Conditions: Psoriatic Arthritis Axial Spondyloarthritis Enthesitis
Keywords: Active psoriatic arthritis Axial spondyloarthritides Subcutaneous Secukinumab in prefilled syringe Enthesitis Achilles tendon AxSpA PsA
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 204
Healthy volunteers: no

Brief summary:
The purpose of this study was to demonstrate efficacy, including effects on inflammation by magnetic resonance imaging (MRI) assessments, of secukinumab on Achilles tendon enthesitis for up to 1 year with a primary focus at Week 24, in patients with active Psoriatic Arthritis and axial Spondyloarthritis despite current or previous non-steroidal anti-inflammatory drugs (NSAID) and/or disease modifying anti-rheumatic drug (DMARD) and/or anti-TNFα therapy.

Detailed description:
Primary endpoint was at week 24 but there was no interim Clinical Study Report. While Protocol states at chapter 9.7 that a week 24 analysis may be provided (not mandatory as per protocol), all data has been analyzed at week 52.

Some of the secondary endpoints include the whole study period up to week 52 (to address questions on switching placebo to active drug)

Arms:
arm 1: Secukinumab 150 mg s.c. or Secukinumab 300 mg s.c., respective dose was assigned according to underlying condition, in case of PsA according to severity of concomitant Psoriasis or pre-exposure to anti-TNFα arm 2: Secukinumab Placebo s.c.

Interventions: intervention 1: Secukinumab intervention 2: Secukinumab Placebo
Intervention descriptions: intervention 1: Induction: Week 0,1,2,3 150 mg or 300 mg Secukinumab s.c. Maintenance: 150 mg or 300 mg Secukinumab s.c. every 4 weeks starting at Week 4 intervention 2: Induction: Week 0,1,2,3 Secukinumab Placebo s.c. Maintenance: Secukinumab Placebo s.c. every 4 weeks starting at Week 4 until Week 24 followed by 150 or 300 mg Secukinumab s.c. every 4 weeks

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
AIN457/Secukinumab
Clinical Trial Protocol CAIN457F3301 / NCT02771210
A randomized, double-blind, placebo-controlled multicenter 
study of subcutaneous secukinumab to demonstrate 
efficacy in the treatment of enthesitis at the Achilles tendon 
up to 1 year in adult patients with active Psoriatic Arthritis 
(PsA) and axial Spondyloarthritis (axSpA) (ACHILLES)
Document type:
Amended Protocol
EUDRACT number:
2016-000972-91
Version number:
Version 03 clean
Clinical trial phase:
IIIb
Release date:
19 June 2017
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)


Novartis
Confidential
Page 2
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 3 ...........................................................................................................................10
Amendment 2 ...........................................................................................................................13
Amendment 1 ...........................................................................................................................14
Protocol summary.....................................................................................................................15
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................22
2
Study objectives and endpoints .........................................................................................22
2.1
Primary objective...................................................................................................22
2.2
Secondary objectives .............................................................................................22
23
3
.Investigational plan ..........................................................................................................24
3.1
Study design...........................................................................................................24
3.2
Rationale for study design .....................................................................................25
3.3
Rationale for dose/regimen, route of administration and duration of treatment....26
3.4
Rationale for choice of comparator .......................................................................28
3.5
Purpose and timing of interim analyses/design adaptations..................................28
3.6
Risks and benefits..................................................................................................28
4
Population..........................................................................................................................29
4.1
Inclusion criteria ....................................................................................................29
4.2
Exclusion criteria...................................................................................................30
5
Treatment...........................................................................................................................33
5.1
Study treatment......................................................................................................33
5.1.1
Investigational and control drugs..........................................................33
5.1.2
Additional treatment..............................................................................33
5.2
Treatment arms ......................................................................................................33
5.3
Treatment assignment and randomization.............................................................34
5.4
Treatment blinding.................................................................................................35
5.5
Treating the patient................................................................................................35
5.5.1
Patient numbering .................................................................................35
5.5.2
Dispensing the study drug.....................................................................36


Novartis
Confidential
Page 3
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
5.5.3
Handling of study and additional treatment..........................................36
5.5.4
Instructions for prescribing and taking study treatment........................37
5.5.5
Permitted dose adjustments and interruptions of study treatment ........38
5.5.6
Rescue medication ................................................................................39
5.5.7
Concomitant medication .......................................................................39
5.5.8
Prohibited medication ...........................................................................41
5.5.9
Emergency breaking of assigned treatment code..................................42
5.6
Study completion and discontinuation...................................................................42
5.6.1
Study completion and post-study treatment..........................................42
5.6.2
Discontinuation of study treatment .......................................................43
5.6.3
Withdrawal of informed consent...........................................................44
5.6.4
Loss to follow-up ..................................................................................45
5.6.5
Early study termination by the sponsor.................................................45
6
Visit schedule and assessments .........................................................................................45
6.1
Information to be collected on screening failures..................................................53
6.2
Patient demographics/other baseline characteristics .............................................53
6.3
Treatment exposure and compliance .....................................................................53
6.4
Efficacy..................................................................................................................54
6.4.1
Assessments in all patients....................................................................54
57
58
6.4.4
Appropriateness of efficacy assessments..............................................59
6.5
Safety.....................................................................................................................59
6.5.1
Physical examination ............................................................................59
6.5.2
Vital signs..............................................................................................59
6.5.3
Height and weight .................................................................................60
6.5.4
QuantiFERON TB-Gold test.................................................................60
6.5.5
Laboratory evaluations..........................................................................60
6.5.6
Electrocardiogram (ECG) .....................................................................61
6.5.7
Pregnancy and assessments of fertility .................................................61
6.5.8
Tolerability of secukinumab .................................................................61
6.5.9
Additional parameters ...........................................................................61
6.5.10
Appropriateness of safety measurements..............................................62
6.6
Other assessments..................................................................................................62
6.6.1
Medical outcome short form (36) health survey...................................62
 
62
63


Novartis
Confidential
Page 4
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
63
6.6.5
Human leukocyte antigen B27..............................................................63
6.6.6
Resource utilization...............................................................................63
6.6.7
Pharmacokinetics ..................................................................................63
6.6.8
Other biomarkers...................................................................................63
7
Safety monitoring ..............................................................................................................63
7.1
Adverse events.......................................................................................................63
7.2
Serious adverse events...........................................................................................65
7.2.1
Definition of SAE .................................................................................65
7.2.2
SAE reporting........................................................................................66
7.3
Liver safety monitoring .........................................................................................66
7.4
Renal safety monitoring.........................................................................................67
7.5
Reporting of study treatment errors including misuse/abuse ................................68
7.6
Pregnancy reporting...............................................................................................68
8
Data review and database management.............................................................................69
8.1
Site monitoring ......................................................................................................69
8.2
Data collection.......................................................................................................69
8.3
Database management and quality control............................................................69
8.4
Data Monitoring Committee..................................................................................70
8.5
Adjudication Committee........................................................................................70
9
Data analysis......................................................................................................................70
9.1
Analysis sets ..........................................................................................................71
9.2
Patient demographics and other baseline characteristics.......................................71
9.3
Treatments .............................................................................................................71
9.4
Analysis of the primary variable............................................................................72
9.4.1
Variable.................................................................................................72
9.4.2
Statistical model, hypothesis, and method of analysis..........................72
9.4.3
Handling of missing values/censoring/discontinuations.......................72
9.4.4
Sensitivity analyses ...............................................................................72
9.5
Analysis of secondary variables ............................................................................73
9.5.1
Efficacy variables..................................................................................73
9.5.2
Safety variables .....................................................................................74
75
9.7
Interim analyses .....................................................................................................75
9.8
Sample size calculation..........................................................................................75
10 Ethical considerations........................................................................................................76
10.1
Regulatory and ethical compliance........................................................................76
10.2
Informed consent procedures.................................................................................76


