products will be recorded, as well as the 
approximate consumption per year. Non-smokers will be advised not to start smoking during 
the study.
6.2.2.3
Co-morbidities – cardiovascular medical history
Any information pertaining to cardiovascular medical history assessed prior to Screening 
should be reported as cardiovascular history in the eCRF. Cardiovascular risk factors should 
also be recorded.
6.2.2.4
Relevant medical history/concurrent medical conditions
Relevant medical history and current medical conditions (not including AxPsA) present prior
to signing the ICF will be recorded in the Medical History eCRF. Whenever possible, 
diagnoses and not symptoms will be recorded.
Significant findings that are observed after the patient has signed the ICF and that meet
the definition of an AE must be recorded in the AE summary pages.
6.2.2.5
Prior and concomitant medications
Prior medications taken within the 6 months preceding the study Screening Visit (Visit 1), any 
other relevant medication taken before 6 months at the discretion of the investigator and any 
concomitant medication irrespective of the start date will be captured in the eCRF.
6.2.2.6
Chest X-ray
If patients do not have a chest X-ray obtained within 3 months preceding the Screening Visit, 
a chest X-ray should be performed. In order to minimize unnecessary exposure to radiation, 
the chest X-ray should only be performed after confirming that the patient meets all 
inclusion/exclusion criteria. In some sites selected by Novartis, the X-ray assessment may be 
replaced by an MRI assessment.
6.2.3
Other baseline characteristics
Baseline characteristic data to be collected for all patients includes (all laboratory tests
are performed centrally except where indicated; see also Table 6-1) the following:


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
Vital signs; hematology, clinical chemistry and urine laboratory tests; fasting laboratory 
tests (glucose, lipid panel,
); cardiovascular panel; electrocardiogram (ECG); 
physical examination, height, weight; TB status (Section 6.5.4). For women of child-
bearing potential, a serum pregnancy test will be performed at Screening and a urine 
pregnancy test will be performed at Baseline. 

Baseline efficacy assessments (see Section 6.4): ASAS components (patient’s global 
assessment of disease activity, patient’s assessment of IBP intensity VAS, BASDAI and 
Bath ankylosing spondylitis functional index (BASFI)); SPARCC; ACR components (78 
tender joint count (TJC), 76 swollen joint count (SJC), physician’s global assessment of 
disease activity, patient’s assessment of PsA pain; other components already captured 
under ASAS components); 
 

Additional PRO assessments not covered under efficacy assessments (see Section 6.6):
HAQ-DI©, Facit-Fatigue© and ASAS health index.
Whenever possible, diagnoses and not symptoms will be recorded.
6.3
Treatment exposure and compliance
All doses of study drug administered will be recorded in the eCRF. Patient compliance to the 
study drug should be assessed by qualified study center personnel at each study visit using
the study kits and documentation regarding study drug dispensation and administration.
Compliance will also be assessed continuously during the conduct of the study by Novartis 
study personnel using medication kits and corresponding documentation. Study drug doses 
and corresponding dates of self-administration at home should be documented in a 
self-administration log. Patients are required to return the self-administration log as well as all 
dispensed study drug at every visit back to the study center for a compliance check.
6.4
Efficacy
All efficacy assessments should be performed prior to administration of the study drug.

Assessment of spondyloarthritis international society (ASAS) responses

Bath ankylosing spondylitis disease activity index (BASDAI)

Bank ankylosing spondylitis functional index (BASFI)

Spinal pain (VAS)

Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index

American College of Rheumatology 20 (ACR 20)
 


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6.4.1
Assessment of spondyloarthritis international society
The ASAS response criteria are presented in full in Appendix 5. The ASAS response 
measures consisted of the following assessment domains (Sieper et al 2009). 
Main ASAS domains:
1. Patient’s global assessment of disease activity measured on a VAS scale (Section 6.4.1.1)
2. Patient’s assessment of IBP, represented by either total or nocturnal pain scores, both 
measured on a VAS scale (Section 6.4.1.2).
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale (Section 6.4.1.6).
4. Morning stiffness, represented by the average of the last 2 questions on the 6-question 
BASDAI regarding morning stiffness as measured by VAS scale (Section 6.4.1.5).
6.4.1.1
Patient’s global assessment of disease activity
The patient’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from ”very good” to ”very poor”, after the question "Considering all the ways 
psoriatic arthritis affects you, please indicate with a vertical mark ( | ) through the horizontal 
line how well you are doing today”. 
6.4.1.2
Patient’s assessment of inflammatory 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?”.
6.4.1.3
ASAS response criteria (ASAS 20)
The ASAS Response Criteria (ASAS 20) was defined as an improvement of ≥20% and ≥1 
unit on a scale of 10 in at least 3 of the 4 main domains and no worsening of ≥20% and ≥1 
unit on a scale of 10 in the remaining domain.
6.4.1.4
ASAS response criteria (ASAS 40)
The ASAS 40 response was defined as an improvement of ≥40% and ≥2 units on a scale of 
10 in at least 3 of the 4 main domains and no worsening at all in the remaining domain.
6.4.1.5
Bath ankylosing spondylitis disease activity index
The BASDAI is the gold standard for measuring and evaluating disease activity in AS 
(Section 17.2). 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. Fatigue
2. Spinal pain
3. Joint pain / swelling


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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. 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 patients 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 secs and 2 mins to complete.
6.4.1.6
Bath ankylosing spondylitis functional index
The BASFI is a set of 10 questions designed to determine the degree of functional limitation 
in those patients with AS. The 10 questions were chosen with a major input from patients with 
AS. The first 8 questions consider activities related to functional anatomy. The final 2 
questions assess the patient’s 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 0 scales 
gives the BASFI score a value of between 0 and 10. 
6.4.2
Spondyloarthritis research consortium of Canada – enthesitis index
The SPARCC (Maksymowych et al 2009) enthesitis index focuses on the clinical evaluation 
and validation of the 16 sites shown in Table 6-3. SPARCC assessments will be performed as 
indicated in the schedule of assessments (Table 6-1). 
Table 6-3
Entheses sites comprising the total spondyloarthritis research 
consortium of Canada enthesitis index
Greater trochanter
R/L
Quadriceps tendon insertion into the patella
R/L
Patellar ligament insertion into the patella and tibial tuberosity
R/L
Achilles tendon insertion
R/L
Plantar fascia insertion
R/L
Medial epicondyles
R/L
Lateral epicondyles
R/L
Supraspinatus insertion
R/L
Abbreviations: R = right, L = left
Note: Tenderness at each site is quantified on a dichotomous basis: 0=non-tender and 1=tender. 
Range of scores: 0 to 16


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6.4.3
American college of rheumatology response
The ACR response (Appendix 9) will be used to determine efficacy (Felson et al 1995). A 
patient is defined as e.g. an ACR 20 responder if, and only if, the following 3 conditions hold:

Patient has a ≥20% improvement in the number of tender joints (based on 78 joints)
(Section 6.4.3.1). 

Patient has a ≥20% improvement in the number of swollen joints (based on 76 joints)
(Section 6.4.3.1).

Patient has a ≥20% improvement in 3 of the following 5 domains:
1. Patient’s global assessment of disease activity (measured on a VAS scale, 0-100) 
(Section 6.4.1.1). 
2. Physician’s global assessment of disease activity (measured on a VAS scale, 0-100) 
(Section 6.4.3.2). 
3. Patient’s assessment of PsA pain (measured on a VAS scale, 0-100) (Section 6.4.3.3) 
4. HAQ-DI© score (Section 6.6.1.1).
5. Acute phase reactant 
An ACR 50 response is defined as a 50% improvement in at least 3 of the 5 measures and a 
50% improvement in the SJC and TJC.
An ACR 70 response is defined as a 70% improvement in at least 3 of the 5 measures and a 
70% improvement in the SJC and TJC.
The ACR response is to be assessed at the visits/time points shown for the components of the 
ACR in Table 6-1.
6.4.3.1
Tender 78 joint count and swollen 76 joint count
Joint counts will be performed by an independent assessor. Whenever possible, the same 
evaluator should perform these assessments at all visits.
The 78 joints to be assessed for tenderness include the following: 

2 temporomandibular, 2 sternoclavicular, 2 acromioclavicular joints

2 shoulders, 2 elbows, 2 wrists

2 first carpometacarpal, 10 metacarpophalangeal, 10 proximal interphalangeal, and 8 distal 
interphalangeal joints of the hands

2 hips, 2 knees, 2 talo-tibial, 2 mid-tarsal, 10 metatarsophalangeal, and 10 proximal 
interphalangeal and 8 distal interphalangeal joints of the feet. 
All of the above (except for the hips) will be assessed for swelling. Joint tenderness and 
swelling are to be graded present (1) or absent (0). 
Synovial fluid and/or soft tissue swelling but not bony overgrowth represents a positive result 
for SJC.
Dactylitis of a digit in the foot or hand counts as 1 tender and swollen joint. 


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Data is recorded for tender and swollen joints (right or left side), i.e. a box (no, yes or not 
applicable) needs to be ticked for all joints. The total number of tender and swollen joints 
(right and left) will be automatically calculated in the eCRF.
6.4.3.2
Physician’s global assessment of disease activity
The physician’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from no disease activity to maximal disease activity, after the question "Considering 
all the ways the disease affects your patient, draw a line on the scale for how well his or her 
condition is today”. To enhance objectivity, the physician must not be aware of the specific 
patient’s global assessment of disease activity, when performing his own assessment on that 
patient.
6.4.3.3
Patient’s assessment of PsA pain
The patient’s assessment of PsA pain will be performed using a 100 mm VAS ranging from 
no pain to unbearable pain after the question “Please indicate with a vertical mark (│) 
through the horizontal line the most pain you had from your psoriatic arthritis today.”


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6.4.7
Appropriateness of efficacy assessments 
Evaluation tools used in this study have been used previously in clinical trials for PsA and AS. 
Evaluation of disease severity based on clinical scoring (ASAS) is commonly used in the 
studied indication.
 
 
 
 
 
 
 


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6.5
Safety
All safety assessments should be performed as indicated in Table 6-1 prior to study drug 
administration. 

Evaluation of AE/SAEs (including injection site reactions)

Physical examination

Vital signs

Height and weight

QuantiFERON TB-Gold test

Electrocardiogram

Laboratory evaluations (hematology, clinical chemistry, urinalysis, lipid panel, 
cardiovascular panel)

Pregnancy and assessment of fertility

Tolerability of secukinumab
Appropriate safety assessments (e.g. evaluation of AEs and SAEs including injection site 
reactions) should be repeated after the dose is administered.
6.5.1
Physical examination
A complete physical examination will be performed that will include the examination of 
general appearance, skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, vascular system and neurological system.
Information for all physical examinations 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 AE eCRF.
6.5.2
Vital signs 
Vital signs (including blood pressure and pulse measurements) will be assessed after the 
patient has been sitting for 5 minutes, with back supported and both feet placed on the floor, 
systolic and diastolic blood pressure will be measured thrice (measurements separated by 
1 to 2 minutes) using a validated device with an appropriately sized cuff and each blood 
pressure measurement will be recorded in the source (Mancia et al 2007). In case the cuff 
sizes available are not large enough for the patient’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. If possible, assessments 
should be performed by the same study site staff member throughout the study.


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Normal blood pressure will be defined as a systolic pressure of 90 to < 120 mmHg, and a 
diastolic blood pressure of 60 to < 80 mmHg under the measurement conditions outlined 
above. Notable blood pressure will be hypertension (systolic blood pressure of ≥140 mmHg 
and/or diastolic blood pressure of ≥ 90 mmHg) or hypotension (systolic blood pressure of 
< 90 mmHg and/or a diastolic blood pressure of < 60 mmHg). A blood pressure indicative of 
prehypertension (systolic blood pressure of 120 to < 140 mmHg and/or diastolic blood 
pressure of 80 to < 90 mmHg) will not be regarded as notable (Chobanian et al 2003).
A normal pulse rate will be defined as a rate of 60 to 100 beats per minute (bpm) under the 
measurement conditions outlined above. Notable pulse rates are a rate below 60 bpm 
(bradycardia) or above 100 bpm (tachycardia).
Whether action needs to be taken to address notable vital signs will be decided by the 
investigator, taking into account the overall status of the patient. No specific action is foreseen 
as part of the study protocol.
6.5.3
Height and weight 
Height in cm and body weight (to the nearest 0.1 kg in indoor clothing) (both without shoes) 
will be measured. 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
QuantiFERON TB-Gold test 
A QuantiFERON TB-Gold test must be performed at the Screening Visit and the results must 
be known prior to randomization to determine the patient’s eligibility for the trial. The test 
will be used to screen the patient population for latent tuberculosis infection. The test will be 
analyzed by the central laboratory. Details on the collection, processing and shipment of 
samples and reporting of results by the central laboratory are provided in the laboratory 
manual.
Patients with a positive test may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that the patient has no evidence of active 
tuberculosis, or if presence of latent tuberculosis is established then treatment according to 
local country guidelines must have been initiated.
6.5.5
Laboratory evaluations
A central laboratory will be used for analysis of all specimens listed below (except urinalysis). 
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 patients with laboratory tests containing clinically significant abnormal values are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 
related AE, is defined.
6.5.5.1
Hematology
Hematology sampling includes hemoglobin, platelet, red blood cell, WBC and differential 
WBC counts will be measured at scheduled visits.


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6.5.5.2
Clinical chemistry
Serum chemistries includes glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), gamma glutamyl transferase (GGT), alkaline phosphatase, sodium, potassium, 
bicarbonate, calcium, phosphorous, total protein, albumin, and uric acid.
6.5.5.3
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.
6.5.5.4
Lipid panel
A lipid profile including high density lipoprotein, low density lipoprotein, cholesterol and 
triglycerides will be measured from a fasting blood sample. 
6.5.5.5
Cardiovascular panel
A cardiovascular profile including lipoprotein (a), apolipoprotein B, apolipoprotein A-1, and 
adiponectin will be measured from a blood sample. 
6.5.6
Electrocardiogram
A standard 12-lead ECG will be performed as indicated in the schedule of assessments (Table 
6-1). The Investigator/qualified site staff must review and initial the tracing. The tracing must 
then be stored with the patient's source documents. If the ECG findings are clinically relevant 
and would prevent the patient from participating in the study (taking into account the patient’s 
overall status as well as the medication profile), the patient should be recorded as a screen 
failure, should NOT be enrolled and should not receive treatment. All ECGs will be 
independently reviewed by a central reader. Instructions for the collection and transmission of 
the ECGs to the independent reviewer will be provided in the ECG Investigator manual. 
Although there is no exclusion criterion specifically based on the ECG, the Baseline ECG 
performed at the Baseline Visit must be reviewed for major abnormalities before dosing at the 
Baseline Visit.
6.5.7
Pregnancy and assessments of fertility
Secukinumab must not be given to pregnant women; therefore effective methods of birth 
control must be used for women of child-bearing potential (see exclusion criteria definitions,
Section 4.2).
A serum β-hCG test will be performed in all women at Visit 1 (Screening). All women who 
are not surgically sterile at Screening will have local urine pregnancy tests as indicated in
Table 6-1. A positive urine pregnancy test requires immediate interruption of study treatment 
until serum β-hCG is performed and found to be negative. If positive, the patient must be 
discontinued from the trial.


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6.5.8
Appropriateness of safety measurements
The safety measures used in this study are reliable and relevant standard measures for a 
biologic in AxPsA. A chest X-ray at Screening (or within 3 months prior to Screening) is 
performed to rule out the presence of a pulmonary malignancy of infectious process in
particular tuberculosis. 
The radiation exposure that results from these safety measurements are estimated to be far 
below 1 mS. For effective radiation doses under 3 mS (300 mrem), the risk is considered to be 
minimal. Therefore, the radiation exposure in this study involves minimal risk and is 
necessary to ensure reliable safety measures before the treatment with a biologic.
6.6
Other assessments
6.6.1
Patient reported outcomes
The impact of secukinumab on various aspects of patients’ health will be assessed using the 
following measures:

Health assessment questionnaire – disability index (HAQ-DI©)

Functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue©)

ASAS health index
The BASDAI, a PRO assessing disease activity, and BASFI, a PRO assessing functional 
limitation, which are part of ASAS are described under efficacy assessments in Section 6.4.1.
6.6.1.1
Health assessment questionnaire – disability index (HAQ-DI©)
The HAQ-DI© was developed by Stanford University and is one of the most widely used 
measures to assess the long-term influence of chronic disease on a patient's level of functional 
ability and activity restriction. The disability assessment component of the HAQ, the 
HAQ-DI©, assesses a patient’s level of functional ability and includes questions of fine 
movements of the upper extremity, locomotor activities of the lower extremity, and activities 
that involve both upper and lower extremities. There are 20 questions in 8 categories of 
functioning including dressing, rising, eating, walking, hygiene, reach, grip, and usual 
activities. The “stem” of each item asks over the past week "Are you able to …" perform a 
particular task. Each item is scored on a 4-point scale from 0 to 3, representing normal 
(normal, no difficulty [0]), some difficulty (1), much difficulty (2), and unable to do (3).
The purpose of the HAQ-DI© in this study is to assess the functional ability of patients with 
PsA.
6.6.1.2
Functional assessment of chronic illness therapy fatigue scale 
(FACIT-Fatigue©)
The FACIT-Fatigue© is a 13-item questionnaire (Cella et al 1993 and Yellen et al 1997) that 
assesses self- reported fatigue and its impact upon daily activities and function.
The purpose of FACIT-Fatigue© in this study is to assess the impact of fatigue on patients 
with PsA.