Novartis
Confidential
Page 5
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
10.3
Responsibilities of the investigator and IRB/IEC..................................................77
10.4
Publication of study protocol and results...............................................................77
10.5
Quality Control and Quality Assurance.................................................................77
11 Protocol adherence ............................................................................................................77
11.1
Protocol amendments.............................................................................................78
12 References .........................................................................................................................78
13 Appendix 1: Clinically notable laboratory values .............................................................82
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................83
15 Appendix 3: The classification criteria for psoriatic arthritis (CASPAR) ........................85
16 Appendix 4: ASAS Classification Criteria for Axial Spondyloarthritis (axSpA).............86
17 Appendix 5: Modified New York criteria .........................................................................86
86
87
20 Appendix 8: Guidelines for administering the questionnaires for patient reported 
outcomes............................................................................................................................88
List of tables
Table 5-1
Prohibited medication ...........................................................................41
Table 6-1
Assessment schedule.............................................................................47
Table 6-2
PsAMRIS scoring of MRIs of PsA feet ................................................56
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................68
Table 13-1
Safety analyses: expanded limits and notable criteria...........................82
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................83
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...83
List of figures
Figure 3-1
Study design..........................................................................................25


Novartis
Confidential
Page 6
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
List of abbreviations
ACR
American College of Rheumatology
AE
Adverse event
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
ANCOVA
Analysis of covariance
Anti-CCP
Anti-cyclic citrullinated peptide
AS
Ankylosing Spondylitis
ASAS
Assessment of Spondyloarthritis International Society
axSpA
axial Spondyloarthritis
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
BASDAI
Bath ankylosing spondylitis disease activity index
CASPAR
Classification criteria for Psoriatic Arthritis
CRO
Contract Research Organization
CRP
C-reactive protein
DMARD
Disease Modifying Anti-rheumatic Drug
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
eCRF
electronic Case Report/Record Form
EMA/EMEA
European Medicines (Evaluation) Agency
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
HIV
Human immunodeficiency virus
HLA-B27
Human Leukocyte Antigen B27
HRQoL
Health-related Quality of Life
hsCRP
High sensitivity C-Reactive Protein
IB
Investigator Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFU
Instructions for Use
IL
Interleukin
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
i.v.
intravenous(ly)
LEI
Leeds Enthesitis Index
LFT
Liver function test (raised serum transaminases and/or bilirubin levels)


Novartis
Confidential
Page 7
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
MRI
Magnetic resonance imaging
MTX
Methotrexate
NRS
Numerical rating scale
NSAID
Non-steroidal anti-inflammatory drug 
PCS
Physical Component Summary
PFS
Prefilled syringe
PRN
pro re nata
PRO
Patient Reported Outcome 
PsA
Psoriatic arthritis
PsAMRIS
Psoriatic Arthritis Magnetic Resonance Imaging Score 
RA
Rheumatoid arthritis
RF
Rheumatoid factor 
SAE
Serious adverse event 
s.c.
Subcutaneous(ly)
SF-36
Medical Outcome Short Form (36) Health Survey
SJC
Swollen Joint Count
SmPC
Summary of Product Characteristics
SpA
Spondyloarthritis
SUSAR
Suspected Unexpected Serious Adverse Reactions
TJC
Tender Joint Count
TNF/TNFα
Tumor necrosis factor
TNF IR / TNFα-
IR
TNFα inhibitor inadequate responder
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
White blood cell


Novartis
Confidential
Page 8
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Glossary of terms
Assessment
A procedure used to generate data required by the study.
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which
is used as a comparator to the drug being tested in the trial.
DMARD
Disease modifying anti-rheumatic drug; in this study this term refers 
only to non-biologics.
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the 
protocol).
Inadequate response 
to TNFα
Active disease despite stable treatment with anti-tumor necrosis factor α 
(TNFα) for at least 3 months at a stable dose or for at least one dose in 
the case of lack of tolerance.
Study drug
The drug whose properties are being tested in the study; this definition is 
consistent with US Code of Federal Regulation 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational medicinal
product.”
Study 
treatment
All study drug(s) whose properties are being tested in the study as well
as their associated treatment controls.
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination.
Study treatment generally does not include protocol-specified 
concomitant background therapies when these are standard treatments 
in that indication.
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.
Period
The planned stage of the patient’s participation in the study. Each 
period serves a purpose in the study as a whole.
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.
Premature 
patient 
withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression and/or survival.
Randomization 
number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment.
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.
Responder
A patient with ≥20% improvement from Baseline in both tender joint count
(TJC) and swollen joint counts (SJC).


Novartis
Confidential
Page 9
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for
any reason; may or may not also be the point/time of premature patient
withdrawal.
Patient number
A number assigned to each patient who enrolls into the study.
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.


Novartis
Confidential
Page 10
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Amendment 3
Amendment rationale
The main purpose of this amendment is to allow inclusion of patients, who have been exposed 
to TNFα inhibitors before the study. This change is warranted based on feedback from the 
investigators. This amendment aims to better reflect the entire population of PsA and axSpA 
patients with achilles tendon enthesitis in the study.
The change in the study eligibility criteria does not affect the sample size calculation as this 
was based on the data from study CAIN457F2312 which also allowed the inclusion of up to 
40% TNF-IR patients. Therefore, the sample size in CAIN457F3301 does not change.
Eligibility criteria incl. definitions of wash out periods were added accordingly.
 
 
 The duration of screening 
phase was extended to up to 10 weeks in order to align with duration of wash out period of 
specific TNFα inhibitors. Subsequently the section describing the prohibited medication was 
also updated.
Further adaptations of eligibility criteria were made for clarification purposes and to remove 
inconsistencies.
The requirement of dedicated renal safety monitoring was removed as up to now there has 
been no safety signal for nephrotoxicity with secukinumab in over 12,000 patients and healthy 
subjects exposed, and from a mechanism of action standpoint there is no known effect of 
blocking IL-17A on the kidney. This is also aligned with previous secukinumab phase III 
studies in PsA and AS. Consequently the related appendix 3 (Specific Renal Alert Criteria and 
Actions) was deleted.
The assessment scheduled was updated in a new format and some inconsistencies were 
resolved.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. The 
wording of various sub-sections to “Introduction” (Section 1), “Study objectives and 
endpoints” (Section 2), “Investigational Plan” (Section 3), “Population” (Section 4), 
“Treatment” (Section 5), “Visit schedule and assessments” (Section 6), “Safety Monitoring” 
(Section 7), “Data review and database management” (Section 8), and “Data analysis” 
(Section 9) have been amended to reflect the rationale given above.
A selection of the main changes encompasses:
 
 
 

Section 3.1 - Study design: information was added that it is planned to enroll no more than 
40% TNF-IR patients in the study. Also figure 3-1 (study design) was updated to reflect 
the screening period of 10 weeks.


Novartis
Confidential
Page 11
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301

Section 4.1 - Inclusion criteria:

Inclusion criterion #3 has been changed to change the number of tender as well as of 
swollen joints in patients with active PsA to ≥1

Inclusion criterion #6 has been updated in order to remove the limit of up to 5 years at 
Baseline regarding the duration of onset of heel pain

Inclusion criterion #8: has been updated in order to include TNF-inhibitors in the 
definition of standard treatments.

Inclusion criterion #10: the duration of use of NSAIDs has been rephrased and TNF-
inhibitors have been included to describe required pre-treatment.

Inclusion criterion #16 was added to clarify, that patients must have experienced an 
inadequate response to previous or current treatment given at an approved dose for at 
least 3 months prior to randomization or have been intolerant to at least one 
administration of an anti-TNFα agent

Inclusion criterion #17 was added to define the wash-out periods appropriate for the 
different TNF-inhibitors.

Section 4.2 – Exclusion criteria:

Exclusion criterion #9 has been updated to describe, that Patients who have previously 
been treated with more than two (2) TNF inhibitors (investigational or approved) are 
not eligible for the study.

Exclusion criterion #10 has been updated to clarify, that pre-treatment with biologic 
immunomodulating agents, except those targeting TNFα, is not allowed.

Exclusion criterion #10 has been changed in order to clarify an inconsistency. The 
contraception methods, that are acceptable in this study, are defined as effective 
contraception methods.

Section 5.2 – Treatment arms: updates were included to describe the secukinumab/placebo 
dose for patients previously exposed to TNF inhibitors.

Section 5.3 - Treatment assignment and randomization: the information was added, that it 
is planned to enroll no more than 40% TNF-IR patients in the study.

Section 5.5.8 – Prohibited medication: Table 5-1 has been updated to include information 
on TNF-inhibitors. It was also clarified, that use of analgesics (NSAIDs, low strength 
opioids, paracetamol/acetaminophen) PRN is not allowed until week 24.

Section 6 - Visit schedule and assessments:

Table 6-1 Assessment schedule: the table was updated in a new format and some 
inconsistencies were corrected.

Section 7.4 – Renal safety monitoring: this paragraph has been updated as described above

Appendix 3 - Specific Renal Alert Criteria and Actions has been deleted due to rationale 
described above. All subsequent appendices have been newly numbered.

Appendix 3 (new numbering) - The classification criteria for psoriatic arthritis (CASPAR): 
some information has been added to increase clarity how this score is to be calculated.


Novartis
Confidential
Page 12
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Additionally, this protocol amendment includes 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 changes herein affect the Informed Consent. Therefore, a revised Informed Consent that 
takes into account the changes described in this protocol amendment will be provided and 
submitted for approval. None of the changes described in this amended protocol are made due 
to newly emerged safety considerations.


Novartis
Confidential
Page 13
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Amendment 2
Amendment rationale
This protocol amendment is issued to remove an inconsistency within exclusion criterion #13 
and to clarify that vital signs should be measured at every visit at which hematology and 
blood chemistry samples are taken

To correct the inconsistency of exclusion criterion #13: The contraceptive methods, 
women of child-bearing potential are required to use, are effective methods of 
contraception (according to Clinical Trial Facilitation Group (CTFG) guidance). The term 
“highly effective methods” has therefore been corrected to “effective methods”. The 
listing of acceptable methods described in exclusion criterion #13 already reflected the 
requirement for “effective methods of contraception” and are aligned with previous Phase 
III trials of secukinumab.

To clarify that vital sign assessments should be performed at all visits at which 
hematology and blood chemistry samples are taken.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 4.2: clarification of exclusion #13: The term “highly effective methods” has been 
corrected to “effective methods”

Section 6, Table 6-1: Addition of vital signs at visit 4 (week 2), visit 6 (week 4), visit 8 
(week 12), and visit 10 (week 20), documented in source documentation.
Additionally, this protocol amendment includes 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 changes herein affect the Informed Consent. Therefore, a revised Informed Consent that 
takes into account the changes described in this protocol amendment will be provided and 
submitted for approval. None of the changes made are due to safety concerns and none of the 
changes have an impact on the conduct of the trial or alter in any way the treatment of study 
subjects.
At the time this amendment was written the study was approved in Germany by health 
authority (Paul-Ehrlich-Institut) as well as ethics committee.


Novartis
Confidential
Page 14
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Amendment 1
Amendment rationale
This protocol amendment is issued for the following reasons:

To add central laboratory testing, including hematology and blood chemistry, as well as 
urine testing at the screening visit in the assessment schedule (Table 6-1 Assessment 
schedule). These tests were outlined in exclusion criteria 17-19 already before and results 
of these tests determine eligibility for the study. Thus, the addition to the assessment 
schedule in this amendment is made in order to clarify and remove inconsistencies in the 
trial protocol.

To clarify that approximately 50% of randomized patients should be PsA and axSpA 
patients respectively in order to allow randomization of all eligible patients in screening at 
time point of enrollment stop. 

To clarify that patients who are unable or unwilling to undergo MRI examination of the 
affected foot are not eligible for the study. This was already outlined in section (6.4.1.7 
Magnetic resonance imaging) before. As all patients will be subject to MRI imaging in 
this study, this is now also reflected in the inclusion and exclusion criteria.

To clarify that there will be no Gadolinium contrast agent used for MRI scans performed 
in this study.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 4.2: Addition of exclusion #30: Clarification that patients unable or unwilling to 
undergo MRI scans are not eligible for this study.

Section 5.5: Modified wording to reflect that it is targeted that approximately 50% of 
randomized patients should be PsA and axSpA patients respectively. 

Section 6, Table 6-1: Addition of assessment hematology, blood chemistry, urinalysis at 
screening visit.

6.4.1.7 Magnetic resonance imaging: Deletion of gadolinium containing contrast agent.
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 changes herein affect the Informed Consent. Therefore, a revised Informed Consent that 
takes into account the changes described in this protocol amendment will be provided and 
submitted for approval. None of the changes made are due to safety concerns and none of the 
changes have an impact on the conduct of the trial or alter in any way the treatment of study 
subjects.
At the time this amendment was written no patient has been enrolled in the study.