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6.6.1.3
ASAS health index
The ASAS health index is a disease-specific questionnaire that was developed based on the 
comprehensive international classification of functioning, disability and health (ICF) Core Set 
for AS (Kiltz et al 2014). The ASAS health index is the first disease-specific PRO measure 
aimed at measurement of overall functioning and health based on the ICF in patients with 
SpA. The ASAS health index is a linear composite measure and contains 17 items 
(dichotomous response option: “I agree” and “I do not agree”), which cover most of the ICF 
core set, as presented in Table 6-4.
Table 6-4
Items of the ASAS health index
Item
Categories
ICF number
Pain sometimes disrupts my normal activities. 
Pain
b280 
I find it hard to stand for long.
Maintaining a body position
d415 
I have problems running.
Moving around
d455 
I have problems using toilet facilities. 
Toileting
d530 
I am often exhausted.
Energy and drive
b130 
I am less motivated to do anything that requires 
physical effort.
Motivation
b1301
I have lost interest in sex.
Sexual functions 
b640 
I have difficulty operating the pedals in my car.
Driving 
d475 
I am finding it hard to make contact with people.
Community life 
d910 
I am not able to walk outdoors on flat ground.
Moving around
d455 
I find it hard to concentrate.
Handling stress
d240 
I am restricted in traveling because of my mobility. 
Recreation and leisure
d920 
I often get frustrated.
Emotional functions 
b152 
I find it difficult to wash my hair.
Washing oneself 
d510 
I have experienced financial changes because of 
my rheumatic disease.
Economic self-sufficiency
d870
I sleep badly at night
Sleep
b134
I cannot overcome my difficulties.
Handling stress
d240
Source: Kiltz et al 2014
7
Safety monitoring
7.1
Adverse events
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom or disease) in a patient or clinical 
investigation patient after providing written informed consent for participation in the study 
until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
AE irrespective if a clinical event has occurred.


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The occurrence of AEs must be sought by non-directive questioning of the patient at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying AEs. Alert ranges for laboratory and other test abnormalities are 
included in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the 

study treatment (no/yes), or

other treatment (no/yes) or

both or indistinguishable

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a SAE (see Section 7.2 for definition of SAE)

action taken regarding study treatment
All AEs must be treated appropriately. Treatment may include one or more of the following: 

no action taken (e.g. further observation only) 

study treatment dosage adjusted/temporarily interrupted 

study treatment permanently discontinued due to this AE

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)


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Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification (IN) or an Aggregate Safety Finding. New information might require an update to 
the informed consent and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. Any Adverse Events that are treatment emergent 
should be reported until 12 weeks after last study treatment. This information must be 
recorded in the investigator’s source documents; however, if the AE meets the criteria of an 
SAE, it must be reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any AE (appearance of (or worsening of any pre-existing)) undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.


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Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 12 weeks (84 days) after last administered dose of study 
treatment or 30 days after the patient has stopped study participation (whichever is later) must 
be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced 
after this period should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper SAE Report Form. The investigator must assess the relationship to each specific 
component of study treatment (if study treatment consists of several components) complete 
the SAE Report Form in English, and send the completed, signed form by fax within 24 hours 
after awareness of the SAE to the local Novartis Drug Safety and Epidemiology Department
or via an equal electronic sponsor system (in case applicable as per local processes and 
regulations). 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 CRF documentation at the study site. Follow-up information 
should be provided using a new paper SAE Report Form stating that this is a follow-up to a 
previously reported SAE.
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the treatment code was broken or not and whether the patient 
continued or withdrew from study participation. Each re-occurrence, complication, or
progression of the original event must be reported as a follow-up to that event regardless of 
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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an IN to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / AEs have to be considered during the course 
of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Appendix 2 for complete definitions of liver laboratory triggers and liver 
events.
Every liver laboratory trigger or liver event as defined in Appendix 2 should be followed up 
by the investigator or designated personal at the trial site as summarized below. Detailed 
information is outlined in Appendix 2.
For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation.
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g. disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 


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These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered 
during the course of the study:

Serum event:

confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to Baseline 
during normal hydration status

Urine event

new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Appendix 3 should be followed up 
by the investigator or designated personnel at the trial site as summarized in Appendix 3. 
7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the eCRF irrespective of whether or not associated with an AE/SAE and reported to Safety 
only if associated with an SAE. 
Misuse or abuse will be collected and reported in the safety database irrespective of it being 
associated with an AE/SAE.
Table 7-1
Treatment error types
Treatment error 
type
Document in DAR 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes 
Yes, even if not associated 
with a SAE
DAR: drug administration record


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7.6
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. 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 must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and good clinical practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of patient records, the accuracy of entries on the (e)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. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis CRA organization. Additionally, a central analytics organization may analyze data 
and identify risks and trends for site operational parameters, and provide reports to Novartis 
Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the patient's file. The 
investigator must also keep the original ICF signed by the patient (a signed copy is given to 
the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.


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8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
CRFs using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the EDC system until they have 
been trained. Web based software will be used: no installation procedure will be needed. Each 
site will be authorized by the Administrator to access into the eCRF. Each investigator site 
qualified personnel would be allowed to access to the eCRF by means of a ‘login mask’ 
requiring User ID and Password and it would be possible to read, modify and update only the 
information he/she had previously reported. All pages should report site code and patient code. 
On-line validation programs check for data discrepancies and, by generating appropriate error 
messages, allow the data to be confirmed or corrected before transfer of the data to the CRO
working on behalf of Novartis. The Investigator must certify that the data entered into the 
eCRFs are complete and accurate. After database lock, the investigator will receive a CD-
ROM with patient data for archiving at the investigational site. 
8.3
Database management and quality control 
The CRO working on behalf of Novartis reviews the data entered into the CRFs by 
investigational staff for completeness and accuracy and instructs 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 the CRO working on behalf of Novartis 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 AEs 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).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using 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).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.


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8.4
Data monitoring committee
Not required.
8.5
Adjudication committee
Not required.
9
Data analysis 
Summary statistics for continuous variables will generally include the number of patients (N), 
minimum, lower quartile, mean, median, upper quartile, and maximum. For categorical or 
binary variables, the number and percent of patients in each category will be presented. 
P-values presented will be 2-sided unless otherwise specified.
Inferential efficacy comparisons with placebo will be done on the first 12 weeks of treatment.
Data analyses will be presented by treatment group. Efficacy and safety data for the placebo-
controlled period (or the entire treatment period as appropriate) will be presented by the 
following 3 treatment groups. Patients may be included in more than 1 treatment group for 
some analyses (e.g. exposure-adjusted AEs over the entire treatment period). 
Patients will be randomized to secukinumab 150 mg (Group 1), secukinumab 300 mg 
(Group 2) or placebo (Group 3) as described in Section 5.2 and Section 5.3. 
Note that the treatment groups above for a patient may differ depending on the time period of 
the analysis and whether one assesses the patient for efficacy or safety (see Section 9.1 for 
details).
The analysis will be conducted on all patient data at Week 12 and at the time the trial ends. 
Any data analysis carried out independently by the investigator should be submitted to 
Novartis before publication or presentation.
9.1
Analysis sets
The following analysis sets will be used in this trial:
Randomized set: The randomized set will be defined as all patients who were randomized.
Unless otherwise specified, mis-randomized patients (mis-randomized in IRT) will be 
excluded from the randomized set.
Mis-randomized patients are defined as those patients who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given. Mis-randomized patients are treated as screen failures.
Full analysis set (FAS): The FAS will be comprised of all patients from the randomized set
to whom study treatment has been assigned. Following the intent-to-treat principle, patients 
will be evaluated according to the treatment assigned to at randomization. 
Safety set: The safety set includes all patients who took at least one dose of study treatment 
during the treatment period. Patients will be evaluated according to treatment received.


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Per-protocol set: This set includes all patients who completed the study without a major 
protocol deviation.
9.2
Patient demographics and other baseline characteristics 
9.2.1 Demographics and baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and for all patients in the randomized set. The number and 
percentage of patients in each category will be presented for categorical variables for each 
treatment group and all patients.
Demographic and baseline disease characteristics will be summarized for the variables listed 
in Section 6.2.
9.2.2 Medical history
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term.
Summaries for cardiovascular and psoriasis specific medical history will also be provided.
9.3
Treatments
9.3.1 Study treatment
The analysis of study treatment data will be based on the Safety set. The number of active and 
placebo injections received will be presented by treatment group up to Week 52.
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number and percentage of patients with cumulative exposure levels (e.g. any 
exposure, ≥1 week, ≥2 weeks, ≥3 weeks, ≥4 weeks, ≥8 weeks, etc.) will be presented.
Duration of exposure is defined as the time from first dose of study treatment to the time of 
treatment switch (for patients who switch treatment) or end of treatment period. For patients 
who discontinue this will be the last visit in the corresponding treatment period. 
9.3.2 Prior and concomitant medication
Prior and concomitant medications will be summarized in separate tables by treatment group.
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized 
study treatment and the date of the last study visit will be a concomitant medication, including 
those which were started pre-baseline and continued into the period where study treatment is 
administered.
Medications will be presented in alphabetical order, by Anatomical Therapeutic 
Classification (ATC) codes and grouped by anatomical main group. 


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Tables will show the overall number and percentage of patients receiving at least one 
treatment of a particular ATC code and at least one treatment in a particular anatomical main 
group.
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term.
The number and percentage of patients receiving prior and concomitant PsA therapy will be 
presented by randomized 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 PsA therapies previously.
9.4
Analysis of the primary and key secondary variable(s)
Details of the testing strategy including primary, key secondary and secondary endpoints are 
provided in Section 9.4.1 and Section 9.5.1 and details are provided in the statistical analysis 
plan.
9.4.1
Variable
The primary and key secondary efficacy variable is the proportion of patients with a response 
to treatment as assessed by the ASAS 20 criteria at Week 12.
The analysis of both the primary and key secondary variables will be based on the FAS.
9.4.2
Statistical model, hypothesis, and method of analysis
The statistical hypothesis for ASAS 20 being tested is that there is no difference in the 
proportion of patients fulfilling the ASAS 20 criteria at Week 12 in the secukinumab group 
versus placebo group.
Let p0 denotes the proportion of ASAS 20 responders at Week 12 for placebo group and pj
denotes the proportion in secukinumab (150 mg or 300 mg) treatment group.

1 corresponds to secukinumab 300 mg and 

2 corresponds to secukinumab 150 mg
In statistical terms, the following hypothesis will be tested for primary objective:
H1: p1 = p0, versus HA1: p1 ≠p0
If primary objective is met, the following hypothesis will be tested for the key secondary 
objective:
H2: p2 = p0, versus HA2: p2 ≠p0,
In other words,
H1: Secukinumab (300 mg) treatment group is not different to placebo group with respect to 
ASAS 20 response at Week 12
H2: Secukinumab (150 mg) treatment group is not different to placebo group with respect to 
ASAS 20 response at Week 12


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The primary and key secondary analyses will be conducted via logistic regression with 
treatment and concomitant MTX intake status as factors. Odds ratios, 95% confidence interval 
(CI) and p-values will be presented comparing each secukinumab group to placebo.
Testing strategy
The family-wise error will be set to α=5% (2-sided). H1 is tested at α (2-sided). The graphical 
approach of Bretz (Bretz et al 2009) for sequentially rejective testing procedures is used to 
illustrate the hierarchical testing strategy (Figure 9-1). 
The following hypothesis will be tested sequentially and are included in the hierarchical 
testing strategy and type-I-error will be set such that a family-wise type-I-error of 5% is kept:
The testing sequence will continue to H2 at α (2-sided) only if H1 has been rejected.
Figure 9-1
Testing strategy
Of note, in the description above, rejection of a hypothesis refers to rejection of the two-sided 
hypothesis; however the level of a rejected hypothesis is only passed on according to the 
graphical procedure for the test of another hypothesis if the treatment effect is in favor of 
secukinumab.
9.4.3
Handling of missing values/censoring/discontinuations
Missing data for ASAS20 response and other binary efficacy variables (e.g. ASAS40, 
ACR 20, BASDAI 50, HAQ-DI©, etc.) for data up to Week 12 will be handled by multiple 
imputations. Multiple imputation is a simulation based approach where missing values are 
replaced by multiple Bayesian draws from the conditional distribution of missing data given 
the observed data and covariates, creating multiple completed data sets. These completed data 
sets can then be analyzed using standard methods. Within this analysis the ACR composites
will be imputed and response variables will be derived based on the imputed scores. In the 
multiple imputation analysis the response status will be imputed based on the individual 
treatment arm information.
Continuous variables (e.g. ACR components, 
.) will be analyzed using a
mixed-effects repeated measures model (MMRM) which is valid under the missing at
random assumption. For analyses of these parameters, if all post-Baseline values are
missing then these missing values will not be imputed and this patient will be removed from


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the analysis of the corresponding variable, i.e. it might be that the number of patients
providing data to an analysis is smaller than the number of patients in the FAS.
9.4.4
Sensitivity analyses
Sensitivity analyses and supportive analyses will be conducted in order to provide evidence 
that the results seen from the primary analysis are robust. These analyses will center on the 
deviations in model assumptions, and the treatment of missing data.
In order to determine the robustness of the logistic regression model used for the primary 
analysis, ASAS20 response at Week 12 may also be evaluated using a non-parametric 
analysis of covariance (ANCOVA) model (Koch et al 1998) model with the same independent 
variables as the logistic regression model. In addition, further logistic regression models may 
be conducted which explore the impact of other baseline or disease characteristics on response.
The impact of missing data on the analysis results may be assessed as well by repeating the 
logistic regression model using ways to handle missing data. These may include, but are not 
limited to:
a. Missing assessment as a responder if patient has met the response criteria already at the 
time of drop-out, otherwise non-responder.
b. Observed data analysis
The details will be provided in the statistical analysis plan.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
The secondary efficacy variables are described below. All secondary efficacy variables will be 
analyzed using the FAS population.
9.5.1.1 ASAS 40 at Week 12
Response to ASAS 40 at Week 12 will be evaluated using a logistic regression model with 
treatment and concomitant MTX intake status as factors.
9.5.1.2 BASDAI 50 at Week 12
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 et al 2003;
Rudwaleit et al 2004). 
Response to BASDAI 50 will be evaluated at Week 12 by the logistic model analogous to the 
primary endpoint.
9.5.1.3 Spinal pain (VAS) at Week 12
The patient’s assessment of back pain will be performed using a 100 mm VAS ranging from 
no pain to unbearable pain. 


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Spinal pain assessment will be evaluated over Week 12 by using an ANCOVA model with 
treatment group, visit and concomitant MTX intake status, as factors and baseline VAS as 
continuous covariate.
9.5.1.4 SPARCC enthesitis index at Week 12
The SPARCC (Maksymowych et al 2009) enthesitis index focuses on the clinical evaluation 
and validation of the 16 sites shown in Table 6-3.
SPARCC enthesitis index will be evaluated over Week 12 by using an ANCOVA model with 
treatment group, visit and concomitant MTX intake status, as factors and baseline SPARCC 
index as continuous covariate.
9.5.1.5 Physical function index (HAQ-DI©) at Week 12
See Section 9.5.4.1 for details. 
9.5.1.6 FACIT-Fatigue© at Week 12
See Section 9.5.4.2 for details. 
9.5.1.7 ASAS Health Index at Week 12
See Section 9.5.4.3 for details. 
9.5.1.8 ACR 20 response at Week 12
The ACR response (Appendix 9) will be used to determine efficacy (Felson et al 1995). 
Response to ACR 20 at Week 12 will be evaluated using a logistic regression model with 
treatment and concomitant MTX intake status as factors. 
9.5.2
Testing strategy for secondary variables
The following hypotheses will be tested for secondary variables

H3a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
ASAS40 response at Week 12

H3b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
ASAS40 response at Week 12

H4a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
BASDAI 50 response at Week 12

H4b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
BASDAI 50 response at Week 12

H5a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
spinal pain (VAS) response at Week 12

H5b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
spinal pain (VAS) response at Week 12

H6a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
SPARCC enthesitis index at Week 12


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
H6b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
SPARCC enthesitis index at Week 12

H7a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
HAQ-DI© at Week 12

H7b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
HAQ-DI© at Week 12

H8a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
FACIT-Fatigue© score at Week 12

H8b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
FACIT-Fatigue© score at Week 12

H9a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
ASAS Health index at Week 12

H9b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
ASAS Health index at Week 12

H10a: secukinumab 300 mg treatment group is not different to placebo group with respect 
to ACR 20 response at Week 12

H10b: secukinumab 150 mg treatment group is not different to placebo group with respect 
to ACR 20 response at Week 12
9.5.3
Safety variables
9.5.3.1
Adverse events
Treatment emergent AEs (events started after the first dose of study treatment or events 
present prior to the first dose of study treatment but increased in severity based on preferred 
term) will be summarized. 
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of patients 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 patient reported more than one AE with the same preferred 
term, the AE with the greatest severity will be presented. If a patient reported more than one 
AE within the same primary system organ class, the patient will be counted only once with 
the greatest severity at the system organ class level, where applicable. Serious adverse events 
will also be summarized.
AE summaries may be presented separately by study periods.
As appropriate, the incidence of AEs will be presented per 100 patient years of exposure. 
Separate summaries will be provided for death, SAE, other significant AEs leading to 
discontinuation and AEs leading to dose adjustment (including study treatment 
discontinuation).
A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, may be presented is required.


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For AEs of special interest time-to-event analysis will be performed, as appropriate and as 
described in the statistical analysis plan. Results will be tabulated and the Kaplan-Meier 
estimates for the cumulative rate will be plotted.
9.5.3.2
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 patients with both baseline and post-baseline. 
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 patient’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.
9.5.3.3
Vital signs
Analysis of the vital sign measurements (including blood pressure and pulse 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 patients with both baseline and post-
baseline values.
9.5.4
Health-related quality of life 
Variables related to health-related quality of life (HR-QoL) are described below. All HR-QoL
variables will be evaluated based on FAS.
9.5.4.1
Health assessment questionnaire – disability index at Week 12
The disability index (HAQ-DI©) will be evaluated over Week 12 using an ANCOVA model 
with treatment group, visit and concomitant MTX intake status, as factors and baseline 
HAQ-DI© index as continuous covariate.
9.5.4.2
FACIT-Fatigue© score at Week 12
The FACIT-Fatigue© total score will be evaluated over Week 12 using an ANCOVA model 
analogous to HAQ-DI© analysis.
9.5.4.3
ASAS Health Index at Week 12
The ASAS health index is a linear composite measure and contains 17 items (dichotomous 
response option: “I agree” and “I do not agree”), which cover most of the ICF core set for AS 


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(Kiltz et al 2014). It will be evaluated over Week 12 using an ANCOVA model analogous to 
HAQ-DI© analysis.