Novartis
Confidential
Page 15
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Protocol summary
Protocol number
CAIN457F3301
Title
A randomized, double-blind, placebo-controlled multicenter study of 
subcutaneous secukinumab to demonstrate efficacy in the treatment of 
enthesitis at the Achilles tendon up to 1 year in adult patients with active 
Psoriatic Arthritis (PsA) and axial Spondyloarthritis (axSpA) (ACHILLES)
Brief title
Study of efficacy and safety of secukinumab in PsA and axSpA patients 
with active enthesitis including one Achilles tendon site
Sponsor and Clinical 
Phase
Novartis and Phase IIIb
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to demonstrate efficacy, including effects on 
inflammation by magnetic resonance imaging (MRI) assessments, of 
secukinumab on Achilles tendon enthesitis for up to 1 year with a primary 
focus at Week 24, in patients with active PsA and axSpA despite current or 
previous non-steroidal anti-inflammatory drugs (NSAID) and/or disease 
modifying anti-rheumatic drug (DMARD) and/or anti-TNFα therapy.
Data from this study are aimed at broadening secukinumab’s profile as a 
novel treatment option for PsA and axSpA patients with active enthesitis 
including one Achilles tendon site.
Primary Objective
To demonstrate that the efficacy of secukinumab is superior to placebo 
based on the percentage of patients with resolution of Achilles tendon 
enthesitis as assessed by the respective subcomponent of the Leeds 
enthesitis index (LEI) at Week 24 in patients with active PsA and axSpA.
Secondary Objectives
Secondary objectives are to evaluate:
1.
The efficacy of secukinumab at Week 24 is superior to placebo based 
on the mean change of heel pain measured on a 10-point numerical 
rating scale (NRS).
2.
The efficacy of secukinumab at Week 24 is superior to placebo based 
on the percentage of patients with an improvement of bone marrow 
edema in the insertion of the Achilles tendon in the upper part of the 
calcaneus and/or in the insertion of the plantar aponeurosis in the 
lower part of the calcaneus as assessed by the respective 
subcomponent of the Psoriatic Arthritis Magnetic Resonance Imaging 
Score (PsAMRIS) in the affected foot at Baseline.
3.
The efficacy of secukinumab at Week 24 is superior to placebo based 
on the percentage of patients with resolution of enthesitis as assessed 
by the LEI.
4.
The efficacy of secukinumab at Week 24 is superior to placebo based 
on the mean change in physician’s global assessment of disease 
activity.
5.
The efficacy of secukinumab at Week 24 is superior to placebo based 
on the mean change in patient’s global assessment of disease activity.
6.
The efficacy of secukinumab at Week 24 is superior to placebo based 
on the mean change in physician’s global assessment of heel 
enthesiopathy activity.
7.
The efficacy of secukinumab at Week 24 is superior to placebo based 
on the mean change in patient’s global assessment of heel 
enthesiopathy activity.


Novartis
Confidential
Page 16
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
8.
The improvement in secukinumab at Week 24 is superior to placebo 
based on the change from Baseline in Short Form-36 Physical 
Component Summary (SF-36 PCS) or SF-36v2.
9.
To describe the increase in percentage of patients with resolution of 
Achilles tendon enthesitis after switching from placebo to 
secukinumab at Week 24.
10. To describe the increase in mean change of heel pain in patients after 
switching from placebo to secukinumab at Week 24.
11. The overall safety and tolerability of secukinumab.


Novartis
Confidential
Page 17
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Study design
This is a 52-week, randomized, parallel-group, double-blind, multicenter, 
international study consisting of a 10-week screening period, a 24-week, 
placebo-controlled, 
double-blind treatment 
period and a 28-week 
open-label treatment period.
Population
The study population will consist of male and female patients (≥18 years 
old at the time of consent) with active PsA or axSpA presenting active 
enthesitis including one Achilles tendon site that is refractory to standard 
treatment. The Achilles tendon enthesitis must be clinically diagnosed and 
must be MRI-positive according to the investigator`s judgement.
Key Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following 
key inclusion criteria (please refer Section 4.1 for complete list):

Male or non-pregnant, non-lactating female patients at least 18 years of 
age.

PsA patients must fulfill the following criteria: 
o
Diagnosis of PsA classified by CASPAR criteria with symptoms for 
at least 6 months and
o
Active PsA as assessed by ≥1 tender joints out of 78 and ≥1 
swollen joints out of 76 at Baseline (dactylitis of a digit counts as 
one joint each).

AxSpA patients must fulfill the following criteria: 
o
AxSpA as per the classification of the ASAS axSpA criteria with 
objective signs of inflammation at Screening, evident by either MRI 
with Sacroiliac joint inflammation or definite radiographic sacroilitis 
according to the modified NY criteria (both according to source 
documentation) and/or hsCRP > ULN (as defined by central lab) 
and
o
Active disease assessed by total BASDAI ≥4 (0–10) at Baseline.

Diagnosis of Achilles tendon enthesitis according to swelling and 
tenderness at the insertional site of the Achilles tendon into the 
calcaneus.

Onset of heel pain ≥1 month at Baseline.

Heel enthesitis that is MRI-positive according to the investigator`s 
judgement. 

Patients who have been exposed to up to two TNFα inhibitors.

Patients who have previously been on a TNFα inhibitor will be allowed 
enter into study after an appropriate wash-out period prior to 
randomization.
Key Exclusion criteria
Patients fulfilling any of the following key exclusion criteria are not eligible 
for inclusion in this study (please refer Section 4.2 for complete list).
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.
Previous exposure to secukinumab or other biologic drug directly 
targeting IL-17 or IL-17 receptor.
3.
Ongoing use of psoriasis treatments / medications (e.g. topical 
corticosteroids, UV therapy) at randomization. The following washout 
periods need to be observed:
o
Oral or topical retinoids: 4 weeks.


Novartis
Confidential
Page 18
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
o
Photochemotherapy (e.g. PUVA): 4 weeks.
o
Phototherapy (UVA or UVB): 2 weeks.
o
Topical skin treatments (except in face, eyes, scalp and genital 
area during Screening, only corticosteroids with mild to moderate 
potency): 2 weeks.
4.
Patients who have previously been treated with more than two (2) TNF 
inhibitors (investigational or approved).
5.
Patients who have ever received biologic immunomodulating agents 
(investigational or approved), except those targeting TNFα.
6.
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.
7.
History of ongoing, chronic or recurrent infectious disease or evidence 
of tuberculosis infection as defined by a positive QuantiFERON TB-
Gold test. 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 have been initiated.
Study treatment
Study treatment:

Secukinumab 150 mg provided in 1 mL pre-filled syringe (PFS)
Placebo:

Secukinumab placebo provided in a 1 mL PFS
Efficacy assessments

Assessments in all patients:
o
Resolution of Achilles tendon enthesitis as assessed by the 
respective subcomponent of the Leeds enthesitis index (LEI).
o
Enthesitis assessment (LEI).
o
Heel pain (NRS).
o
Physician`s global assessment of disease activity (VAS).
o
Patient’s global assessment of disease activity (VAS).
o
Physician`s global assessment of heel enthesiopathy activity 
(VAS).
o
Patient’s global assessment of heel enthesiopathy activity (VAS).
o
Magnetic Resonance Imaging (MRI) including subcomponents of 
the Psoriatic arthritis magnetic resonance imaging scoring system 
(PsAMRIS).
Key safety assessments

Evaluation of adverse events (AEs)/serious adverse events (SAEs).

Physical examination.

Vital signs.

Height and weight.


Novartis
Confidential
Page 19
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301

QuantiFERON TB-Gold test.

Laboratory evaluations (Hematology, Clinical Chemistry, Urinalysis).

Electrocardiogram (ECG).

Pregnancy and assessment of fertility.

Tolerability of secukinumab.
Other assessments

Medical outcome short form (36) health survey (SF-36 v2).
 

Human leukocyte antigen B27 (HLA-B27)
Data analysis
The primary endpoint, the resolution of Achilles tendon enthesitis at 24 
weeks will be analyzed using a logistic regression model with the factors 
treatment, TNFα inhibitor status and stratification factor diagnosis (PsA or 
axSpA).
Key words
Active 
psoriatic 
arthritis, 
axial 
spondyloarthritides, 
subcutaneous, 
secukinumab in prefilled syringe, enthesitis, achilles tendon


Novartis
Confidential
Page 20
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
1
Introduction
1.1
Background 
Psoriatic Arthritis (PsA) and axial Spondyloarthritis (axSpA) are chronic inflammatory 
diseases which belong to the spectrum of conditions commonly referred to as 
spondyloarthritides (SpA). While the various SpA may be diverse in their clinical 
presentations, common environmental as well as genetic factors associated with susceptibility 
to SpA are suspected (Turkiewicz and Moreland 2007). Axial Spondyloarthritis (axSpA), a 
form of spondyloarthritis, composed of both non-radiographic axial SpA and AS, and where 
radiographic sacroiliitis may or may not be present, is among the most common chronic 
inflammatory joint disorders, with recent estimates of prevalence in Caucasian populations in 
the range of 1–2% (Baraliakos and Braun 2011). Patients with chronic back pain (onset before 
45 years of age) are classified according to the Assessment of Spondyloarthritis international 
Society (ASAS) classification criteria (Rudwaleit et al 2009) for axSpA if they fulfill either 
the clinical arm or the imaging arm of the criteria. Psoriatic arthritis is a frequent chronic 
immune-mediated disease encompassing a spectrum of overlapping clinical entities 
(Moll and Wright 1973). About 10-40% of patients with psoriasis suffer from PsA. It is not 
only more common but also more severe than previously thought (Gladman 2004, 
Taylor et al 2006).
Enthesitis is a frequent manifestation in PsA and SpA and approximately 40% of patients with 
SpA have enthesitis (Haibel and Sieper 2015). The main clinical manifestations of enthesitis 
are represented by pain and swelling at the entheseal sites. The pain, in particular, may be 
severe, persistent and resistent to treatment (D’Agostino et al 2002). Enthesitis is represented 
by inflammation at the enthesis, which is an anatomical area where ligaments, tendons and 
joint capsules attach to the bone (D’Agostino and Olivieri 2006). Enthesitis can occur at any 
site but most frequently localizes in the heel at the ‘premiere enthesis’, the Achilles tendon 
(D’Agostino and Olivieri 2006, Haibel and Sieper 2015, D’Agostino et al 2002). In terms of 
diagnosing enthesitis differential diagnosis should be considered, e.g. mechanical-
degenerative causes and fibromyalgia (Haibel and Sieper 2015). Therefore a straightforward 
approach combining physician-based assessment of Achilles tendon enthesitis with patient-
reported outcomes and imaging techniques such as magnetic resonance imaging (MRI) would 
be the most reliable and appropriate (D’Agostino and Olivieri 2006).
The therapeutic options for enthesitis are limited since only a small number of controlled trials 
have been performed to date. Non-steroidal anti-inflammatory drugs (NSAID) and local 
injections of corticosteroids are recommended for treatment of enthesitis although efficacy 
has only been reported in case studies (Zochling et al 2006, Ritchlin et al 2009). In patients 
with refractory enthesitis therapeutic approach using NSAIDs, physiotherapy or steroid 
injections are often not sufficient (D’Agostino et al 2002). For disease modifying anti-
rheumatic drugs (DMARD) no efficacy could be demonstrated in small open-label clinical 
trials (Haibel et al 2005, Haibel et al 2007). Treatment efficacy in PsA/AS associated 
enthesitis with anti-TNF therapy has been shown using composite indices in clinical trials 
investigating the overall efficacy, tolerability and safety of anti-TNFα agents in PsA/AS 
(Kavanaugh et al 2009, Mease et al 2014, van der Heijde et al 2006). A randomized, double-
blind, placebo-controlled interventional proof-of-concept trial specifically dedicated to 
enthesitis has been performed only by one compound so far (Dougados et al 2010). In this 


Novartis
Confidential
Page 21
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
study efficacy of the TNF antagonist etanercept versus placebo has been studied in 24 SpA 
patients (as defined by Amor’s criteria; Amor et al 1990) that presented heel enthesitis at 
Baseline including positive MRI according to the local radiologist (Dougados et al 2010). 
Endpoints of this 12 week trial included patient’s global assessment of heel enthesiopathy 
activity as the primary endpoint as well as heel pain (on a 100-mm visual analogue scale 
(VAS) scale) and MRI analysis as secondary endpoints. Patient’s global assessment of heel 
enthesiopathy and heel pain showed a statistical significant difference in the etanercept versus 
placebo group whereas no significant changes were observed in the MRI analysis.
Suboptimal treatment with TNF blockers has been further demonstrated by a retrospective 
systematic monocenter study that assessed the frequency and effectiveness of switching TNF 
blockers in SpA and compared patient characteristics with regard to requirement for switching. 
Interestingly patients who switched the TNF blocker had more peripheral enthesitic symptoms 
(59.7% switchers versus 40.3% non-switchers, p = 0.01) and a tendency for more peripheral 
involvement (65.3% switchers vs. 51.0% non-switchers, p = 0.06) (Dadoun et al 2011). 
Considered together, these study findings indicate there is still a large unmet medical need for 
optimal conventional drug treatment in patients suffering from enthesitis and enthesitis-related 
diseases.
Interleukin (IL) - 17 antagonism represents a novel therapeutic approach aimed at interference 
with the chronic inflammatory process by selectively targeting the predominant 
proinflammatory cytokine of the helper T17 cell subset. Over the past years data accumulated 
that strongly support IL-17 to be a key mediator in enthesial inflammation 
(Sherlock et al 2012, Lories and McInnes 2012). Several approaches in the pre-clinical setting 
give a rationale that IL-17 could be the cytokine of interest when specifically targeting 
enthesitis (Sherlock et al 2012, Ebihara et al 2015, Benham et al 2014). Secukinumab 
(AIN457) is a high-affinity fully human monoclonal anti-human antibody that neutralizes IL-
17A activity that is approved in Europe for the treatment of PsA (involving pivotal Phase III 
trials: CAIN457F2306 and CAIN457F2312) and AS (involving pivotal Phase III trials 
CAIN457F2305 and CAIN457F2310).
In the CAIN457F2312 study in patients with PsA, 48.2% and 42.2% of patients treated with 
secukinumab 300 mg and 150 mg s.c. showed complete resolution of enthesitis at Week 24 
versus 21.5% of patients treated with placebo (P< 0.05) for those patients with symptoms at 
Baseline. These responses were sustained and even further increased up to 53.6% (300 mg) 
and 48.4% (150 mg) at Week 52. Similar findings were obtained in the CAIN457F2306 study 
in patients with PsA, where 80.0% of patients in the secukinumab 10 mg/kg-75 mg group and 
75.0% of patients in the secukinumab 10 mg/kg-150 mg group achieved complete resolution 
of enthesitis in the enthesitis subset at Week 104. Furthermore in the CAIN457F2305 study in 
patients with AS, secukinumab showed greater improvement in enthesitis compared with
placebo; the change from Baseline in total maastricht ankylosing spondylitis enthesitis score 
(MASES) was −1.70 for intravenous (IV)-75 mg (p = 0.0183) and −1.79 for IV-150 mg 
(p = 0.0089) vs. −0.87 for placebo. The improvements observed at Week 16 in the IV-75 mg 
and IV-150 mg groups were sustained up to Week 52. However, in the CAIN457F2310 study 
findings on the MASES index did not consistently show improvements in the secukinumab 
dose groups compared with placebo. At Week 16, the LS mean change from Baseline in the 
MASES total score was −0.82 for 150 mg (unadjusted p=0.4264) and −1.43 for 75 mg 
(unadjusted p=0.5950) vs. −1.19 for placebo. But, the numerical improvements observed at 
Week 16 in the 75 mg and 150 mg groups were generally sustained up to Week 52.