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9.8
Sample size calculation
The selected criterion for the primary objective, the ASAS 20 score, is intended to be used in 
patients with axial skeleton involvement. Consequently, secukinumab data available from 
previous studies on this outcome measure, related to AS patients, can be taken into account. 
Compared to PsA patients, in AS patients the peripheral joints involvement is less pronounced. 
Thus the ASAS 20 score for AS patients is expected to capture information entirely related to 
the axial skeleton involvement. Patients with PsA who will be included in the present study, 
are characterized by concomitantly experiencing axial and peripheral joints disease. Thus the 
ASAS 20 score is expected to also reflect the peripheral joints components. 
To assume the magnitude of ASAS 20 response for PsA patients treated with secukinumab 
data from CAIN457F2310 (AS patients) and the CAIN457F2312 (PsA patients) have been 
considered. 
The CAIN457F2310 study compared secukinumab to placebo in AS patients, and the ASAS 
20 response rate at Week 12 was 57% for 150 mg secukinumab and 28% for placebo (300mg 
secukinumab was not tested). These results are a basis to extrapolate the expected results for 
the current study.
In a phase 3 study of Secukinumab in PsA patients, CAIN457F2312, the performance of 300 
mg secukinumab is, compared to 150 mg secukinumab, numerically better in the achievement 
of the ACR 20 score. Assuming comparable trends in treatment response of the spine and the 
peripheral joints, a slightly different response between the 300 mg and the 150 mg treatment 
group 
was 
chosen. 
In 
addition, 
from 
data 
available 
in 
the 
literature 
(Lubrano and Spadaro 2012) it appears that the spinal involvement in PsA is milder compared 
to AS in terms of inflammation and impact on physical function, so that it can be expected 
that PsA patients might more easily achieve an ASAS 20 score compared to AS patients. 


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Similarly we can assume, that placebo response rates in AxPsA patients may be higher 
compared to AS. 
For the 150 mg secukinumab treatment group a response rate of 57% is expected at Week 12. 
For the 300 mg secukinumab treatment group a response rate of 60% is expected at Week 12. 
An overall type I error (2-sided) 5% will be used to control type I error. Since two 
secukinumab doses will be tested versus placebo in a hierarchical manner, no type-I-error 
adjustment is required for each comparison with respect to the primary endpoint (ASAS20 
response at Week 12). To achieve 92% power and assuming conservatively a response rate of 
40% in the placebo group, at least 150 patients per group would be needed under equal 
allocation to show a response rate of 60% in the secukinumab 300 mg group. Using the same 
number of patients per group, the second test will have at least 80% power to detect a 
difference, if the true response rates are 57% in secukinumab 150 mg group and 40% in 
placebo. The above sample size calculation is based on Fisher’s exact test.
To compensate for drop-outs and protocol violations, 165 patients per group (=495 total) 
should be recruited into this trial.
SAS version 9.4 software was used for the calculation of sample size.
10
Ethical considerations 
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed ICF 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.


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Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the IRB/IEC for the trial protocol, written ICF, consent form updates, patient recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those 
involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.


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Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References
Asare K (2007) Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient. 
Pharmacotherapy; 25(11): 1512-28.
Baeten D, Sieper J, Braun J et al; MEASURE 1 Study Group; MEASURE 2 Study Group 
(2015) Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis. N Engl J Med;
373(26):2534-48.
 
Biagioni BJ, Gladman DD, Cook RJ, et al (2014) Reliability of radiographic scoring methods 
in axial psoriatic arthritis. Arthritis Care Res (Hoboken);66(9):1417-22. 
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 28(4):586-604.
Braun J, Pham T, J Sieper, et al for the ASAS Working Group (2003) International ASAS 
consensus statement for the use of anti-tumour necrosis factor agents in patients with
ankylosing spondylitis. Ann Rheum Dis 2003; 62:817–24
 
 
 
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):570-9.


Novartis
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Page 80
Amended Protocol Version v01 (Clean)
Protocol No. CAIN457F3302
 
 
Chen J, Lin S, Liu C (2014) Sulfasalazine for ankylosing spondylitis. Cochrane Database Syst 
Rev; 11:CD004800. 
Chobanian AV, Bakris GL, Black HR, et al (2003) National Heart, Lung, and Blood Institute 
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood 
Pressure; National High Blood Pressure Education Program Coordinating Committee (2003) 
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, 
and Treatment of High Blood Pressure: the JNC 7 report. Hypertension; 42:1206-52. 
 
Coates LC, Kavanaugh A, Mease PJ, et al (2016) Group for research and assessment of 
psoriasis and psoriatic arthritis: treatment recommendations for psoriatic arthritis 2015. 
Arthritis Rheumatol; doi: 10.1002/art.39573 (Epub ahead of print), Accessed 05 Feb 2016. 
Colburn NT (2012) Review of Rheumatology. 1st ed; London:Springer.
Dougados M, Simon P, Braun J, et al (2011) ASAS recommendations for collecting, 
analysing and reporting NSAID intake in clinical trials/epidemiological studies in axial 
spondyloarthritis. Ann Rheum Dis;70(2):249-51.
European Medicine Agency (EMA) (2005) Guideline on clinical investigation of medicinal 
products for the treatment of psoriatic arthritis. Accessed at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00003414.pdf
EMA guidance document (EMA) Note for guidance on choice of control group in clinical 
trials. Accessed at:
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00002925.pdf
Felson DT, Anderson JJ, Boers M, et al (1995) American College of Rheumatology. 
Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum; 38(6):727-35.
Fries JF, Spitz P, Kraines G, Holman H. (1980) Measurement of Patient Outcome in Arthritis.
Arthritis Rheum; 23:137-45.
Gladman DD (2007) Axial disease in psoriatic arthritis. Curr Rheumatol Rep; 9:455-60.
Gladdman DD (2012) Inflammatory spinal disease in psoriatic arthritis: a report from the 
GRAPPA 2010 annual meeting. J Rheumatol; 39(2):418-20.
Gossec L, Smolen JS, Ramiro S, et al (2015) European League Against Rheumatism (EULAR) 
recommendations for the management of psoriatic arthritis with pharmacological therapies: 
2015 update. Ann Rheum Dis; 75(3):499-510.
Grover VK, Babu R, Bedi SPS (2007) Steroid Therapy – Current Indications in Practice. 
Indian J of Anaesth; 51: 389-93.


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Helliwell PS, Hickling P, Wright V (1998) Do the radiological changes of classic ankylosing 
spondylitis differ from the changes found in the spondylitis associated with inflammatory 
bowel disease, psoriasis, and reactive arthritis? Ann Rheum Dis; 57:135–40.
ICH E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited 
Reporting.
Kiltz U, van der Heijde D, Boonen A, et al (2014) The ASAS Health Index (ASAS HI) - a 
new tool to assess the health status of patients with spondyloarthritis. Clin Exp Rheumatol;
32(5 Suppl 85):S-105-8.
Koch GG, Tangen CM, Jung J-W, et al (1998) Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Stat Med; 17(15-16):1863-92.
Liu D, Ahmet A, Ward L, Krishnamoorthy P, et al. (2013) A practical guide to the monitoring 
and management of the complications of systemic corticosteroid therapy. Allergy Asthma 
Clin Immunol; 9(1): 30-54.
Lubrano E, Marchesoni A, Olivieri I, et al (2009) Psoriatic arthritis spondylitis radiology 
index: a modified index for radiological assessment of axial involvement in psoriatic arthritis. 
J Rheumatol; 36:1006-11.
Lubrano E, Spadaro A, Marchesoni A, et al (2011) The effectiveness of a biologic agent on 
axial manifestations of psoriatic arthritis. A twelve months observational study in a group of 
patients treated with etanercept. Clin Exp Rheumatol; 29(1):80-4. 
Lubrano E and Spadaro A (2012) Axial psoriatic arthritis: an intriguing clinical entity or a 
subset of an intriguing disease?. Clin Rheumatol; 31(7):1027-32.
 
 
Maksymowych WP, Mallon C, Morrow S et al (2009) Development and validation of the 
Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index. Ann Rheum 
Dis; 68:948–53.
Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, et al (2007) Guidelines for the 
Management of Arterial Hypertension: The Task Force for the Management of Arterial 
Hypertension of the European Society of Hypertension (ESH) and of the European Society of 
Cardiology (ESC). J Hypertens; 25:1105-87.
Mease PJ, McInnes IB, Kirkham B, et al (2014) Secukinumab, a human anti-interleukin-17A 
monoclonal antibody, improves active psoriatic arthritis and inhibits radiographic progression: 
efficacy and safety data from a phase 3 randomized, multicenter, double-blind, placebo-
controlled study. Oral presentation at: ACR/ARHP Annual Meeting, Boston, MA, USA. 
Presentation number 948.


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McInnes IB, Kavanaugh A, Gottlieb AB, et al (2013) Efficacy and safety of ustekinumab in 
patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, 
placebo-controlled PSUMMIT 1 trial. Lancet; 382(9894):780-9. 
McInnes, Iain B et al (2015) Secukinumab, a human anti-interleukin-17A monoclonal 
antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, 
placebo-controlled, phase 3 trial. Lancet; 386(9999):1137-46. 
 
Official Journal of the European Union. Communication from the Commission – Detailed 
guidance on the collection, verification and presentation of adverse event/reaction reports 
arising from clinical trials on medicinal products for human use (CT-3) 2011/C 172/01. 
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.
Saviola G, Abdi Ali L, Shams Eddin S et al (2007) Compared clinical efficacy and bone 
metabolic effects of low-dose deflazacort and methyl prednisolone in male inflammatory 
arthropathies: a 12-month open randomized pilot study. Rheumatology; 46(6): 994-8.
Shaikh S, Verma H, Yadav N, et al. (2012) Applications of Steroid in Clinical Practice: A
Review. ISRN Anesthesiology; 2012: 1-11.
Sieper J, Rudwaleit M, Baraliakos X et al (2009) The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis.; 
68 Suppl 2:ii1-44.
Taylor W, Gladman D, Helliwell, et al (2006) Classification criteria for psoriatic arthritis. 
Arthritis Rheum; 54:2665-73. 
Van der Heijde D, Sieper J, Maksymowych WP, et al (2011) 2010 Update of the international 
ASAS recommendations for the use of anti-TNF agents in patients with axial 
spondyloarthritis. Ann Rheum Dis; 70 (6): 905-8.
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.


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13
Appendix 1: Clinically notable laboratory values 
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/CRO at the same time that they are 
sent to investigators. Any action based on these laboratory values should be discussed with 
Novartis/CRO personnel.
Table 13-1
Safety analyses: expanded limits and notable criteria
Laboratory variable
Notable criteria
Liver function and related variables
SGOT (AST)
> 3 × ULN
SGPT (ALT)
> 3 × ULN
Bilirubin
> 2 × ULN
Alkaline phosphatase
> 2.5 × ULN
Renal function, metabolic and electrolyte variables
Creatinine (serum)
> 2 × ULN
Hematology variables
Hemoglobin
20 g/L decrease from Baseline
Platelet count
< 100 × 109/L
White blood cell count
< 0.8 × LLN
Neutrophils
< 0.9 × LLN


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Appendix 2: Liver event and laboratory trigger definitions 
and follow-up requirements
Table 14-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers

3 × ULN < ALT/AST 5 × ULN

1.5 × ULN < TBL 2 × ULN
Liver events

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2
Follow-up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN and INR > 
1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the study 
drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 1.5 to ≤2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.


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


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Appendix 4: Classification criteria for psoriatic arthritis
To meet the ClASsification of Psoriatic ARthritis (CASPAR) criteria for diagnosis of 
psoriatic arthritis according to Taylor et al 2006, a subject must have inflammatory articular 
disease (joint, spine or entheseal) and at least 3 points from the following 5 categories:
1. Evidence of current psoriasis, a personal history of psoriasis, or a family history of 
psoriasis (2 points).

Current psoriasis is defined as psoriatic skin or scalp disease present today as judged 
by a rheumatologist or dermatologist.† 

A personal history of psoriasis is defined as a history of psoriasis that may be 
obtained from a patient, family physician, dermatologist, rheumatologist, or other 
qualified health care provider. 

A family history of psoriasis is defined as a history of psoriasis in a first- or second-
degree relative according to patient report.
2. Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis 
observed on current physical examination (1 point).
3. A negative test result for the presence of rheumatoid factor by any method except latex 
(1 point).
4. Either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis 
recorded by a rheumatologist (1 point).
5. Radiographic evidence of juxta-articular new bone formation appearing as ill-defined 
ossification near joint margins (but excluding osteophyte formation) on plain radiographs 
of the hand or foot (1 point).
Total score: _______
(The CASPAR criteria eCRF will autopopulate the total number of points of the CASPAR 
criteria met by the subject. If the total score ≥3, the subject meets CASPAR criteria for PsA 
diagnosis.)
† Current psoriasis is assigned a score of 2; all other features are assigned a score of 1.


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Appendix 5: Assessment of Spondyloarthritis International 
Society (ASAS) criteria
The ASAS response measures consist of the following assessment domains (Sieper et al 2009):
1. Patient’s global assessment of disease activity measured on a VAS scale.
2. Patient’s assessment of IBP, 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 scale.
17.1
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 subjects’ ability to cope with everyday life. A 10 cm 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.
17.2
Bath ankylosing spondylitis disease activity Index (BASDAI)
The gold standard for measuring and evaluating disease activity in AS is the BASDAI. The 
BASDAI consists of a one 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 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 Ankylosing Spondylitis. BASDAI is a quick and simple index (taking 
between 30 secs and 2 mins to complete).


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Appendix 7: Health assessment questionnaire – disability 
index (HAQ-DI©)
The HAQ(Fries et al 1980) is a validated measure of physical disability and functional 
status. It has four dimensions: disability, pain, drug side effects and dollar costs, although, the 
latter three are rarely used in clinical trials. In this trial only the disability dimension will be 
used. The disability dimension consists of 20 multiple choice items concerning difficulty in 
performing eight common activities of daily living; dressing and grooming, arising, eating, 
walking, reaching, personal hygiene, gripping and activities. Patients choose from four 
response categories, ranging from ‘without any difficulty' to 'unable to do'. The ACR 
Rheumatology Committee on Outcome Measures in RA recommends the use of this 
questionnaire in clinical trials.
Scoring of the HAQ©
The HAQ© will be scored in accordance with the recommendation from the developers 
outlined in the “HAQ PACK” from Stanford University, California.
The following coding (Table 19-1) is to be used for the 8 categories of the disability outcome 
dimension:
Table 19-1
Coding for disability outcome dimension
Without ANY Difficulty
0
With SOME Difficulty
1
With MUCH Difficulty
2
UNABLE to do
3
Within each of the 8 categories only the item indicating the most severe impairment 
contributes to the category score. If the patient requires the use of aids, devices, or help from 
another to accomplish any of the activities in an associated category, then the score for that 
category will be assigned the value 2, unless the score is already 3 (i.e. scores of 0 or 1 are 
increased to 2). Associated categories are defined in the “HAQ PACK”. From the scores for 
each category a Standard Disability Index (SDI) is computed by summing the computed 
scores for each category and dividing by the number of categories answered. The SDI is not 
computed if the patient does not have scores for at least 6 categories. This SDI is the HAQ©
score, which will be used in the statistical analyses of this instrument. The range for this score 
is (0, 3).
HAQ© Data Collection
The HAQ© is to be completed by the patients in their local languages, using an electronic 
device. The questionnaires should be completed by the patients in a quiet area free from 
disturbance, and before any visit assessments. Patients should receive no help from family 
members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the patient’s 


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responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a patient has missed a question or given more than one response 
per question, then this should be brought to patient. Incomplete questions should not be 
accepted without first encouraging the patient to complete unanswered questions.
The investigator must complete the patient/visit information on the electronic device and 
ensure that the center number, patient’s number and initials are identical to the Case Record 
Form. As there are no source data for this questionnaire, the data queries will be restricted to 
patient/visit information.


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Appendix 8: ASAS recommendations for collecting, 
analyzing and reporting NSAID intake
Table 20-1
ASAS-NSAID equivalent score
NSAID
Dose comparable to 
150 mg diclofenac
Maximum dose used in 
AS
Consensus
Diclofenac
/
n=60*
150 (150-200)
150
Naproxen
n=57
1000 (1000-1000)
n=59
1000 (1000-1500)
n=47/50†
1000
Aceclofenac
n=15
200 (200-200)
n=14
200 (200-200)
n=29/29
200
Celecoxib
n=61
400 (300-400)
n=60
400 (400-400)
n=47/50
400
Etodolac
n=15
600 (400-800)
n=13
600 (600-600)
n=17/20
600
Etoricoxib
n=36
90 (90-90)
n=37
120 (90-120)
n=42/46
90
Flurbiprofen
n=13
200 (200-300)
n=13
300 (200-300)
n=15/18
200
Ibuprofen
n=54
2400 (1600-2400)
n=54
2400 (2400-2400)
n=39/45
2400
Indometacin
n=57
150 (100-150)
n=58
150 (150-200)
n=42/47
150
Ketoprofen
n=26
200 (200-200)
n=25
200 (200-300)
n=21/23
200
Meloxicam
n=58
15 (15-15)
n=55
15 (15-22.5)
n=42/48
15
Nimesulide
n=8
200 (200-200)
n=9
200 (200-200)
n=16/16
200
Phenylbutazone
n=28
400 (200-500)
n=28
400 (250-600)
n=25/28
400
Piroxicam
n=51
20 (20-20)
n=50
20 (20-40)
n=46/46
20
Tenoxicam
n=17
20 (20-20)
n=16
25 (20-40)
n=18/18
20
Source: Dougados et al 2011
Results of the survey evaluating the opinion of ASAS members about the comparable efficacy of each NSAID with 
150 mg of diclofenac. 
Values given are:
*first row, n-number of ASAS members giving an answer to the question;
second row, median dose in mg (tertiles)
† first row, n=number of ASAS members who have voted in favour of such a dose/the total number of ASAS 
members who have voted; second row, agreed dose.
AS, ankylosing spondylitis; ASAS, Assessment of Spondyloarthritis International Society; NSAID, non-steroidal 
anti-inflammatory drug


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Appendix 9: American College of Rheumatology measures 
and criteria of response
Number of tender joints
Joint counts will be performed by the independent assessor(s) who must be well trained and 
part of the site personnel. Whenever possible, the same evaluator should perform these 
assessments at all visits.
The 78 joints assessed for tenderness include the 2 temporomandibular, 2 sternoclavicular, 
2 acromioclavicular joints, 2 shoulders, 2 elbows, 2 wrists, 2 first carpometacarpal, 
10 metacarpophalangeal, 10 proximal interphalangeal, 8 distal interphalangeal joints of the 
hands, the 2 hip, 2 knee, 2 talo-tibial, 2 mid-tarsal, 10 metatarsophalangeal, 10 proximal 
interphalangeal, and 8 distal interphalangeal joints of the feet.
Joint tenderness and swelling are to be graded present (1) or absent (0).
Number of swollen joints
Joints are to be scored as either swollen (1) or not swollen (0). The 76 joints to be examined 
for swelling are the same as those examined for tenderness, however excluding both hip joints.
Patient’s assessment of psoriatic arthritis pain
On a 100 mm non-anchored VAS, from no pain to unbearable pain.
Patient’s global assessment of disease activity
On a 100 mm non-anchored VAS, from no arthritis activity to maximal arthritis activity, after 
the question “Considering all the ways your arthritis affects you, draw a line on the scale for 
how well you are doing.”
Physician’s global assessment of disease activity
On a 100 mm non-anchored VAS, from no arthritis activity to maximal arthritis activity.
Patient’s assessment of physical function
Health Assessment Questionnaire – HAQ-DI©.
ACR 20/50/70*
A patient will be considered as improved according the ACR 20 criteria* if she/he has at least 
20% improvement in the 2 following measures:

Tender joint count (TJC)

Swollen joint count (SJC)

and at least 3 of the following 5 measures:

Patient’s assessment of pain

Patient’s global assessment of disease activity

Physician’s global assessment of disease activity


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
Health assessment questionnaire (HAQ©) score

 erythrocyte sedimentation rate 
 
ACR 50 = 50% improvement in at least 3 of the 5 measures and 50% improvement in the 
swollen and tender joint count.
ACR 70 = 70% improvement in at least 3 of the 5 measures and 70% improvement in the 
swollen and tender joint count.
Source: Felson et al 1995.

SAP_001.pdf: 
Clinical Development
AIN457/Secukinumab
CAIN457F3302 / NCT02721966
MAXIMISE (Managing AXIal Manifestations in PsorIatic Arthritis with 
SEcukinumab), a randomized, double-blind, placebo-controlled, 
multicenter, 52-week study to assess the efficacy and safety of 
secukinumab 150 mg or 300 mg s.c. in patients with active psoriatic 
arthritis and axial skeleton involvement who have inadequate 
response to non-steroidal anti-inflammatory drugs (NSAIDs)
Statistical Analysis Plan (SAP)
Author:
Trial statistician, 
Document type:
SAP Documentation
Document status:
Final Amendment v3
Release date:
09-Sep-2019
Number of pages:
67
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason 
for update
Outcome for update
Section and title impacted 
(Current)
27-Sep-
16
Prior to 
DB lock
Final v1 
20-Jun-
18
Prior to 
DB lock
Final 
v1
Amendme
nt
As per medical comments
Section 
2.1.3 
Multiple 
assessments within visit 
windows
Section 2.8.1.1 Adverse 
events of special interest 
(AESIs)
Section 2.8.4 Other safety 
data
20-
Nov-18
Prior to 
DB lock
Final 
v2 
Amendme
nt 
As per medical comments
Section 2.1
Data 
analysis 
general 
information
Section 2.1.2 Visits 
windows
Section 
2.3.2
Patient 
demographic and other 
baseline characteristics
Section 
2.5.1 
Primary 
endpoint
 
Section 
2.8.1 
Adverse 
events (AEs)
Section 2.8.4.1 ECG and 
cardiac imaging data


Date
Time 
point
Reason 
for update
Outcome for update
Section and title impacted 
(Current)
Section 
5.5 
Rule 
of 
exclusion 
criteria 
of 
analysis sets
09-Sep-
2019
Prior to 
DB 
Lock
Final 
v3 
Amendme
nt
As per medical comments
Section 
2.1.2 
Visit 
windows
Section 2.2 Analysis sets
Section 
2.3.1 
Patient 
disposition
Section 
2.3.2 
Patient 
demographic and other 
baseline characteristics
Section 
2.8.1 
Adverse 
events
 
 
Section 
4 
Change 
to 
protocol 
specified 
analyses
Section 5.1.2 AE date 
imputation
Section 
5.5 
Score 
derivations and response 
criteria
Section 
5.7 
Rule 
of 
exclusion 
criteria 
of 
analysis sets


Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................7
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................11
2
Statistical methods.............................................................................................................15
2.1
Data analysis general information .........................................................................15
2.1.1
General definitions................................................................................16
2.1.2
Visits windows......................................................................................17
2.1.3
Multiple assessments within visit windows..........................................19
2.2
Analysis sets ..........................................................................................................20
2.2.1
Subgroup of interest ..............................................................................21
2.3
Patient disposition, demographics and other baseline characteristics ...................21
2.3.1
Patient disposition.................................................................................21
2.3.2
Patient demographic and other baseline characteristics........................21
2.3.3
Medical history......................................................................................22
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................22
2.4.1
Study treatment / compliance................................................................22
2.4.2
Prior, concomitant and post therapies...................................................23
2.5
Analysis of the primary objective..........................................................................24
2.5.1
Primary endpoint...................................................................................24
2.5.2
Statistical hypothesis, model, and method of analysis..........................25
2.5.3
Handling of missing values/censoring/discontinuations.......................25
25
2.6
Analysis of the key secondary objective ...............................................................26
2.6.1
Key secondary endpoint........................................................................26
2.6.2
Statistical hypothesis, model, and method of analysis..........................26
2.6.3
Handling of missing values/censoring/discontinuations.......................27
2.7
Analysis of secondary efficacy objective(s)..........................................................27
2.7.1
Secondary endpoints .............................................................................27
2.7.2
Statistical hypothesis, model, and method of analysis..........................28
2.7.3
Handling of missing values/censoring/discontinuations.......................30
2.8
Safety analyses.......................................................................................................30
2.8.1
Adverse events (AEs)............................................................................30


2.8.2
Deaths....................................................................................................32
2.8.3
Laboratory data .....................................................................................33
2.8.4
Other safety data ...................................................................................35
2.9
Pharmacokinetic endpoints....................................................................................37
2.10
PD and PK/PD analyses.........................................................................................37
2.11
Patient-reported outcomes .....................................................................................37
2.12
Biomarkers.............................................................................................................37
38
41
3
Sample size calculation .....................................................................................................42
4
Change to protocol specified analyses ..............................................................................43
5
Appendix ...........................................................................................................................43
5.1
Imputation rules.....................................................................................................43
5.1.1
Study drug.............................................................................................43
5.1.2
AE date imputation ...............................................................................43
5.1.3
Medical history date of diagnosis imputation.......................................45
5.1.4
Concomitant medication date imputation .............................................45
5.2
AEs coding/grading ...............................................................................................47
5.3
Laboratory parameters derivations ........................................................................47
5.4
Statistical methodology and assumptions..............................................................48
5.4.1
Crude incidence and 100*(1-α) % confidence interval.........................48
5.4.2
Odds ratio and 100*(1-α)% confidence interval...................................48
5.4.3
Exposure adjusted incidence rate and 100*(1-α) % confidence 
interval...................................................................................................49
5.5
Score derivations and response criteria .................................................................50
5.5.1
Assessment of Spondyloarthritis International Society (ASAS) ..........50
50
5.5.3
Bath ankylosing spondylitis disease activity index (BASDAI) ............51
5.5.4
Bath ankylosing spondylitis functional index (BASFI)........................51
52
5.5.6
Health assessment questionnaire-disability index (HAQ-DI)...............53
5.5.7
American college of Rheumatology (ACR) response...........................54
5.5.8
ASAS Health Index...............................................................................54
5.5.9
Spondyloarthritis Research Consortium of Canada (SPARCC) 
enthesitis index......................................................................................55
5.5.10
FACIT-Fatigue©...................................................................................55


5.6
Statistical models...................................................................................................56
5.6.1
Primary analysis....................................................................................56
5.6.2
Key secondary analysis.........................................................................60
5.6.1
Secondary analyses ...............................................................................60
5.7
Rule of exclusion criteria of analysis sets..............................................................61
6
Reference...........................................................................................................................66


List of abbreviations
ACR
American College of Rheumatology 
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
ANCOVA
analysis of covariance
AS
Ankylosing spondylitis
ASAS
Assessment of spondyloarthritis international society
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
ATC
Anatomical Therapeutic Classification
AxPsA
Axial psoriatic arthritis (i.e. psoriatic arthritis with axial involvement)
BASDAI
BCC
Bath ankylosing spondylitis disease activity index
Basal cell carcinoma
BMI
Body mass index
Bpm
Beats per minute
CASPAR
Classification criteria for psoriatic arthritis
CI
Confidence interval
CMD
Concomitant medication
CRF
Case Report Form
CRO
Clinical research organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Drug administration record
DMARD
Disease-modifying anti-rheumatic drug
DVU
Disc Vertrebral Unit
ECG
Electrocardiogram
FACIT-Fatigue©
Functional assessment of chronic illness therapy fatigue scale
FAS
Full Analysis Set
GGT/γGT
Gamma glutamyl transferase
HAQ-DI©
Health assessment questionnaire – disability index
HDL
High density lipoprotein
HGB
Hemoglobine
HR-QoL
Health-related quality of life
ICF
Informed consent form
IL
Interleukin
IRT
Interactive response technology
i.v.
Intravenous(ly)
LDL
Low density lipoprotein
LFT
Liver function test 
LLN
Lower limit of normal
LOCF
Last observation carried forward


MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRMM
Mixed-effects repeated measures model
MRI
Magnetic resonance imaging
MTX
Methotrexate
NMQ
Novartis MedDRA Queries
NSAID
Non-steroidal anti-inflammatory drug 
PD
Protocol Deviation
PFS
Prefilled syringe
PsA
Psoriatic arthritis
PPS
Per-protocol set
PSOC
Primary system organ class
PT
Preferred term
QFT
QuantiFERON tuberculosis gold test
RAN
Randomized set
SAE
Serious adverse event 
SAF
Safety set
SAP
Statistical Analysis Plan
s.c.
Subcutaneous(ly)
SCC
Squamous cell carcinoma
SMQ
Standardised MedDRA Queries
SOC
System Organ Class
SPARCC
Spondyloarthritis Research Consortium of Canada
SPP
Safety Profiling-Plan
TB
Tuberculosis
TBL
Total bilirubine
TNF
Tumor necrosis factor
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
White blood cells


1
Introduction
This document describes the planned statistical methods for all safety and efficacy analyses, 
which will be used in the phase IIIb clinical trial AIN457F3302. 
The main purpose of this document is to provide summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
Analyses plan in this document refers to the related statistical analysis sections in clinical 
study report.
Data will be analyzed by Novartis using statistical software SAS version 9.4 according to the 
data analysis section 9 of the study protocol, which is available in Appendix 16.1.1 of the 
CSR. That statistical methodology is described below and any deviations from the protocol are
documented. Additional detailed information regarding the analysis methodology is contained
in the Appendix section 16.1.9 of CSR.
Please refer to the following document:
Clinical Protocol CAIN457F3302
1.1
Study design
This is a 52-week, randomized, double-blind, double-dummy, placebo-controlled, multicenter 
study to assess the efficacy of secukinumab 150 mg or 300 mg in patients with AxPsA who 
have had an inadequate response to two different NSAIDs. The study will consist of two
treatment periods; a double-blind placebo-controlled period from Baseline to Week 12 
followed by a double-blind secukinumab treatment period from Week 12 to Week 52.
The schematic of study design is given in Figure 1.1 below.
Planned number of patients and randomization
A total of 495 patients (165 patients per group) will be recruited to compensate dropouts and 
protocol violators.
Patient eligibility will be assessed during a maximum screening period of 8-weeks. At 
Baseline, all patients whose eligibility is confirmed will be randomized in a 1:1:1 ratio to 
secukinumab 150 mg, secukinumab 300 mg or placebo. At Week 12, patients randomized to 
placebo at Baseline will be re-randomized (1:1) to active treatment with secukinumab 150 mg 
or secukinumab 300 mg.
Group 1: secukinumab 150 mg 
Treatment Period 1
secukinumab 150 mg (1 × 1.0 mL prefilled syringes (PFS)) + placebo (1 × 1.0 mL PFS) at 
Baseline, Week 1, 2, 3 and 4, then 4 weeks later at Week 8.
Treatment Period 2
secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) administered every 
4 weeks from Week 12 to Week 52 (last dose on Week 48).
Group 2: secukinumab 300 mg


Treatment Period 1 
secukinumab 300 mg (2 × 1.0 mL PFS) administered at Baseline, Week 1, 2, 3 and 4, then 4 
weeks later at Week 8.
Treatment Period 2
secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from Week 12 to Week 
52 (last dose on Week 48).
Group 3: placebo
Treatment Period 1
placebo (2 × 1.0 mL PFS) administered at Baseline, Week 1, 2, 3 and 4, then 4 weeks later at 
Week 8.
Treatment Period 2
secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) administered every 
4 weeks from Week 12 to Week 52 (last dose on Week 48), OR
secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from Week 12 to Week 
52 (last dose on Week 48).
Patients, investigator staff, persons performing the assessments and data analysts will remain
blinded to the identity of the treatment from the time of randomization until database lock. No 
stratification at randomization will be performed. 
Primary analysis time point 
The primary and key secondary analyses will be performed at Week 12.
 


Figure 1.1: Study Design
* Randomization
** RE-randomization for placebo group
, PE = primary endpoint, SE = Secondary endpoints
1.2
Study objectives and endpoints
Table 1.2-1
Objectives and related endpoints
Objective
Endpoint
Primary objective
To demonstrate that secukinumab 300 mg 
s.c. is superior to placebo in the achievement 
of ASAS 20 response at Week 12.
Proportion of patients with ASAS 20 
response at Week 12
Key secondary objective
To demonstrate that secukinumab 150 mg 
s.c. is superior to placebo in the achievement 
of ASAS 20 response at Week 12 after 
superiority of 300 mg is established
Proportion of patients with ASAS 20 
response at Week 12, after superiority of 
300 mg is established


Secondary objectives
To evaluate secukinumab 300 mg s.c. versus 
placebo in the achievement of ASAS 40 at 
Week 12
Proportion of patients with ASAS 40 
response at Week 12
To evaluate secukinumab 150 mg s.c. versus 
placebo in the achievement of ASAS 40 at 
Week 12
To evaluate secukinumab 300 mg s.c. versus 
placebo in the achievement of BASDAI 50 
at Week 12
Proportion of patients with BASDAI 50
response at Week 12
To evaluate secukinumab 150 mg s.c. versus 
placebo in the achievement of BASDAI 50 
at Week 12
To evaluate secukinumab 300 mg s.c. versus 
placebo in the reduction of spinal pain 
measured by visual analog scale (VAS) at 
Week 12
Mean change from baseline of spinal pain 
assessed by VAS at Week 12
To evaluate secukinumab 150 mg s.c. versus 
placebo in the reduction of spinal pain 
measured by VAS at Week 12
To evaluate secukinumab 300 mg s.c. versus 
placebo in achieving an improvement in 
Spondyloarthritis Research Consortium of 
Canada (SPARCC) enthesitis index at 
Week 12
Mean change from baseline of SPARCC 
enthesitis index at Week 12.
To evaluate secukinumab 150 mg s.c. versus 
placebo in achieving an improvement in 
SPARCC enthesitis index at Week 12
To evaluate secukinumab 300 mg s.c. versus 
placebo in achieving an improvement in 
health assessment questionnaire disability 
index (HAQ-DI©) at Week 12
Mean change from baseline of health 
assessment questionnaire disability index 
(HAQ-DI©) at Week 12.
To evaluate secukinumab 150 mg s.c. versus 
placebo in achieving an improvement in 
HAQ-DI© at Week 12
To evaluate secukinumab 300 mg s.c. versus 
placebo in achieving an improvement in the 
functional assessment of chronic illness 
therapy fatigue scale (FACIT-Fatigue©) at 
Week 12
Mean change from baseline of functional 
assessment of chronic illness therapy fatigue 
scale (FACIT-Fatigue©) at Week 12
To evaluate secukinumab 150 mg versus 
placebo in achieving an improvement in the 
FACIT-Fatigue© at Week 12


To evaluate secukinumab 300 mg s.c. versus 
placebo in achieving an improvement in the 
ASAS health index at Week 12
Mean change from baseline of ASAS health 
index at Week 12
To evaluate secukinumab 150 mg s.c. versus 
placebo in achieving an improvement in the 
ASAS health index at Week 12
To evaluate secukinumab 300 mg s.c. versus 
placebo based on the proportion of patients 
achieving an ACR 20 response at Week 12
Proportion of patients with ACR 20 
response at Week 12
To evaluate secukinumab 150 mg s.c. versus 
placebo based on the proportion of patients 
achieving an ACR 20 response at Week 12
To evaluate the safety and tolerability of 
secukinumab
Overall safety, as measured by frequency 
and severity of adverse events and changes 
in laboratory, vital signs and ECG values 
from baseline




2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis and/or by the designated CRO. It is planned that the 
data from all centers that participate in this protocol will be used for analysis. Analysis 
datasets and statistical outputs will be produced using the most recent SAS® Version 9.4 (SAS 
Institute Inc., Cary, NC, USA), and stored in Novartis global programming & statistical 
environment (GPS).
As the primary endpoint analysis will be performed at Week 12, there will be a database 
freeze after all patients have completed Week 12 assessments. A selected Novartis clinical 
team will be unblinded to the Week 12 results. Summary results may be shared internally and 
externally; however, individual unblinded patient data will not be disclosed. A final database 
lock will occur when all patients have completed the study.
Summary statistics for continuous variables will include number of patients (N), mean, 
standard deviation, minimum, lower quartile, median, upper quartile, maximum. Summary 
statistics for discrete variables will be presented in the number and percent of patients in each 
category. Summary statistics will also be presented graphically wherever applicable. 
If not otherwise specified, p-values and confidence interval (CI) will be presented as two-
sided. Unless otherwise stated, the default level of significance will be set to 5% (two-sided, 
family-wise type-I-error).
Data analyses will be presented by treatment group. Efficacy and safety data for the placebo-
controlled period (or the entire treatment period as appropriate) will be presented by the 
following 3 treatment groups. Patients may be included in more than one treatment group for 
some analyses (e.g. exposure-adjusted adverse events over the entire treatment period).
Eligible patients will be randomized to secukinumab 150 mg (Group 1), secukinumab 300 mg 
(Group 2) or placebo (Group 3) for the first 12 weeks. Note that the treatment groups for a 
patient may differ depending on the time period of the analysis and whether one assesses the 
patient for efficacy or safety.