Novartis
Confidential
Page 22
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Given (1) the suboptimal treatment of refractory enthesitis to date, (2) the crucial role of IL-17 
for the inflammatory process at the entheses, and (3) the promising enthesitis data from the 
large phase III trials of secukinumab great pre-requisites are in place to gain deeper 
understanding of enthesitis treatment with an anti-IL-17A approach. Therefore this trial would 
aim for a straightforward approach by (1) focusing on the heel with the Achilles tendon as the 
primary enthesial site, (2) using physician-based assessment of Achilles tendon enthesitis for 
the primary endpoint and (3) monitor treatment efficacy by patient-reported outcomes and 
MRI as a high-resolution imaging technique.
1.2
Purpose 
The purpose of this study is to demonstrate efficacy, including effect on inflammation by MRI 
assessments, of secukinumab on Achilles tendon enthesitis for up to 1 year with a primary 
focus at Week 24, in patients with active PsA and axSpA despite current or previous NSAID ,
DMARD and/or anti-TNFα therapy.
Data from this study are aimed at broadening secukinumab’s profile as a novel treatment 
option for PsA and axSpA patients with active enthesitis including one Achilles tendon site.
2
Study objectives and endpoints
2.1
Primary objective
To demonstrate that the efficacy of secukinumab is superior to placebo based on the 
percentage of patients with resolution of Achilles tendon enthesitis as assessed by the 
respective subcomponent of the Leeds enthesitis index (LEI) at 24 weeks in patients with 
active PsA and axSpA.
2.2
Secondary objectives
Secondary objectives of the study are to evaluate:
1. The efficacy of secukinumab at Week 24 is superior to placebo based on the mean change 
of heel pain measured on a 10-point numerical rating scale (NRS).
2. The efficacy of secukinumab at Week 24 is superior to placebo based on the percentage of 
patients with an improvement of bone marrow oedema in the insertion of the Achilles 
tendon in the upper part of the calcaneus and/or in the insertion of the plantar aponeurosis 
in the lower part of the calcaneus as assessed by the respective subcomponent of the 
Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) in the affected foot at 
Baseline.
3. The efficacy of secukinumab at Week 24 is superior to placebo based on the percentage of 
patients with resolution of enthesitis as assessed by the LEI.
4. The efficacy of secukinumab at Week 24 is superior to placebo based on the mean change 
in physician’s global assessment of disease activity.
5. The efficacy of secukinumab at Week 24 is superior to placebo based on the mean change 
in patient’s global assessment of disease activity.
6. The efficacy of secukinumab at Week 24 is superior to placebo based on the mean change 
in physician’s global assessment of heel enthesiopathy activity.


Novartis
Confidential
Page 23
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
7. The efficacy of secukinumab at Week 24 is superior to placebo based on the mean change 
in patient’s global assessment of heel enthesiopathy activity.
8. The improvement in secukinumab at Week 24 is superior to placebo based on the change 
from Baseline in Short Form-36 Physical Component Summary (SF-36 PCS) or SF-36v2.
9. To describe the increase in percentage of patients with resolution of Achilles tendon 
enthesitis after switching from placebo to secukinumab at Week 24.
10. To describe the increase in mean change of heel pain in patients after switching from 
placebo to secukinumab at Week 24.
11. The overall safety and tolerability of secukinumab.


Novartis
Confidential
Page 24
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
3
.Investigational plan
3.1
Study design
This 
study 
uses 
a 
2-treatment arm, 
randomized, 
parallel-group, 
double-blind, 
placebo-controlled design in patients with PsA and axSpA. The dosing of secukinumab will 
be applied according to the approved European Summary of Product Characteristics (SmPC)
in PsA and AS disease. In case of axSpA patients with objective signs of inflammation at 
screening, evident by either MRI with Sacroiliac joint inflammation (according to source 
documentation) and/or hsCRP > upper limit of normal (ULN, as defined by central lab) ,
secukinumab/placebo will be applied as 1 (1.0 mL pre-filled syringe (PFS) of 150 mg dose) 
s.c. injection. At Baseline approximately 200 patients will be randomized. Randomization will 
occur to 1 of the following 2 treatment groups in a ratio of 1:1:

Group 1 (secukinumab): secukinumab as 1 (1.0 mL pre-filled syringe (PFS) of 150 mg 
dose) s.c. or 2 (2 x 1.0 mL PFS of 150 mg dose, 300 mg) s.c. injections according to 
axSpA or PsA disease (including extent of psoriasis and TNF-inhibitor status) at Baseline, 
Weeks 1, 2, and 3, followed by administration every 4 weeks starting at Week 4.

Group 2 (placebo): placebo as 1 (1.0 mL PFS) or 2 (2 x 1.0 mL PFS) s.c. injections 
according to axSpA or PsA disease (including extent of psoriasis and TNF-inhibitor status) 
at Baseline, Weeks 1, 2, 3, followed by administration every 4 weeks starting at Week 4.
Additionally, it is planned to enroll no more than 40% TNF-IR patients in the study.
Starting at Week 24, patients who have been randomized to placebo at Baseline will all 
switch to secukinumab. They will receive the dose according to their disease (PsA or axSpA). 
Therefore they will receive secukinumab 150 mg (1.0 mL PFS of 150 mg dose s.c.) or 300 mg 
(2 x 1.0 mL PFS of 150 mg dose s.c.). Secukinumab will be administered without a loading 
phase every 4 weeks (Figure 3-1). Thus, starting at Week 24, patients in both groups will 
receive secukinumab either 150 mg or 300 mg as 1 or 2 injections of 1 mL/150 mg in PFS in 
an open-label fashion until Week 52 (last dose given at Week 48). However, original
randomized treatment assignment to secukinumab or placebo will remain double-blinded to 
all patients, investigators, and site personnel, whereas the Sponsor (including the Region 
Europe Clinical Team, statisticians and data management) will be unblinded after the 
Week 24 database lock (see Section 3.5) and analyses are completed (see Section 9.7).
After the Week 52 database lock and analyses have been completed, investigators, site 
personnel and patients may be unblinded to the original randomized treatment assignment at 
Baseline. nr-axSpA patients with objective signs of inflammation at Screening, evident by 
either MRI with sacroiliac joint inflammation (according to source documentation) and/or 
hsCRP > ULN (as defined by central lab) who successfully complete the 1 year trial duration 
and were benefiting from secukinumab may be given the opportunity to enter an extension 


Novartis
Confidential
Page 25
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
study. If an extension study is agreed on, it will be described in a separate extension study 
protocol.
Rescue medication will not be allowed before the completion of Week 24 assessments (see 
Section 5.5.6). Although no patient will be restricted from receiving necessary rescue 
medications for lack of benefit or worsening of disease, if rescue with prohibited biologics (as 
described in Section 5.5.8) occurs prior to completion of Week 24 assessments, patients will 
be discontinued from the study after an end of study visit (see Table 6-1).
Primary endpoint is the percentage of patients with resolution of Achilles tendon enthesitis as 
assessed by the respective subcomponent of the LEI at Week 24. Patient-/Physician-reported 
outcomes and outcome measures of feet MRI imaging performed by central reading will serve 
as secondary 
 endpoints. For patients switched from placebo to secukinumab 
at Week 24, efficacy assessments at Week 52 will be particularly important.
Figure 3-1
Study design
3.2
Rationale for study design
The double-blind, randomized, parallel-group, placebo-controlled design used in this study up 
to Week 24 is in alignment with phase III trials of other biologics in this disease area and in 
compliance with the European Medicines (Evaluation) Agency (EMA/EMEA) guidelines 


Novartis
Confidential
Page 26
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
(EMA 2005). Placebo group will be re-assigned to active treatment at Week 24. Unblinding of 
the Novartis Clinical Team will occur after the Week 24 database lock for primary endpoint 
analysis. Nevertheless all investigators, site personnel, patients, and monitors will continue to 
remain blinded to the original randomization to active treatment vs. placebo until the Week 52 
database lock and analyses are completed so as to ensure reliable efficacy and safety 
assessments over time. All patients will be on secukinumab treatment from Week 24 up to 
Week 48. However, data up to 52 weeks is being generated to evaluate the safety and the 
sustainability of response in this population.
The patient population will be described in more detail in the Section 4 below.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The dose (150 mg and 300 mg), dosing regimen (weekly from Baseline to Week 3, monthly 
from Week 4 to Week 52), formulation (liquid in PFSs) and route of administration (s.c.) of 
secukinumab used in this study for patients with PsA are in accordance with the approved 
European SmPC which was supported by the comprehensive PsA (including the pivotal 
Phase 3 CAIN457F2306 and CAIN457F2312 studies) clinical trial program performed to 
assess the efficacy, tolerability and safety of secukinumab. For PsA patients in this trial, 
patients with concomitant moderate to severe psoriasis and patients previously inadequately 
responding to TNF-α inhibitors will receive 300 mg and all other PsA patients will receive 
150 mg secukinumab, according to applicable local regulations.
The dose (150 mg), dosing regimen (weekly from Baseline to Week 3, monthly from Week 4
to Week 52), formulation (liquid in PFSs) and route of administration (s.c.) of secukinumab 
used in this study for patients with AS are in accordance with the approved European SmPC 
which was supported by the comprehensive AS (including the pivotal Phase 3 
CAIN457F2305 and CAIN457F2310 studies) clinical trial program performed to assess the 
efficacy, tolerability and safety of secukinumab.
The dose for patients with nr-axSpA (150 mg secukinumab) as well as dosing regimen 
(weekly from Baseline to Week 3, monthly from Week 4 to Week 52) was chosen in 
accordance with the ongoing clinical development program for this condition (phase 3 study 
CAIN457H2315).
The dose (150 mg), dosing regimen (weekly from Baseline to Week 3, monthly from Week 4 
to Week 52), formulation (liquid in PFSs) and route of administration (s.c.) of secukinumab 
used in this study for axSpA patients with objective signs of inflammation at screening, 
evident by either MRI with Sacroiliac joint inflammation (according to source documentation) 
and/or hsCRP > ULN (as defined by central lab) is based on the Phase 3 trials in AS, 
CAIN457F2305 and CAIN457F2310, assessing the efficacy of both 75 mg and 150 mg s.c. 
maintenance doses with loading regimens consisting of either intravenous doses 
(CAIN457F2305: 3 doses of 10 mg/kg given every 2 weeks at Baseline, Weeks 2 and 4) or 
subcutaneous doses (CAIN457F2310: four weekly doses matching the maintenance dose of 
either 75 mg or 150 mg given at Baseline, Weeks 1, 2, and 3). Given the similarity of the 
ASAS20 and ASAS 40 response at the Week 16 primary endpoint for the 150 mg dose in 
each of these studies, regardless of whether the loading dosing was i.v. (CAIN457F2305: 
60.8% for IV-150 mg vs 28.7% for placebo for ASAS20 and 41.6% for IV-150 mg vs 13.1% 
for placebo for ASAS 40) or s.c. (CAIN457F2310: 61.1% for SC-150 mg vs 27.0% for 


Novartis
Confidential
Page 27
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
placebo for ASAS20 and 36.1% for SC-150 mg vs 10.8% for placebo for ASAS 40), 
secukinumab 150 mg s.c. is a sufficient dose to provide clinically and statistically significant 
efficacy, whereas higher loading doses of secukinumab do not appear to confer greater 
efficacy in AS. Of note, the 75 mg s.c. loading and maintenance regimen tested in 
CAIN457F2310 did not achieve statistically significant improvements in any of the efficacy 
endpoints tested in a pre-defined testing hierarchy, including ASAS20, ASAS 40, hsCRP, 
ASAS5/6, BASDAI, SF-36 PCS and ASQoL. Therefore, there are currently no plans to 
further pursue the 75 mg dose in future axSpA studies. Furthermore, a meta-analysis of trials 
examining TNF-α inhibitors, demonstrated that nr-axSpA patients respond similarly well to 
biologic anti-TNF treatments as AS patients (Callhoff et al 2014). There was no evidence that 
different axSpA populations (e.g. AS and nr-axSpA) could require different dose regimens 
(Callhoff et al 2014, Landewé et al 2014). As other phase III trials of TNF-α inhibitors in 
nr-axSpA also evaluated dosages that already proved to be efficacious in AS, this study will 
use the secukinumab dose of 150 mg s.c. for axSpA patients with objective signs of 
inflammation at Screening, evident by either MRI with Sacroiliac joint inflammation 
(according to source documentation) and/or hsCRP > ULN (as defined by central lab).
This study is evaluating the efficacy, including effects on inflammation of secukinumab 
150 mg s.c. dose with or without loading regimen and 300 mg s.c. dose with or without 
loading regimen for the treatment of Achilles tendon enthesitis in patients with active PsA and 
axSpA.
Data from this study are aimed at broadening secukinumab’s profile as a novel treatment 
option for PsA and axSpA patients with active enthesitis including one Achilles tendon site.
This study employs active secukinumab treatment groups with:

Loading regimen at 150 mg s.c. administered at Baseline, Weeks 1, 2 and 3, followed by a 
maintenance regimen of 150 mg s.c. every 4 weeks starting at Week 4.