The analysis will be conducted on all patients’ data at Week 12 and at the time, the trial ends
(Week 52). 
Comparative efficacy data
Comparative efficacy analyses (i.e. inferential efficacy comparisons with placebo) will focus
on the time period when both active drug and the placebo are given in a manner suitable for
making comparisons (i.e., first 12-weeks of treatment). Comparative efficacy will be 
performed based on the FAS population using the randomized treatment. After week 12 till
week 52, the efficacy endpoints will be summarized descriptively or otherwise specified using 
inferential analysis, on the FAS population.
2.1.1
General definitions
Study treatment: Study treatment refers to:  
Secukinumab 150 mg provided in 1 ml PFS or Secukinumab placebo provided in 1 ml PFS.
Study treatment start and end date: Study treatment start date is defined as the first date 
when a non-zero dose of study drug is administered and recorded on the Drug Administration 
Record (DAR) CRF page. Similarly, study drug end date is defined as the last date when a 
non-zero dose of study drug is administered and recorded on the DAR CRF page of the core 
study.
Study day: Study day will be calculated as (event date – study drug start date + 1 day) for 
events that occurred on or after study drug start date (e.g., visit, lab samples, AEs). For events 
prior to study drug start date (e.g., time of diagnosis), study day will be negative and 
calculated as (event date – study drug start date). Note that study drug start date is study day 1 
and the day before study drug start date is study day -1 (i.e. no study day 0).
Due to the study drug dosing schedule, one month will be considered as 28 days. However, 
for “time since event” data (e.g., medical history), one month will be considered as 365.25/12 
days for events that occurred prior to study Day 1. Time from events prior to the start of study 
drug, e.g., time since diagnosis, is calculated as the difference between the start date of study 
drug and the date of prior event. 
Note that, the first dose day is Day 1, and the day before the first dose day is counted as Day -
1 (not Day 0).
Baseline and post baseline: In general, a baseline value refers to the last measurement made 
prior to administration of the first dose of study treatment. A post-baseline value refers to a 
measurement taken after the first dose of study treatment.
Treatment Period: There are 2 treatment periods for this study defined as:
Treatment Period 1 is defined as a 12 Week placebo-controlled, double-blind treatment period 
starting from baseline till Week 12.
Treatment Period 2 is a 40 Week double-blinded active treatment period starting from Week 
12 till Week 52.


Lost to follow up: The patients, whose study completion status is unclear, because they fail to 
appear for study visits without stating an intention to withdraw.
On-treatment period: The period where the patients are exposed to the study treatment. For 
this study, the treatment phase consists of 52 weeks. For this study, the treatment phase 
consists of 52 weeks (for treatment group 1 or group 2) for secukinumab, and 12 weeks of on-
treatment period for placebo and 40 weeks of on treatment for secukinumab (for treatment 
group 3). 
2.1.2
Visits windows
Visit-windows will be used for the data that is summarized by visit; they are based on the 
study evaluation schedule and comprise a set of days around the nominal visit day. For any 
assessment, there are the protocol defined scheduled visits around which visit windows were 
created to cover the complete range of days within the study.  The visit windows are shown in 
Table 2-1. These apply to measurements taken at every visit. For assessments, collected less 
often different visit windows will be applied as detailed below.
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one 
of the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 46 
instead of on Day 29, say, it will be re-aligned to visit window Week 8. In the case of major 
deviations from the visit schedule, or due to unscheduled visits, several assessments of a 
subject may fall in a particular visit window (either scheduled or unscheduled). Statistical 
approaches to handle multiple assessments in a given visit window are specified below.
Of note, subjects are allowed to have gaps in visits.
Table 2-1
Assessment windows for scheduled visits 
Analysis Visit
Week
Scheduled Day
Visit Window
Baseline
BSL
1
-28 days to Day 1*
Week 1
1
8
Day 2-11
Week 2
2
15
Day 12-18
Week 3
3
22
Day 19-25
Week 4
4
29
Day 26-43
Week 8
8
57
Day 44-71
Week 12
12
85
Day 72-104
Week 16
16
113
Day 105-141
Week 24
24
162
Day 142-183
Week 32
32
218
Day 184-253
Week 40
40
289
Day 254-323
Week 48
48
337
Day 324-351
Week 52
52
365
Day 352 onwards
* Baseline measurement before the first drug administration for safety assessments and before the 
randomization for efficacy assessments. For efficacy visit windows, refer to date of randomization.


For parameters, which are not collected at every visit (e.g., FACIT-Fatigue©, HAQ-DI©), 
visit windows defined in Table 2-4 will be combined. For example, if a parameter is measured 
at Week 12 and Week 24 only, Week 12 visit window will extend from Day 2 to Day 104
(combining Week 1 to Week 12 visit windows), Week 24 will extend from Day 105 to Day 
183 (combining Week 16 to Week 24). If more than one assessment falls into the interval, the 
rules defined in Section 2.1.3 below are applied.
Table 2-4a
Drug administration windows for scheduled visits of Exposure Data
The administration of study drug at weeks 20, 28, 36, and 44 is not in relation to a study visit. 
For exposure data, a specific assessment window for those weeks is used in order to account for 
the home administrations at those weeks.
Analysis Visit
Week
Scheduled Day
Visit Window
Baseline
BSL
1*
Week 1
1
8
Day 2-11
Week 2
2
15
Day 12-18
Week 3
3
22
Day 19-25
Week 4
4
29
Day 26-43
Week 8
8
57
Day 44-71
Week 12
12
85
Day 72-99
Week 16
16
113
Day 100-127
Week 20
20
141
Day 128-155
Week 24
24
169
Day 156-183
Week 28
28
197
Day 184-211
Week 32
32
225
Day 212-239
Week 36
36
253
Day 240-267
Week 40
40
281
Day 268-295
Week 44
44
309
Day 296-323
Week 48
48
337
>= 324 Days
 


2.1.3
Multiple assessments within visit windows
When there are multiple assessments in a particular visit window, the following rules are 
applied to select one value “representing” the subject in summary statistics in a visit window 
(See Table 2-2).
For baseline assessment definition, see Section 2.1.1. For post-baseline visit windows, the 
following applies (unless otherwise specified):

for quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen); 

for qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined.

in case qualitative variables are based on quantitative variables, e.g. ACR 20 response, the 
visit will be assigned to the quantitative variable, and this visit will be used for the derived 
qualitative variable. 
Table 2-2
Rules for selecting values for analysis
Timing of measurement
Type of data
Rule
Baseline
All data
The last non-missing measurement made prior to 
or on the date of administration of the first dose of 
study treatment (the reference start date / Day 1). 
If a patient did not receive any dose of study 
treatment, then the randomization date will be 
used. Only date part is considered if just one 
assessment on Day 1.
If there are multiple assessments on Day 1, 
following rules will apply:
a. If assessment time exists,

select the last available measurement 
prior to reference start date/time 
considering time;

if no measurement prior to reference start 
date/time considering time, select the 
earliest measurement post reference start 
date/time considering time.
b. If assessment time does not exist, select the 
available measurement from the lowest CRF visit 
number.


Timing of measurement
Type of data
Rule
Post-baseline efficacy
All data
The measurement closest to the target day will be 
used. In the event two measurements are taken 
equally apart (e.g., 1 day before target date and 1 
day after), the earlier one will be used.
Cases where the same parameter is recorded 
more than once on the same date will be handled 
as follows:

If time of completion exists, the earliest 
measurement will be used;

If time does not exist, the measurement 
from the lowest CRF visit number will be 
used.
2.2
Analysis sets
The following analysis sets will be used in this trial:
Randomized set: The randomized set will be defined as all patients, who were randomized.
Unless otherwise specified, mis-randomized patients (mis-randomized in IRT) will be 
excluded from the randomized set.
Mis-randomized patients are defined as those patients, who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given. Mis-randomized patients are treated as screen failures.
Any in-eligible patient, who has been randomized and treated during the study, should be part 
of Randomized Set and Safety Set but excluded from FAS.
Full analysis set (FAS): The FAS will be comprised of all patients from the randomized set,
to whom study treatment has been assigned. Following the intent-to-treat principle, patients 
will be evaluated according to the treatment assigned to at randomization. 
 
Per-protocol set: This set includes all patients, who completed the study without a major 
protocol deviation.
Safety set: The safety set includes all patients, who took at least one dose of study treatment 
during the treatment period. Patients will be evaluated according to treatment received.


2.2.1
Subgroup of interest
There is no planned subgroup of interest. 
2.3
Patient disposition, demographics and other baseline 
characteristics
Summary statistics will be presented for continuous demographic and baseline characteristics 
for each treatment group and for all patients in the randomized set. The number and 
percentage of patients in each category will be presented for categorical variables for each 
treatment group and for all patients.
2.3.1
Patient disposition
The number and percentage of patients screened will be presented. In addition, the reasons for 
screen failures will be provided. 
The number and percentage of patients in the randomized set who enrolled, and who 
completed the treatment period and who discontinued the study prematurely (including the
primary reason for discontinuation) will be presented at the end of each treatment period 
(Week 12 and Week 52), if appropriate, for each treatment group and all patients.
The number and percentage of patients who took rescue medication and hence discontinued at 
week 12 and week 52 will be presented. For each protocol deviation (PD), the number and 
percentage of patients for whom the PD applies will be tabulated.
PDs will be assigned to TP1 and TP2 based upon the starting dates. These dates are not part of 
the clinical database, therefore they will be provided by the clinical team in a separate file to 
the statistical team for analysis.
2.3.2
Patient demographic and other baseline characteristics
The following demographic and baseline variables, if collected, will be summarized:
Continuous variables:

Age (which is derived from date/year of birth and the screening assessment date)

Height

Weight

Body mass index (BMI) = (body weight in kilograms) / (height in meters)2

For BMI, height and body weight used is the last value prior to randomization. If there 
is no weight recorded prior to taking of study drug, BMI will be missing.
Categorical variables:

Age categories (<65 years, ≥65-<75years, 75 years and older; <45 and >=45 years for 
final analysis)
For final analysis, age groups will be redefined as <45 years, 45 years and older.

Sex



Race

Ethnicity

Child-bearing potential (for females only)

Smoking status at baseline

Source of patient referral
Baseline disease characteristics will also be summarized for the following variables, in two 
separate tables:

History of AxPsA including time (years) since first diagnosis of AxPsA, time since 
first signs and symptoms, previous treatments of AxPsA and reasons for 
discontinuation of these treatments.

CASPAR criteria, Patient’s global assessment of disease activity and other ASAS 
components, SPARCC, ACR components,
 
 HAQ-DI©, FACIT-Fatigue©,
ASAS health index, Spinal pain VAS.
Unless otherwise specified, summary statistics will be presented for continuous variables for
each treatment group and for all patients (total) in the randomized set. The number and
percentage of patients in each category will be presented for categorical variables for each
treatment group and all patients (total) in the randomized set.
Disease severity at baseline will be defined based upon BASDAI score at baseline as 
following:

Group 1: 4 <= BASDAI <= 6.5

Group 2: 6.5 < BASDAI <= 8.5

Group 3: BASDAI >8.5
2.3.3
Medical history
Any condition entered on the relevant medical history / current medical conditions CRF will
be coded using the MedDRA dictionary. They will be summarized by system organ class
(SOC) and preferred term (PT) of the MedDRA dictionary. Summaries for cardiovascular and 
medical history will be provided as well. Smoking history (baseline) will be summarized and 
listed. Analyses will be based on the randomized set.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Study Treatment
The summaries by treatment will be performed by the actual treatment received (as follows)
or treatment sequence for each treatment period. 


Randomized treatment:

AIN457 300 mg

AIN457 150 mg

Placebo
Treatment sequence:

AIN457 300 mg

AIN457 150 mg

Placebo to AIN457 300 mg

Placebo to AIN457 150 mg
The analysis of study treatment data will be based on the safety set. The number of active and
placebo injections will be summarized by treatment group up to Week 12 and Week 52. 
Duration of exposure
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number and percentage of patients with cumulative exposure levels (e.g. any 
exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented.
Duration of exposure for secukinumab groups will be defined as the time from first dose of 
study treatment to the time of treatment end for each treatment period. Duration of exposure 
for the placebo group will be defined as the time from first dose of placebo treatment to the 
time of treatment end in treatment period 1 and the time from first dose of active treatment to 
the time of treatment end in treatment period 2. 
For patients who discontinue, this will be the patient’s last visit in the corresponding treatment 
period.
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 patient years) = duration of exposure (years) / 100
The analyses of duration of exposure described above will be done for the entire study
treatment periods.
Compliance
Compliance will be calculated based on documented study drug administrations and syringe 
counts and displayed by treatment group. 
Compliance is expected to be 100%, unless temporary interruption is needed for safety 
reasons. Compliance will also be assessed by a Novartis monitor using information provided 
by the authorized site personnel.
2.4.2
Prior, concomitant and post therapies
Prior and concomitant therapies
Prior and concomitant medications will be summarized in separate tables by treatment group.


Prior medications are defined as treatments taken and stopped prior to first dose of study
treatment. Any medication given at least once between the day of first dose of randomized
study treatment and the date of the last study visit will be a concomitant medication, including
those, which were started pre-baseline and continued into the period where study treatment is 
administered.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification
(ATC) codes and grouped by anatomical main group. Tables will show the overall number
and percentage of patients receiving at least one treatment of a particular ATC code and at
least one treatment in a particular anatomical main group.
Significant prior and concomitant surgeries and procedures will be summarized by primary
system organ class and MedDRA preferred term.
The number and percentage of patients receiving prior and concomitant PsA therapy will be 
presented by randomized 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 PsA therapies previously.
In addition to that, summary of doses will also be performed for NSAID, MTX and 
corticosteroids. Comparison of median dose with ASAS recommendations will also be 
summarized.
Prior or concomitant medication will be identified by comparing recorded or imputed start
and end dates of medication taken to the reference start date. 
Rescue medication
Rescue medication is defined as medication used to control symptoms that are not adequately 
controlled on study treatment.
No patient will be restricted from receiving necessary rescue medications for lack of benefit
or worsening of disease, if rescue with prohibited treatments occurs prior to completion of 
Week 52 assessments, patients can be discontinued from the study treatment (as per the CTT’s 
discretion) but can continue with the study visit assessments until at least Week 12.
Rescue medication will be summarized similarly to concomitant medication.
2.5
Analysis of the primary objective
The primary objective is to demonstrate that efficacy of secukinumab 300 mg s.c. is superior 
to placebo in the achievement of ASAS 20 response at Week 12.
2.5.1
Primary endpoint
The primary efficacy endpoint is the proportion of patients with ASAS 20 response in
secukinumab 300 mg s.c. and placebo at Week 12. The total spinal pain will be used for the 
calculation of the ASAS response.
The analysis of the primary variable will be based on the FAS.


2.5.2
Statistical hypothesis, model, and method of analysis
The statistical hypothesis for ASAS 20 being tested is that there is no difference in the 
proportion of patients fulfilling the ASAS 20 criteria at Week 12 in the Secukinumab 300 mg 
treatment group versus placebo group.
Let p0 denotes the proportion of ASAS 20 responders at Week 12 for placebo group and p1
denotes the proportion in secukinumab 300 mg treatment group.
In statistical terms, the following hypothesis will be tested:
H1: p1 = p0, versus HA1: p1 ≠p0
In other words,
H1: Secukinumab 300 mg treatment group is not different to placebo group with respect to 
ASAS 20 response at Week 12
The primary analyses will be conducted via logistic regression with treatment and 
concomitant MTX intake status as factors. The Odds ratio, 95% confidence interval (CI) and 
p-value will be presented comparing secukinumab 300 mg treatment group to placebo group 
at Week 12.
The study is said to be positive/declared as success if the lower limit of 95% CI of odds ratio 
is greater than 1.
Summary statistics will also be reported for each treatment group, concomitant MTX intake 
status and by visit. Graphical representation will also be performed.
2.5.3
Handling of missing values/censoring/discontinuations
Missing data for ASAS 20 response for data up to Week 12 will be handled by multiple 
imputations technique. 
Multiple imputation is a simulation based approach where missing values are replaced by
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets. These completed data sets can then 
be analyzed using standard methods. Within this analysis, the ASAS composites will be 
imputed and response variables will be derived based on the imputed scores. In the multiple 
imputation analysis, the response status will be imputed based on the individual treatment arm 
information.


2.6
Analysis of the key secondary objective
The key secondary objective is to demonstrate that efficacy of secukinumab 150 mg s.c. is 
superior to placebo in the achievement of ASAS 20 response at Week 12, after primary 
objective is met i.e., after superiority is demonstrated for secukinumab 300 mg to placebo at 
Week 12.
2.6.1
Key secondary endpoint
The key secondary efficacy endpoint is the proportion of patients with ASAS 20 response in
secukinumab 150 mg s.c. and placebo at Week 12.
The key secondary analyses will only be performed if superiority is demonstrated for 
secukinumab 300 mg to placebo at Week 12. The analysis of the key secondary variable will 
be based on the FAS.
2.6.2
Statistical hypothesis, model, and method of analysis
The statistical hypothesis for ASAS 20 being tested is that there is no difference in the 
proportion of patients fulfilling the ASAS 20 criteria at Week 12 in the Secukinumab 150 mg 
treatment group versus placebo group, after superiority is demonstrated for secukinumab 300
mg to placebo at Week 12.
Let p0 denotes the proportion of ASAS 20 responders at Week 12 for placebo group and p2
denotes the proportion in secukinumab 150 mg treatment group.
If primary objective (superiority of secukinumab 300mg to placebo) is met, the following 
hypothesis will be tested:
H2: p2 = p0, versus HA2: p2 ≠p0
In other words,


H2: Secukinumab 150 mg treatment group is not different to placebo group with respect to 
ASAS 20 response at Week 12
The key secondary analyses will be conducted analogous to the primary analyses, i.e., via 
logistic regression with treatment and concomitant MTX intake status as factors. The Odds 
ratio, 95% confidence interval (CI) and p-value will be presented comparing secukinumab 150 
mg treatment group to placebo group at Week 12.
Summary statistics will also be reported for each treatment group and by visit. Graphical 
representation will also be performed.
Testing strategy
The family-wise error will be set to α=5% (2-sided). H1 is tested at α (2-sided). The graphical 
approach of Bretz (Bretz et al 2009) for sequentially rejective testing procedures is used to 
illustrate the hierarchical testing strategy (Error! Reference source not found.).
The following hypothesis will be tested sequentially and are included in the hierarchical 
testing strategy and type-I-error will be set such that a family-wise type-I-error of 5% is kept:
The testing sequence will continue to H2 at α (2-sided) only if H1 has been rejected.
Figure 2.6-1:
Testing Strategy
Of note, in the description above, rejection of a hypothesis refers to rejection of the two-sided 
hypothesis; however, the level of a rejected hypothesis is only passed on according to the 
graphical procedure for the test of another hypothesis if the treatment effect is in favor of 
secukinumab.
2.6.3
Handling of missing values/censoring/discontinuations
Missing data for ASAS 20 response for data up to Week 12 will be handled by multiple 
imputation technique as defined in Section 2.5.3.
2.7
Analysis of secondary efficacy objective(s)
Refer to Table 1.2-1 of Section 1 for the list of secondary objectives.
2.7.1
Secondary endpoints
All the secondary efficacy evaluation will be performed on FAS population.


Refer to Table 1.2-1 of Section 1 for the list of secondary endpoints.
2.7.2
Statistical hypothesis, model, and method of analysis
The following hypotheses will be tested for secondary variables. All secondary endpoints will 
be tested exploratively outside the confirmatory framework:

H3a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
ASAS 40 response at Week 12

H3b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
ASAS 40 response at Week 12

H4a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
BASDAI 50 response at Week 12

H4b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
BASDAI 50 response at Week 12

H5a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
spinal pain (VAS) response at Week 12

H5b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
spinal pain (VAS) response at Week 12

H6a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
SPARCC enthesitis index at Week 12

H6b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
SPARCC enthesitis index at Week 12

H7a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
HAQ-DI© at Week 12

H7b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
HAQ-DI© at Week 12

H8a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
FACIT-Fatigue© score at Week 12

H8b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
FACIT-Fatigue© score at Week 12

H9a: secukinumab 300 mg treatment group is not different to placebo group with respect to 
ASAS Health index at Week 12

H9b: secukinumab 150 mg treatment group is not different to placebo group with respect to 
ASAS Health index at Week 12

H10a: secukinumab 300 mg treatment group is not different to placebo group with respect 
to ACR 20 response at Week 12

H10b: secukinumab 150 mg treatment group is not different to placebo group with respect 
to ACR 20 response at Week 12


Analysis of secondary endpoints:
o
ASAS 40 at Week 12
Response to ASAS 40 at Week 12 will be analyzed using a logistic regression model with 
treatment and concomitant MTX intake status as factors. The Odds ratio, 95% confidence 
interval (CI) and p-value will be presented comparing secukinumab to placebo.
o
BASDAI 50 at Week 12
BASDAI 50 response is defined as at least a 50% improvement (decrease) in total BASDAI 
score, as compared to the Baseline total BASDAI score. 
Response to BASDAI 50 at Week 12 will be analyzed using a logistic regression model with 
treatment and concomitant MTX intake status as factors. The Odds ratio, 95% confidence 
interval (CI) and p-value will be presented comparing secukinumab to placebo.
o
Spinal pain (VAS) at Week 12
The patient’s assessment of back pain will be performed using a 100 mm VAS ranging from 
no pain to unbearable pain. 
The mean change from baseline of spinal pain at Week 12 will be analyzed by using an 
ANCOVA model with treatment group, visit and concomitant MTX intake status, as factors 
and baseline measurement in VAS as continuous covariate. The adjusted (LS) mean 
difference will be calculated as a point estimate together with the corresponding 95% 
confidence interval and p-value.
o
SPARCC enthesitis index at Week 12
The SPARCC enthesitis index focuses on the clinical evaluation and validation of 16 defined
sites.
The mean change from baseline of SPARCC enthesitis index at Week 12 will be analyzed by 
using an ANCOVA model with treatment group, visit and concomitant MTX intake status, as 
factors and baseline SPARCC index as continuous covariate. The adjusted (LS) mean 
difference will be calculated as a point estimate together with the corresponding 95% 
confidence interval and p-value.
o
Physical function index (HAQ-DI©) at Week 12
Refer to Section 2.11
o
FACIT-Fatigue© score at Week 12
Refer to Section 2.11
o
ASAS Health Index at Week 12
Refer to Section 2.11


o
ACR 20 response at Week 12
Response to ACR 20 at Week 12 will be analyzed using a logistic regression model with 
treatment and concomitant MTX intake status as factors. The Odds ratio, 95% confidence 
interval (CI) and p-value will be presented comparing secukinumab to placebo.
Summary statistics will include relative and absolute frequencies for the binary variable
(ASAS 40, BASDAI 50 and ACR 20) and the number of patients (N), minimum, mean, 
median and maximum for the continuous variable (VAS, SPARCC, etc.,) for each treatment 
group and by visit. Graphical representation will also be performed.
2.7.3
Handling of missing values/censoring/discontinuations
Missing data for ASAS 40, BASDAI 50 and ACR 20 for data up to Week 12 will be handled 
by multiple imputations. 
Continuous variables (Spinal pain (VAS), SPARCC enthesitis index, HAQ-DI©, 
FACIT--Fatigue© score and ASAS Health index) will be analyzed using a mixed-effects
repeated measures model (MMRM) which is valid under the missing at random assumption.
For analyses of these parameters, if all post-Baseline values are missing then these missing
values will not be imputed and this patient will be removed from the analysis of the 
corresponding variable, i.e. it might be that the number of patients providing data to an 
analysis is smaller than the number of patients in the FAS.
2.8
Safety analyses
All the safety analysis will be performed on the Safety set.
Summaries may be performed separately for the initial (Week 1-12) and entire treatment 
periods.
The analyses of the follow-up period will be limited to summaries for treatment-emergent
adverse events, and serious adverse events.
Safety analyses will be performed on treatment received or actual treatment as described
below:
The actual treatment or treatment received for summaries of safety data will differ to the
treatment assigned at randomization only if a subject received the wrong treatment during the
entire study.
For those patients who did not receive the randomized treatment, i.e. who received 
erroneously the wrong treatment at least once, an additional AE listing will be prepared 
displaying which events occurred after the treatment errors and also the relationship with 
study drug.
2.8.1
Adverse events (AEs)
The crude rates of treatment emergent adverse events (i.e. events started after the first
dose of study treatment or events present prior to the first dose of study treatment but
increased in severity based on preferred term, and events until 12 weeks after last dose of 
study treatment) will be summarized by primary system organ class and preferred term. 


In addition, exposure time-adjusted incidence rates including 95% confidence intervals will be 
provided for the entire treatment period to adjust for differences in exposure. A graphical 
display of the crude rates and exposure-adjusted incidence rates will be presented for all AEs 
and serious AEs by system organ class.
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having at least one AE, having an AE in each primary system organ 
class and having each individual AE (preferred term). Summaries (crude rates only) will also 
be presented for AEs by severity and for study treatment related AEs. If a particular AE 
‘severity’ is missing, this variable will be listed as missing and treated as missing in 
summaries. If a subject reported more than one adverse event with the same preferred term, 
the adverse event with the greatest severity will be presented. If a subject reported more than 
one adverse event within the same primary system organ class, the subject will be counted 
only once with the greatest severity at the system organ class level, where applicable.
Separate summaries will be provided for 

adverse events suspected to be related to study drug by the investigator

deaths

serious adverse events

adverse events leading to discontinuation

adverse events leading to temporary dose interruption.

adverse events of special interest
Adverse events will also be reported separately by SMQ according to MedDRA, using a
narrow search. The MedDRA version used for reporting the study will be described in a
footnote.
Follow-up period summaries will be done for all patients in follow-up.
A listing of non-treatment emergent adverse events will be done. These adverse events 
occurred before the first dose of the study treatment. The crude rates will be
provided without treatment information.
For SAEs occurred during screening a listing will be prepared for all patients screened
including screening failures.
Algorithms for date imputations will be provided in Programming Specifications.
For legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment-
emergent adverse events which are not serious adverse events with an incidence greater than 
2% and on treatment emergent serious adverse events and SAE suspected to be related to 
study treatment will be provided by system organ class and preferred term on safety set 
population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:


•
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
•
more than one occurrence will be counted if there is > 1day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by system organ class and preferred 
term.
2.8.1.1
Adverse events of special interest (AESIs)
Safety topics of interest, such as risks defined in the Safety Profiling Plan (SPP), Risk 
Management Plan or topics of interest regarding signal detection or routine analysis are 
defined in the Program Case Retrieval Sheet that is stored in CREDI at the path 
Cabinets/CREDI Projects/A/AIN457A/Integrated Medical Safety.
To this end, the following events will be considered as adverse events of special interest:

Major adverse cardiovascular events (MACE): identified per Novartis MedDra Query 
(NMQ) “MACE (MI, Stroke, Cardiovascular death)”

Inflammatory bowel disease: identified per NMQ “Inflammatory bowel disease”

Infections and infestations: identified per SOC “Infections and infestations”

Malignancy: identified per NMQ “Malignant or unspecified tumors (excluding BCC 
and SCC)”

Hypersensitivity and injection site reaction: identified per SMQ “Hypersensitivity”
The crude rates and exposure-adjusted incidence rates for AESIs will be summarized. In 
addition, listings will be provided presenting which subjects experienced which risk.
Important note: For the evaluation of AESIs risks primary and secondary system organ classes 
of the MedDRA dictionary will be considered. 
Adverse events of special interest analysis will be performed using the time to event analysis, 
the number of patients with an event, number of patients remaining at risk in the treatment 
group, estimate of the event rate and its estimated standard error, as estimable, will be 
provided for each treatment group. Median time to event and quartiles including 95% 
confidence intervals will be provided. The Kaplan-Meier estimates of the cumulative rate for 
each treatment group will be plotted.
2.8.2
Deaths
Separate summaries and listings will be provided for deaths for each treatment period.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.


2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests
(hematology, chemistry and urinalysis). In addition to the individual laboratory parameters the
ratios “total cholesterol / HDL” and “apolipoprotein B / apolipoprotein A1” will be derived
and summarized.
For urinalysis, frequency tables will be presented.
Descriptive summary statistics for the change from baseline to each study visit will be
presented. These descriptive summaries will be presented by laboratory test and treatment
group. Change from baseline will only be summarized for patients with both baseline and
post baseline values and will be calculated as:
change from baseline = post baseline value – baseline value
For each parameter, the maximum change from baseline within each study period will be 
analyzed analogously.
QuantiFERON TB-Gold test will also be analyzed by the central laboratory.
In addition, shift tables will be provided for all parameters to compare a patient’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. Also the shifts to the most extreme laboratory test value within a 
treatment period will be presented as well (including category “high and low”). These 
summaries will be presented by laboratory test and treatment group.
The following laboratory parameters will be analyzed with respect to numerical Common
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2.8-2: hemoglobin,
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL),
gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG).
These summaries will be split into hematology and chemistry for study level reports and the
pooled summary of clinical safety.
Table 2.8-1
CTCAE grades for laboratory parameters to be analyzed
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
HGB decreased
(Anemia)
<LLN – 100 g/L
<100 – 80 g/L
<80 g/L
Platelet count
Decreased
<LLN – 75.0 x10e9 
/L
<75.0 - 50.0 x10e9 
/L
<50.0 – 25.0 x10e9 /L
<25.0 x 10e9 /L
White blood cell
Decreased
<LLN - 3.0 x 10e9 /L <3.0 - 2.0 x 10e9 /L
<2.0 - 1.0 x 10e9 /L
<1.0 x 10e9 /L
Neutrophil count
Decreased
<LLN - 1.5 x 10e9 /L <1.5 - 1.0 x 10e9 /L
<1.0 - 0.5 x 10e9 /L
<0.5 x 10e9 /L
Lymphocyte 
count
Decreased
<LLN - 0.8 x 10e9/L <0.8 - 0.5 x 10e9 /L
<0.5 - 0.2 x 10e9 /L
<0.2 x 10e9 /L


Creatinine 
increased*
>1 - 1.5 x baseline;
>ULN - 1.5 x ULN
>1.5 - 3.0 x
baseline; 
>1.5 - 3.0 xULN
>3.0 baseline;
>3.0 - 6.0 x ULN
>6.0 x ULN
TBL increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALP increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Glucose 
increased
(Hyperglycemia 
)
>ULN - 8.9 mmol/L
>8.9 - 13.9 mmol/L
>13.9 - 27.8 mmol/L
>27.8 mmol/L
Glucose 
decreased
(Hypoglycemia)
<LLN - 3.0 mmol/L
<3.0 - 2.2 mmol/L
<2.2 - 1.7 mmol/L
<1.7 mmol/L
Cholesterol high
>ULN - 7.75 mmol/L
>7.75 - 10.34 
mmol/L
>10.34 - 12.92 mmol/L >12.92 mmol/L
Hypertriglycerid
emia
1.71 - 3.42 mmol/L
>3.42 - 5.7mmol/L
>5.7 - 11.4 mmol/L
>11.4 mmol/L
*Note: for “creatinine increased” the baseline criteria do not apply
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the
worst results (expressed in CTCAE grade) during the treatment phase (either initial or entire)
analyzed. Of note, baseline will be defined as last assessment prior to first dosing in initial
treatment phase. Patients with abnormal laboratory values will be listed and values outside
the normal ranges will be flagged.
Summaries for newly occurring or worsening clinically notable lipid abnormalities will also
be provided cumulatively for each of the following parameters and categories:

HDL:

<=LLN

<0.8 x LLN

LDL, cholesterol, triglycerides:

>=ULN

>1.5 x ULN

>2.5 x ULN
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on
the event criteria given in Table 2.8-3 below:
Table 2.8-2
Liver-related events
Parameter
Criterion
ALT
AST
ALT or AST
TBL
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
>1.5xULN, >2xULN, >3xULN,


ALP
ALT or AST & 
TBL
>2xULN, >3xULN. >5xULN
ALT or AST>3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >8xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN
ALP & TBL
ALP >3xULN & TBL >2xULN
ALP >5xULN & TBL >2xULN
ALT or AST &
TBL & ALP
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law)
Note: elevated ALP may suggest obstruction as a consequence of gall 
bladder or bile duct disease; ALP may also be increased in 
malignancy. FDA therefore terms Hy’s Law cases as indicators of 
pure hepatocellular injury. This does not mean that cases of ALT or 
AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result
in severe DILI.
Notes:
In studies which enroll patients with pre-existing liver disease, baseline LFT may be increased above
ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the abnormality
Criteria
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit.
The criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for
ALT >3xULN and ALT>5x ULN.
Individual subject data listings will be provided for patients with abnormal laboratory data.
Data of patients with newly occurring or worsening liver enzyme abnormalities will be listed
in an additional listing.
Separate summaries and listings will be provided for urine pregnancy results by visit for each 
treatment period. 
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
The following quantitative variables will be summarized: RR interval, PR
interval, QRS duration, QT interval, and Fridericia (QTcF) correction will be presented for 
QTc.
QTcF will summarized by computing the number and percentage of patients (including 95%
confidence intervals for pooled analyses, e.g. DMC or SCS) with:
QTcF > 500 msec
QTcF > 480 msec
QTcF > 450 msec
QTcF changes from baseline > 30 msec
QTcF changes from baseline > 60 msec
PR > 250 msec
Summary statistics will be presented for ECG variables by visit and treatment group.
In addition, shift tables comparing baseline ECG interpretation (normal, abnormal, not
available, total) with the worst on-study interpretation (normal, abnormal, not available, total)
will be provided.


A listing of all newly occurring or worsening abnormalities will be provided, as well as a by
subject listing of all quantitative ECG parameters.
2.8.4.2
Vital signs
Analysis in vital signs measurement using descriptive 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 patients with both baseline and post-baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value
The number and percentage of patients with newly occurring notable vital signs will be
presented. Criteria for notable vital sign abnormalities are provided in Table 2.8-4 below.
Table 2.8-3
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg)
>= 140 mmHg or < 90 mmHg
Diastolic blood pressure (mmHg)
>=90 mmHg or <60 mmHg
Pulse (bpm)
> 100 bpm or <60 bpm
An overview of the safety analyses is described in Table 2.8-1 below.
Table 2.8-4
Overview of analyses on some safety endpoints
Analysis 
period
SAEs
AEs 
Study drug 
related AEs 
AESI
Notables for
vitals/ECG/ 
lab criteria
Day 1 –
Week 12
Crude rates
Exposure 
time 
adjusted 
incidence 
rates*
Crude rates
Exposure 
time 
adjusted 
incidence 
rates*
Crude rates
Crude rates
Exposure 
time 
adjusted 
incidence 
rates*
Crude rates
Entire 
Treatment 
(upto 
Week 52)
Crude rates
Exposure 
time 
adjusted 
incidence
rates*
Crude rates
Exposure 
time 
adjusted 
incidence 
rates*
Crude rates
Crude rates
Exposure 
time 
adjusted 
incidence 
rates*
Crude rates
*Exposure time adjusted incidence rates will be done for the following:
• at the PSOC level for all SAEs and all AEs
• at the preferred term level for 
o
all SAEs and AESIs


o
the common AEs, which are defined as at least 2% of the patients in the 
combined AIN457 groups during the initial treatment period or events that had 
an incidence rate of at least 5.0 cases per 100 subject-years in the combined 
AIN457 groups during the entire treatment period
2.9
Pharmacokinetic endpoints
Not Applicable.
2.10
PD and PK/PD analyses
Not Applicable.
2.11
Patient-reported outcomes
Variables related to health-related quality of life (HR-QoL) are described below. All HR-QoL
variables will be evaluated based on FAS patients. 
Physical function index (HAQ-DI©)
The mean change from baseline of Physical function index (HAQ-DI©) at Week 12 will be 
analyzed by using an ANCOVA model with treatment group, visit and concomitant MTX 
intake status, as factors and baseline HAQ-DI index as continuous covariate. The adjusted 
(LS) mean difference will be calculated as a point estimate together with the corresponding 
95% confidence interval and p-value.
FACIT-Fatigue© score
The mean change from baseline of FACIT-Fatigue© total score at Week 12 will be analyzed
by using an ANCOVA model with treatment group, visit and concomitant MTX intake status, 
as factors and baseline FACIT-Fatigue score as continuous covariate. The adjusted (LS) mean 
difference will be calculated as a point estimate together with the corresponding 95% 
confidence interval and p-value.
ASAS Health Index 
The mean change from baseline of ASAS health index at Week 12 will be analyzed by using 
an ANCOVA model with treatment group, visit and concomitant MTX intake status, as 
factors and baseline ASAS Health Index as continuous covariate. The adjusted (LS) mean 
difference will be calculated as a point estimate together with the corresponding 95% 
confidence interval and p-value.
Additionally, summary statistics will be provided for all the visits till Week 52 for all patient-
reported outcomes. Graphical representation will also be performed if required.
2.12
Biomarkers
Not Applicable.








.


3
Sample size calculation
The selected criterion for the primary objective, the ASAS 20 score, is intended to be used in 
patients with axial skeleton involvement. Consequently, secukinumab data available from 
previous studies on this outcome measure, related to AS patients, can be taken into account. 
Compared to PsA patients, in AS patients the peripheral joints involvement is less 
pronounced. Thus, the ASAS 20 score for AS patients is expected to capture information 
entirely related to the axial skeleton involvement. Patients with PsA, who will be included in 
the present study, are characterized by concomitantly experiencing axial and peripheral joints 
disease. Thus, the ASAS 20 score is expected to also reflect the peripheral joints components. 
To assume the magnitude of ASAS 20 response for PsA patients treated with secukinumab 
data from CAIN457F2310 (AS patients) and the CAIN457F2312 (PsA patients) have been 
considered. 
The CAIN457F2310 study compared secukinumab to placebo in AS patients, and the ASAS 
20 response rate at Week 12 was 57% for 150 mg secukinumab and 28% for placebo (300mg 
secukinumab was not tested). These results are a basis to extrapolate the expected results for 
the current study.
In a phase 3 study of Secukinumab in PsA patients, CAIN457F2312, the performance of 300 
mg secukinumab is, compared to 150 mg secukinumab, numerically better in the achievement 
of the ACR 20 score. Assuming comparable trends in treatment response of the spine and the 
peripheral joints, a slightly different response between the 300 mg and the 150 mg treatment 
group was chosen. In addition, from data available in the literature 
(Lubrano and Spadaro 2012) it appears that the spinal involvement in PsA is milder compared 
to AS in terms of inflammation and impact on physical function, so that it can be expected 
that PsA patients might more easily achieve an ASAS20 score compared to AS patients. 
Similarly, we can assume that placebo response rates in AxPsA patients may be higher 
compared to AS. 


For the 150 mg secukinumab treatment group a response rate of 57% is expected at Week 12. 
For the 300 mg secukinumab treatment group a response rate of 60% is expected at Week 12. 
An overall type I error (2-sided) 5% will be used to control type I error. Since two 
secukinumab doses will be tested versus placebo in a hierarchical manner, no type-I-error 
adjustment is required for each comparison with respect to the primary endpoint (ASAS 20 
response at Week 12). To achieve 92% power and assuming conservatively a response rate of 
40% in the placebo group, at least 150 patients per group would be needed under equal 
allocation to show a response rate of 60% in the secukinumab 300 mg group. Using the same 
number of patients per group, the second test will have at least 80% power to detect a 
difference, if the true response rates are 57% in secukinumab 150 mg group and 40% in 
placebo. The above sample size calculation is based on Fisher’s exact test.
To compensate for drop-outs and protocol violations, 165 patients per group (=495 total) 
should be recruited into this trial.
SAS® version 9.4 software was used for the calculation of sample size.
5
Appendix
5.1
Imputation rules
5.1.1 Study drug
Not applicable
5.1.2 AE date imputation
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date as mentioned in the Table 1-2 below.  
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment.  Therefore:


a.
If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY).
b. Else, if the AE year is less than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the mid-month point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:
a.
If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY).
b. Else, if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing or the AE month is equal to the treatment start 
month, the imputed AE start date is set to one day after treatment start.
b. Else, if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
c.
Else, if the AE month is greater than the treatment start month, the imputed AE 
start date is set to the start month point (01MONYYYY).
Table 5.1-2: AE start date imputation
MON
MON < CFM
MON = CFM
MON > CFM
MISSING
YYYY 
MISSING NULL
NULL
NULL
NULL
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < 
CFY
( D ) = 01JULYYYY
( C )= 15MONYYYY ( C )= 15MONYYYY ( C )= 15MONYYYY
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start
YYYY = 
CFY
(B)= TRTSTD+1
( C )= 15MONYYYY (A)= TRTSTD+1
(A)= 01MONYYYY
Uncertain
Before Treatment Start Uncertain
After Treatment Start
YYYY > 
CFY
(E)= 01JANYYYY
(A)= 01MONYYYY
(A)= 01MONYYYY
(A)= 01MONYYYY
After Treatment Start After Treatment Start After Treatment Start After Treatment Start 
Before Treatment Start 
Partial indicates date prior to Treatment Start Date
After Treatment Start 
Partial indicates date after Treatment Start Date
Uncertain
Partial insufficient to determine relationship to Treatment Start Date
LEGEND:
(A)
         MAX(01MONYYYY,TRTSTD+1)
(B)
         TRTSTD+1
(C)
15MONYYYY


(D)
01JULYYYY
(E)
01JANYYYY
AE end date imputation
For the purpose of date imputation, the study treatment follow-up period date is defined as 
the last available visit date, i.e. including unscheduled visits after the end of study visit.
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (study treatment follow-up period date, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(study treatment follow-up period date, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
If the imputed AE end date is less than the existing AE start date then use AE start date as AE 
end date.
5.1.3
Medical history date of diagnosis imputation
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the treatment start date.

If DIAG year < study treatment start date year and DIAG month is missing, the imputed 
DIAG date is set to the mid-year point (01JULYYYY).

Else if DIAG month is not missing, the imputed DIAG date is set to the mid-month point 
(15MONYYYY).

If DIAG year = study treatment start date year and (DIAG month is missing OR DIAG 
month is equal to study treatment start month), the imputed DIAG date is set to one day 
before study treatment start date.
5.1.4 Concomitant medication date imputation
Concomitant medication (CMD) start date imputation (#IMPUTMED)
Rules for imputing the CMD start date:
This algorithm is used when event is the partial start date of the concomitant medication,
non- drug therapy/procedure, or prior study indication therapy.
The following table explains the notation used in the logic matrix. Please note that
completely missing start dates will not be imputed.
Day
Month
Year
Partial CM Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSDT)
Not used
TRTM
TRTY


The following 
matrix explains the 
logic behind the
MON
MISSING
MON<TRTM
MON=TRTM
MON>TRTM
YYYY
(C2)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
MISSING
YYYY<TRTY
(D)
Before Treatment
Start
(A)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
YYYY=TRTY
(C2)
Uncertain
(A)
Before Treatment Start
(C1)
Uncertain
(B)
After Treatment Start
YYYY>TRTY
(E)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
The following table is the legend to the logic matrix.
Relationship
Before Treatment Start
Partial date indicates CMD start date prior to
Treatment Start Date
After Treatment Start
Partial date indicates CMD start date after
Treatment Start Date
Uncertain
Partial date insufficient to determine
relationship of CMD start date relative to 
Treatment
Start Date
Imputation Calculation
(A)
15MONYYYY
(B)
01MONYYYY
(C1 or C2)
IF relative reference start = before treatment 
start THEN TRTSDT-1
ELSE IF relative reference start = ‘ ’ THEN
TRTSDT+1
(D)
01JULYYYY
(E)
01JANYYYY


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Concomitant medication end date imputation
If not ongoing then –

If the CM end date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed
CM end date is set to NULL.

Else, if the CM end date month is missing, the imputed end date should be set to
the earliest of the following options: treatment follow up period date, 31DECYYYY,
date of death.

If the CM end date day is missing, the imputed end date should be set to the
earliest of the following: treatment follow up period date, last day of the month, date 
of death.

If the imputed CM end date is less than the existing CM start date, use the CM start
date as the imputed CM end date.
Concomitant medication date flag
If not a complete date then
Y - If year of the imputed date is not equal to YYYY else
M – If month of the imputed date is not equal to MON 
else D
5.1.4.1
Prior therapies date imputation
Not applicable
5.1.4.2
Post therapies date imputation
Not applicable
5.2
AEs coding/grading
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1 and above.
5.3
Laboratory parameters derivations
Refer to main section of SAP.


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5.4
Statistical methodology and assumptions 
5.4.1
Crude incidence and 100*(1-α) % confidence interval
For n subjects, each at risk to experience a certain event with probability π, the crude
incidence is estimated as p=x/n, where x is the number of subjects with the event.
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the
relative frequency based on the score method including continuity correction (Newcombe
1998).
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/2),
n as total number of subjects (i.e. number of subjects in the denominator), and p as
estimated crude incidence (number of subjects with event / n ) it is q =1− p .
Then the lower limit is
Note: if p = 0 then L = 0 and if p = 1 then U = 1.
If appropriate, an exact 100*(1-α)% confidence interval (Clopper-Pearson 1934) will be
obtained by using the SAS procedure PROC FREQ with the EXACT BINOMIAL statement.
However, the confidence interval derived via the score method including continuity correction
will be the default in safety analyses.
5.4.2
Odds ratio and 100*(1-α)% confidence interval
For an investigational drug group with n1 subjects at risk, independent from the control group
(e.g. placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain
event with probability π1 and π0 respectively, the odds ratio is estimated as
with p1= x1/n1 and p0=x0/n0. A conditional exact 100*(1-α)% confidence 
interval can be obtained by using the SAS procedure PROC FREQ with statement EXACT 


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OR. However, to be able to adjust for covariates odds ratios will primarily be obtained from 
PROC GENMOD.
5.4.3
Exposure adjusted incidence rate and 100*(1-α) % confidence 
interval
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first
occurrence of a certain event is observed, or if the event was not experienced, the (censored)
time to the end of the observation period. The sequence of first occurrences of an event will
be modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where
and D is the number of subjects with at least one event. Conditionally on T, an exact 100*(1-
α)% confidence interval for a Poisson variable with parameter θT and observed value D can 
be obtained based on (Garwood 1936), from which an exact 100*(1-α)% confidence interval 
for D/T will be derived as follows (Sahai 1993; Ulm 1990):
The example below shows how this should be handled for cases where subjects switch
treatment. In particular for summarizing ‘Any AIN’ as a group, one should take into
consideration the sequence of treatments while calculating exposure time for subjects.
Table 16-3 Examples for calculating exposure time for incidence rates (IR)


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5.5
Score derivations and response criteria
5.5.1
Assessment of Spondyloarthritis International Society (ASAS)
The ASAS response measures consist of the following assessment domains (Sieper et al 2009):
1. Patient’s global assessment of disease activity measured on a VAS scale.
2. Patient’s assessment of IBP, 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 scale.
ASAS response criteria (ASAS 20)
The ASAS Response Criteria (ASAS 20) was defined as an improvement of ≥ 20% and ≥ 1 unit 
on a scale of 10 in at least 3 of the 4 main domains and no worsening of ≥ 20% and ≥ 1 unit on 
a scale of 10 in the remaining domain.
ASAS response criteria (ASAS 40)
The ASAS 40 response was defined as an improvement of ≥ 40% and ≥ 2 units on a scale of
10 in at least 3 of the 4 main domains and no worsening at all in the remaining domain.


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5.5.3
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 axSpA:
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 2 scores relating to morning 
stiffness is taken (questions 5 and 6). The resulting 0 to 10 score is added to the scores from 
questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0-10 BASDAI score. 
If one or more items are unanswered, the average of the non-missing items is used for the total 
score. 
BASDAI 50 response is defined as at least a 50% improvement (decrease) in total BASDAI 
score, as compared to the Baseline total BASDAI score
5.5.4
Bath ankylosing spondylitis functional index (BASFI)
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those patients with AS. A 0 through 10 scale (captured as a continuous VAS) is used to answer 
the questions. The mean of the 0 scales gives the BASFI score a value of between 0 and 10.


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5.5.6
Health assessment questionnaire-disability index (HAQ-DI)
The Health Assessment Questionnaire (HAQ©) was developed by Stanford University and is 
one of the most widely used measures to assess the long-term influence of chronic disease on a 
subject's level of functional ability and activity restriction. The disability assessment component 
of the HAQ (Health Assessment Questionnaire – Disability Index), the HAQ-DI, assesses a 
subject's level of functional ability and includes questions of fine movements of the upper 
extremity, locomotor activities of the lower extremity, and activities that involve both upper 
and lower extremities. There are 20 questions in eight categories of functioning including 
dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The stem of each 
item asks over the past week "Are you able to …" perform a particular task. Each item is scored 
on a 4-point scale from 0 to 3, representing normal (normal, no difficulty [0]), some difficulty 
[1], much difficulty [2], and unable to do [3]. 
Scoring for the eight functional categories and overall disability index scoring will be performed 
as follows: 
There are eight categories; first score within each category: 

Dressing and Grooming, includes items 1 and 2 

Arising, includes items 3 and 4 

Eating, includes items 5, 6 and 7 

Walking, includes items 8 and 9 

Hygiene, includes items 10, 11, and 12 

Reach, includes items 13 and 14 

Grip, includes items 15, 16 and 17 

Activities, includes items 18, 19, and 20
The score for each category will be the single response within the category with the highest 
score (greatest difficulty). For example, in the "Eating" category, there are two answers (one 
for each item). If "Cut your food with a knife or fork" is marked as "3" and "Lift a full cup or 
glass to your mouth" is marked as "0", then the score for the "Eating" category would be "3" 
(the response indicating the greatest difficulty within the category). If a component question is 
left blank or the response is too ambiguous to assign a score, then the score that that category 
will be determined by the remaining completed question(s). However, if any "aids or devices" 
and/or "help from another person" items at the bottom of each page are checked, the category 
to which they apply will be adjusted upward to "2". If the basic score is already "2" or "3", the 
score remains unchanged. "Aids or devices" and "help from another person" can only change a 
category's score to "2"; they do not change the score to a "1" or a "3".
The score for the disability index will be the mean of the eight category scores. If more than 
two of the categories, or 25%, are missing, scale will not be scored. Otherwise, divide the sum 


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of the categories by the number of answered categories. The higher score indicates greater 
disability.
HAQ-DI response is defined by an improvement of at least 0.35 score points compared to 
baseline.
5.5.7
American college of Rheumatology (ACR) response
A patient will be considered as improved according the ACR 20 criteria if she/he has at least
20% improvement in the 2 following measures:

Tender joint count (TJC)

Swollen joint count (SJC)
and at least 3 of the following 5 measures:

Patient’s assessment of pain

Patient’s global assessment of disease activity

Physician’s global assessment of disease activity

Health assessment questionnaire (HAQ©) score

C-reactive protein (CRP) or erythrocyte sedimentation rate (note: CRP only will be 
assessed in this study)
If the number of joints for which data were available (e.g., T) is less than 78/76 for the 
tender/swollen joint assessment, the number of tender/swollen joints (e.g., t) will be scaled up 
proportionately (i.e., 78*t/T or 76*t/T for tender or swollen joint count).
5.5.8
ASAS Health Index
The ASAS health index is a linear composite measure and contains 17 items (dichotomous 
response option: “I agree” and “I do not agree”). 
Each statement on the ASAS Health Index is given a score of 1 = I agree OR 0 = I do not agree. 
All item scores are summed up to give a total score that ranges from 0 (good functioning) to 17
(poor functioning). Items No 7 and 8 are not applicable for all patients. For those patients who 
ticked the response “not applicable”, the sum score is analysed based on n=16 or n=15, 
respectively.
A total score can be analysed if no more than 20% of the data are missing. The total score is
calculated as follows for respondents with one to a maximum of three missing responses:


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Cases with more than three missing responses cannot be allocated a total score.
5.5.9
Spondyloarthritis Research Consortium of Canada (SPARCC) 
enthesitis index
SPARCC assessments will be performed for following entheses sites, where tenderness at each 
site is quantified on a dichotomous basis: 0=non-tender and 1=tender.  The score is obtained by 
summing up these values and the range of score is 0-16.
If the number of entheses sites for which data were available (e.g., T) is less than 16 for the 
SPARCC assessment, the number of tender entheses sites (e.g., t) will be scaled up 
proportionately (i.e., 16*t/T for SPARCC score).
5.5.10
FACIT-Fatigue©
The FACIT-Fatigue© is a 13-item questionnaire. The following instructions are to be followed 
to calculate fatigue subscale score:

Perform reversals as indicated for the recorded responses and sum individual items to 
obtain a score.

Multiply the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered.  This produces the subscale score.

The higher the score, the better the QOL.
When there are missing data, prorating by subscale in this way is acceptable as long as more 
than 50% of the items were answered (i.e., 7 or more items were answered).


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5.6
Statistical models
5.6.1
Primary analysis
The primary statistical hypothesis for ASAS 20 being tested is that there is no difference in 
the proportion of patients fulfilling the ASAS 20 criteria at Week 12 in the Secukinumab 300 
mg treatment group versus placebo group.
The primary analyses will be conducted via logistic regression with treatment and 
concomitant MTX intake status as factors. The Odds ratio, 95% confidence interval (CI) and 
p-value will be presented comparing secukinumab 300 mg treatment group to placebo group 
at Week 12.
SAS Code for logistic model
Proc logistic data=aaa;
Class TRT STRATA / param=glm;
Model AVAL = TRT STRATA;
Lsmeans TRT / diff cl exp;
Ods output diffs=lsm_diff;
Run;
In cases where separation is a concern for the primary endpoint at Week 12, e.g. 0% or 100%
response in one treatment (sub)group, an exact logistic regression model will be applied to all
visits. To ensure convergence, this model will not include any continuous covariates.
Proc logistic data=aaa exactonly;


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Class TRT STRATA / param=glm;
Model AVAL = TRT STRATA;
Exact TRT / estimate=both;
Ods output exactoddsratio=exactoddsratio;
Run;
Missing data for ASAS 20 response for data up to Week 12 will be handled by multiple 
imputations technique. 
Multiple Imputation
A multiple imputation will be performed based on MAR by treatment group for baseline
weight, baseline and post-baseline of each parameter for visits up to the primary time point of
12 weeks using Markov Chain Monte Carlo (MCMC) method with EM algorithm.
Impute the missing values 100 times (NIMPUTE) with a seed=457<studycode> as shown
below:
proc mi data= min=<min of scale> max=<max of scale> out=imp minmaxiter=100000
nimpute=100 seed=4572310;
by trt;
var weight_base var1_base var1_week1-var1_week16;
mcmc chain=multiple initial=em;
run;
If needed repeat for each component necessary to calculate the final score, e.g. as follows:
proc mi data=imp min=<min of scale> max=<max of scale> out=imp2 minmaxiter=100000
nimpute=1 seed=4572310;
by trt _imputation_;
var weight_base var2_base var2_week1-var2_week16;
mcmc chain=multiple initial=em;
run;
The score and ASAS response can now be calculated based on the complete data. The
response rate will be calculated for each imputation and then combined using Rubin’s rules.
In order to calculate the response rate for each imputation, PROC FREQ will be used as
follows.
Calculate binomial proportion and standard error for each imputation.
proc freq data=<ASAS20>;
by treat visit _imputation_ ;
tables <response> / binomial (level=2 cl=wilson correct) ;
ods output BinomialProp=imp_bpr;
run;


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Transpose the dataset for subsequent use with PROC MIANALYZE.
proc transpose data=imp_bpr out=imp_trs(drop=_name_) ;
by treat visit _imputation_ ;
var nvalue1; id name1; idlabel label1;
run;
Apply LOGIT transformation: y=log(p/(1-p)) and std. err. transformation: <new se> =
se/(p*(1-p))
data logit;
set imp_trs(rename=(_bin_=p e_bin=se));
by treat visit _imputation_ ;
lmean=log(p/(1-p));
lse=se/(p*(1-p));
run;
The transformed binomial proportion estimates and standard errors are combined by applying
Rubin’s rules for multiple imputed data sets.
proc mianalyze data=logit;
by treat visit ;
modeleffects lmean;
stderr lse;
ods output ParameterEstimates=logitres;
run;
The combined data should be transformed back using the following formula: p=1/(1+exp(-y))
data miexpres;
set logitres;
by treat visit ;
resti = 1/(1+exp(-estimate));
rlow = 1/(1+exp(-lclmean));
rupp = 1/(1+exp(-uclmean));
run;
Of note, sometimes all responses may be imputed to 0 or 1 at a given combination of response
variable, treatment group and visit. Such cases should be considered separately. The
combined final response rate would be the same as the original response but the 95% CI will
be undefined.
The odds ratio will be derived using GENMOD for each imputation, then combined using
Rubin’s rules again.


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proc genmod data = asas20_mi descending;
by avisitn _imputation_;
class trt_ TNFRESN ;
model aval = trt_ TNFRESN weight / link=logit dist=bin;
lsmeans trt_ / diff;
estimate 'AIN457 75mg mg vs Placebo' trt_ 1 0 -1;
estimate 'AIN457 150mg mg vs Placebo' trt_ 0 1 -1;
ods output Estimates=imp_est;
run;
proc mianalyze data=imp_est;
by avisitn trt_ ;
modeleffects LBetaEstimate;
stderr StdErr;
ods output ParameterEstimates=res;
run;
For sensitivity analysis, the above code will be used for non-responder imputation.
In addition to that, the above analysis will also be performed for each baseline variables (e.g: 
sex, age class, disease severity at Baseline).
Non-parametric ANCOVA model
A non-parametric ANCOVA model (Koch 1998) will be used as sensitivity analysis for
ASAS 20 and possibly also for continuous endpoints that are not normally distributed. The
macro NParCov3 will be used (Zink 2012).
 For continuous response variable, the macro call will be as follows:
%NParCov3(OUTCOMES = response, COVARS = weight baseline, C = 1, HYPOTH = 
ALT,
STRATA = TNFα status, TRTGRPS = treatment, TRANSFORM = NONE, COMBINE =
FIRST, DSNIN = RESP, DSNOUT = OUTDAT);
Data set _OUTDAT_DEPTEST provides results for the treatment difference, and
_OUTDAT_CI provides a 95% confidence interval for the treatment estimate.
 For binary response variable, the macro call will be as follows:
%NParCov3(OUTCOMES = response, COVARS = weight, C = 1, HYPOTH = ALT,
STRATA = TNFα status, TRTGRPS = treatment, TRANSFORM = LOGISTIC, COMBINE =
FIRST, DSNIN = RESP, DSNOUT = OUTDAT);
The odds ratio and confidence interval are to be obtained from _OUTDAT_RATIOCI.


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5.6.2
Key secondary analysis
The statistical hypothesis for ASAS 20 being tested is that there is no difference in the 
proportion of patients fulfilling the ASAS 20 criteria at Week 12 in the Secukinumab 150 mg 
treatment group versus placebo group, after superiority is demonstrated for secukinumab 300 
mg to placebo at Week 12.
The above code will be used for key secondary analysis.
5.6.1
Secondary analyses
Categorical variables will be analyses using the logistic model, code is described above.
Endpoints with continuous data type expected to be normally distributed will be analyzed
using an analysis of covariance (ANCOVA) model with treatment and baseline stratification
factor, and baseline value as covariate. Confidence intervals for the difference between each 
dose of secukinumab and placebo will be calculated.
SAS code for ANCOVA
proc mixed data=aaa;
class TRT STRATA;
model response = TRT STRATA BASE / s;
lsmeans TRT / diff;
run;
In addition, key secondary variables measured at all post baseline visits up to Week 52 will be
analyzed using longitudinal mixed effects ANCOVA model with treatment, baseline
stratification factor and analysis visit as factors; and weight, baseline value, treatment by visit
and baseline by visit interactions as covariates. An unstructured covariance structure will be
assumed for this model. The significance of the treatment effects for secukinumab regimens at
different analysis visits will be determined from the pairwise comparisons performed between
secukinumab regimens and placebo at the appropriate analysis visits.
SAS code for mixed model:
proc mixed data=aaa;
class TRT USUBJID AVISITN STRATA;
model CHG=TRT STRATA AVISITN WEIGHT BASE TRT*AVISITN BASE*AVISITN
/ s ddfm=kr;
lsmeans TRT*AVISITN / diff cl;
repeated AVISITN / type=un subject=USUBJID;
Run;
In case the MMRM model does not converge the following sequential steps will be used:
1. change ddfm=kr to ddfm=bw. If still no convergence, perform step 2.
2. change type=un to type=cs. If still no convergence, perform step 3.


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3. remove covariates in the following order until convergence: WEIGHT, BASE*AVISITN,
STRATA.
Crude and adjusted incidence rates
The SAS codes of crude and adjusted incidence rates and confidence intervals will be referred
from the MAP or AIN457F2310 M3.
5.7
Rule of exclusion criteria of analysis sets
Table 5-1 Protocol deviations that cause subjects to be excluded
Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
INCL01
Informed consent not obtained before 
study inclusion
EXCLUDE FROM FAS 
AND SAF
3
INCL02
Informed consent not signed or missing or 
date of signing ICF is missing.
EXCLUDE FROM FAS 
AND SAF
3
INCL03
BASDAI score is < 4 at baseline
EXCLUDE FROM FAS
1
INCL04
Spinal Pain VAS score is < 40 at Baseline 
EXCLUDE FROM FAS
1
INCL05
No inadequate response to at least 2 
NSAIDs over a period of 4 weeks
EXCLUDE FROM PPS
4
INCL06
Subject <18 years of age
EXCLUDE FROM FAS 
AND SAF
3
INCL07
Patient has no axial PsA diagnosis at 
screening
EXCLUDE FROM PPS
4
INCL08
CASPAR score is < 3 at screening
EXCLUDE FROM PPS
4
INCL09
Patient is a lactating woman 
INCLUDE IN 
EVERYTHING
0
EXCL01
Evidence of ongoing infectious or 
malignant processes, obtained within 3 
months prior to Screening by Chest X ray 
or MRI
INCLUDE IN 
EVERYTHING
0
EXCL02
Patient takes high potency opioid 
analgesics 
EXCLUDE FROM PPS
4
EXCL03
History of exposure to other IL-17 or IL-23 
inhibitor biologic drug(s) 
EXCLUDE FROM PPS
4
EXCL04
History of exposure to previous biologic 
DMARD(s) 
EXCLUDE FROM PPS
4


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Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
EXCL05
Current treatment with DMARD(s) other 
than MTX at baseline 
EXCLUDE FROM PPS
4
EXCL06
Any therapy by intra-articular injections 
within 4 weeks before randomization 
EXCLUDE FROM PPS
4
EXCL07
Patient taking NSAIDs is not on a stable 
dose for at least 2 weeks before 
randomization.
EXCLUDE FROM PPS
4
EXCL08
Patient taking systemic corticosteroids is 
not on a stable dose ≤ 10 mg/day of 
prednisone for at least 2 weeks before 
randomization.
EXCLUDE FROM PPS
4
EXCL09
Patients who are on MTX (≤ 25 mg/week) 
who are not on a stable dose for at least 4 
weeks before randomization 
EXCLUDE FROM PPS
4
EXCL10
Patients on MTX who are not on folic acid
supplementation at randomization 
INCLUDE IN 
EVERYTHING
0
EXCL11
Patients who are on DMARD(s) other 
than MTX and who have not discontinued 
the DMARD(s) 4 weeks before
randomization (8 weeks for leflunomide 
unless cholestyramine washout has been 
performed)
EXCLUDE FROM PPS
4
EXCL12
Active ongoing inflammatory diseases 
other than psoriais that might confound 
the evaluation of the benefit of 
secukinumab therapy 
EXCLUDE FROM PPS
4
EXCL13
Positive pregnancy test result before 
randomization 
INCLUDE IN 
EVERYTHING
0
EXCL14
History of an ongoing, chronic or recurrent 
infectious disease 
EXCLUDE FROM PPS
4
EXCL15
Subject enrolled with latent TB and 
without therapy initiated as per local 
guidelines.
INCLUDE IN 
EVERYTHING
0
EXCL16
Subject enrolled with active TB.
EXCLUDE FROM PPS
4
EXCL17
Use of any other investigational drug 
within 4 weeks prior to Visit 2 or within a 
period of 5 half-lives of the investigational 
drug
EXCLUDE FROM PPS
4
EXCL18
Any intramuscular or intravenous (i.v.) 
corticosteroid treatment within 4 weeks 
before randomization 
EXCLUDE FROM PPS
4


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Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
EXCL19
Previous treatment with any cell-depleting 
therapies.
EXCLUDE FROM PPS
4
EXCL20
Significant medical problems excluded by 
the protocol such as but not limited to 
excluded cardiovascular diseases.
EXCLUDE FROM PPS
4
EXCL21
History of renal trauma,
glomerulonephritis, or patients with 1 
kidney only 
INCLUDE IN 
EVERYTHING
0
EXCL22
Serum creatinine level exceeding 1.5 
mg/dL (132.6 μmol/L) prior to 
randomization
INCLUDE IN 
EVERYTHING
0
EXCL23
Subject enrolled with WBC, platelets, 
neutrophils or hemoglobin less than 
values detailed in protocol at screening.
INCLUDE IN 
EVERYTHING
0
EXCL24
Active systemic infections during the 2 
weeks prior to randomization (exception: 
common cold) or any infection that 
reoccurs on a regular basis
INCLUDE IN 
EVERYTHING
0
EXCL25
Past medical history record of or current 
infection with human immunodeficiency 
virus (HIV), hepatitis B or hepatitis C prior 
to baseline 
INCLUDE IN 
EVERYTHING
0
EXCL26
History of lymphoproliferative disease / 
known malignancy / history of malignancy 
of any organ system within the past 5 
years.
INCLUDE IN 
EVERYTHING
0
EXCL27
History or evidence of ongoing alcohol or 
drug abuse, within the last 6 months prior 
to baseline
INCLUDE IN 
EVERYTHING
0
EXCL28
Administration of live vaccines within 6 
weeks preceding randomization 
INCLUDE IN 
EVERYTHING
0
EXCL31
Women of childbearing potential who do 
not agree to be compliant with protocol 
specified contraception
INCLUDE IN 
EVERYTHING
0
EXCL32
History of hypersensitivity reactions to any 
of the excipients
INCLUDE IN 
EVERYTHING
0
EXCL33
Underlying condition at enrolment which 
immunocompromised the patient and/or 
places the patient at unacceptable risk.
INCLUDE IN 
EVERYTHING
0
EXCL34
Any single parameter (ALT, AST, AP) 
must not exceed 2 × upper limit of normal 
(ULN) prior to randomization.
INCLUDE IN 
EVERYTHING
0
EXCL35
In any case, serum bilirubin should not 
exceed the value of 1.6 mg/dL (27 
μmol/L) prior to randomization.
INCLUDE IN 
EVERYTHING
0


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Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
EXCL36
Current severe progressive or 
uncontrolled disease, which renders the 
patient unsuitable for the trial.
INCLUDE IN 
EVERYTHING
0
EXCL37
Medical or psychiatric condition, which
would preclude the patient from adhering 
to/ completing the protocol.
INCLUDE IN 
EVERYTHING
0
EXCL39
Evidence of tuberculosis infection as 
defined by a positive or indeterminate 
QuantiFERON tuberculosis (TB) Gold test 
(QFT) at Screening, but no workup 
performed
INCLUDE IN 
EVERYTHING
0
WITH01
Positive pregnancy test result but patient 
has not discontinued the study.
INCLUDE IN 
EVERYTHING
0
WITH02
Uncontrolled hypertension (≥ 160/95 
mmHg) but patient has not discontinued 
the study.
INCLUDE IN 
EVERYTHING
0
WITH03
Administration of live vaccines during the 
study period and patient not discontinued.
INCLUDE IN 
EVERYTHING
0
TRT01
Less than 2 injections of secukinumab or 
matching placebo administered and the 
reason is not “Adverse event”.
EXCLUDE FROM PPS
4
TRT02
More than two injections of secukinumab 
or matching placebo administered on the 
same day.
EXCLUDE FROM PPS
4
TRT03
Incorrect study medication administered.
EXCLUDE FROM PPS
4
TRT07
Use of medication which could have been 
damaged based on storage conditions / 
temperature deviations
EXCLUDE FROM PPS
4
TRT08
Minimum interval between two 
administrations of study drug was not 
respected
INCLUDE IN 
EVERYTHING
0
COMD01
Treatment with biological
immunomodulating agents at any time 
during the study
EXCLUDE FROM PPS
4
COMD02
Current treatment with DMARD(s) other 
than MTX at any time during the study
EXCLUDE FROM PPS
4
COMD03
Any therapy by intra-articular injections 
during the study.
EXCLUDE FROM PPS
4
COMD04
Patient taking NSAIDs is not on a stable 
dose during the study.
EXCLUDE FROM PPS
4
COMD05
NSAIDs intake during 24h before a visit 
involving a disease activity assessment
EXCLUDE FROM PPS
4
COMD06
Patient taking systemic corticosteroids is 
not on a stable dose ≤ 10 mg/day of 
prednisone during the study.
EXCLUDE FROM PPS
4
COMD07
Patients taking MTX at an unstable dose 
during the study.
EXCLUDE FROM PPS
4
COMD07a
Patients taking MTX 48 hours before a 
clinical laboratory evaluation
EXCLUDE FROM PPS
4


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Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
COMD08
Patients on leflunomide any time during 
the study.
EXCLUDE FROM PPS
4
COMD09
Use of any investigational drug and/or 
devices during the study
EXCLUDE FROM PPS
4
COMD10
Any intramuscular or intravenous (i.v.) 
corticosteroid treatment during the study.
EXCLUDE FROM PPS
4
COMD12
Patients receiving analgesics other than 
NSAIDs, paracetamol/acetaminophen and 
low strength opioids PRN during the 
study.
EXCLUDE FROM PPS
4
COMD13
Patient is taking systemic corticosteroids 
> 10 mg/day of prednisone or equivalent.
EXCLUDE FROM PPS
4
COMD14
Patient taking MTX > 25 mg/week during 
the course of the study.
EXCLUDE FROM PPS
4
OTH02
Patient did not complete ASAS 
component at baseline visit.
INCLUDE IN 
EVERYTHING
0
OTH02a
Patient did not complete ASAS 
component at week 12 visit.
EXCLUDE FROM PPS
4
OTH06
PRO data was not collected according to 
the protocol. A non-validated process was 
used to collect PRO data
EXCLUDE FROM PPS
0
OTH07
Data not intended for the study have been
submitted to a vendor database
INCLUDE IN 
EVERYTHING
0
OTH08
Maximum protocol timelines were not 
adhered too
INCLUDE IN 
EVERYTHING
0
The following criteria will lead to exclusion of subjects from the respective analysis sets, as 
they might have some impact on the outcome of the study.
Deviation text description
Severity code 
Excluded from analysis set
Compliance to study 
medication < 80% or >120%
4
Exclude from PPS
Table 5-2
Analysis set exclusions based on population codes
Analysis set 
Population codes that cause a subject to be 
excluded
RAN 
NA
SAF 
2, 3
FAS 
1, 3
PPS
1, 4
 


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Table 5-3
Population code text
Population Code
Population Code text
0
INCLUDE IN EVERYTHING
1
EXCLUDE FROM FULL ANALYSIS SET (FAS)
2
EXCLUDE FROM SAFETY SET (SAF)
3
EXCLUDE FROM FAS AND SAF
4
EXCLUDE FROM PER-PROTOCOL SET (PPS) 
 
6
Reference
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective
multiple test procedures. Stat Med; 28(4):586-60
Clopper CJ and Pearson ES (1934) The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika; 26 (4), 404-13.
Fries JF, Spitz P, Kraines G, Holman H (1980) Measurement of Patient Outcome in Arthritis. 
Arthritis Rheum; 23:137-45.  
Garwood F (1936) Fiducial Limits for the Poisson Distribution. Biometrika; 28(3-4).
Koch GG, Tangen CM, Jung J-W, et al (1998) Issues for covariance analysis of dichotomous
and ordered categorical data from randomized clinical trials and non-parametric strategies for
addressing them. Stat Med; 17(15-16):1863-92.
Lubrano E and Spadaro A (2012) Axial psoriatic arthritis: an intriguing clinical entity or a 
subset of an intriguing disease?. Clin Rheumatol; 31(7):1027-32.
 
 
 
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods; Stat Med.;17(8):857-72.
Sahai (1993) Confidence Intervals for the Mean of a Poisson Distribution: A Review.
Biometrical Journal; 35 (7): 857-67.
Sieper J, Rudwaleit M, Baraliakos X et al (2009) The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis,; 
68 Suppl 2:ii1-44. 
Ulm K (1990) A simple method to calculate the confidence interval of a standardized mortality 
ratio (SMR). Am J Epidemiol.; 131 (2):373-5.


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Zink RC and Koch GG (2012). NParCov3: A SAS/IML Macro for Nonparametric 
Randomization-Base Analysis of Covariance. Journal of Statistical Software; 50(3): 1-17.