Loading regimen at 300 mg s.c. administered at Baseline, Weeks 1, 2 and 3, followed by a 
maintenance regimen of 300 mg s.c. every 4 weeks starting at Week 4.

No load regimen of doses of 150 mg s.c. or 300 mg s.c. administered every 4 weeks in 
placebo group starting at Week 24.
The loading regimen is supported by model-based analyses using data from psoriasis studies, 
predicting significantly improved psoriasis area and severity index 75 response rate after 
12 weeks of treatment, compared to the response rates with monthly dosing. A loading 
regimen with 4 weekly doses of either 150 mg s.c. or 300 mg s.c. is expected to sustain rapid 
onset and greater magnitude of the effect of secukinumab on resolution of Achilles tendon 
enthesitis in patients with PsA and axSpA. The loading regimen with 4 weekly doses of either 
150 mg s.c. or 300 mg s.c. is also expected to have a rapid and improved effect on the 
inhibition of inflammation and structural damage. The approach for the no-load regimen has 
also been employed in this study in placebo group starting at Week 24 to investigate the onset 
and sustainability of efficacy of secukinumab 150 mg s.c. and 300 mg s.c. administered every 
4 weeks in patients with PsA and axSpA. Assessment of joint and/or bone structure 
preservation is planned to be assessed using MRI scan.
Duration of treatment for up to 1 year has been chosen since Achilles tendon enthesitis ne eds 
comparably more time to resolve than other PsA and axSpA manifestations especially with 
regards to structural preservation. In the "Heel" trial no significant changes in MRI parameters 


Novartis
Confidential
Page 28
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
could be observed at Week 12 (Dougados et al 2010). Placebo patients who switch at 
Week 24 would thereby be on active treatment for 6 months.
3.4
Rationale for choice of comparator
A placebo group is included in this study up to Week 24. Due to the nature of the disease and
the primary outcome measure used (percentage of patients with resolution of Achilles tendon 
enthesitis as assessed by the respective subcomponent of the LEI), 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 24 weeks. The continuation of the 
placebo group up to Week 24 can be supported from an ethical standpoint. Firstly, patients 
can continue on 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 Food and Drug Administration (FDA) 1999/EMA 2006, 
and the parallel-group, placebo-controlled design is in alignment with phase III trials of other 
biologics in this therapeutic domain as outlined in EMA guidelines (EMA 2006).
3.5
Purpose and timing of interim analyses/design adaptations
The primary endpoint analysis will be performed after all patients have completed the visit 
associated with the primary endpoint (Week 24). The interpretation of the MRI data will be 
performed by an imaging service provider and readers will be blinded to the treatment as well 
as visit information. The final analysis will be conducted after all patients have completed the 
study (Week 52). Additional analyses may be performed to support interactions with health 
authorities, as necessary.
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) 
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.
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, RA, AS, PsA, multiple sclerosis 
and uveitis). Overall secukinumab was generally safe and well-tolerated.
The risk profile of secukinumab in AS and PsA 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 


Novartis
Confidential
Page 29
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
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. No new or unexpected safety signals were detected in any AS and PsA study for any 
dose regimen and the safety profile in this patient population was consistent with the safety 
profile observed in other indications including psoriasis.
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 brochure (IB).
4
Population
The study population will consist of male and female patients (≥18 years old at the time of 
consent) with active PsA or axSpA presenting active enthesitis including one Achilles tendon 
site that is refractory to standard treatment as defined in Section 4.1 and Section 4.2.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Patient must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must provide written, signed and dated informed 
consent before any study assessment is performed.
2. Male or non-pregnant, non-lactating female patients at least 18 years of age.
3. PsA patients must fulfill the following criteria: 

Diagnosis of PsA classified by CASPAR criteria with symptoms for at least 6 months
( Appendix 3) and

Active PsA as assessed by ≥1 tender joints out of 78 and ≥1 swollen joints out of 76 
at Baseline (dactylitis of a digit counts as 1 joint each).
4. AxSpA patients must fulfill the following criteria: 

AxSpA as per the classification of the ASAS axial SpA criteria (Appendix 4) with 
objective signs of inflammation at screening, evident by either MRI with Sacroiliac 
joint inflammation or definite radiographic sacroilitis according to the modified 
New York criteria (Appendix 5) (both according to source documentation) and/or 
hsCRP > ULN (as defined by central lab) and

Active disease assessed by total BASDAI ≥ 4 (0-10) (Appendix 6) at Baseline.
5. Diagnosis of Achilles tendon enthesitis according to swelling and tenderness at the 
insertional site of the Achilles tendon into the calcaneus.
6. Onset of heel pain ≥1 month at Baseline.
7. Heel enthesitis that is MRI-positive according to the investigator`s judgement.
8. The heel enthesitis must have been refractory to standard treatment defined as either
NSAIDs for at least 1 month at the maximal recommended or tolerated dose unless 
withdrawal because of intolerance, toxicity or contraindications or TNF-inhibitors as 
described in inclusion criterion 16.
9. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies 
negative at Screening.
10. Patients should have been on NSAIDs at the highest recommended dose for at least 1 
month prior to randomization with an inadequate response or failure to respond, or less if 


Novartis
Confidential
Page 30
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
therapy had to be withdrawn due to intolerance, toxicity or contraindications or on TNF-
inhibitors as described in inclusion criterion 16.
11. Patients who are regularly taking NSAIDs as part of their PsA or axSpA therapy are 
required to be on a stable dose for at least 2 weeks before study randomization and should 
remain on a stable dose up to Week 24.
12. Patients taking corticosteroids must be on a stable dose of ≤10 mg/day prednisone or 
equivalent for at least 2 weeks before randomization and should remain on a stable dose 
up to Week 24.
13. Patients taking MTX (7.5 mg/week to 25 mg/week) or - only in case of axSpA -
sulfasalazine (≤3 g/day) are allowed to continue their medication and must have taken it 
for at least 3 months and have to be on a stable dose for at least 4 weeks prior to 
randomization and should remain on a stable dose up to Week 24.
14. Patients on MTX must be on folic acid supplementation at randomization.
15. Patients who are on a DMARD other than MTX or - only in case of axSpA - sulfasalazine 
must discontinue the DMARD 4 weeks prior to randomization, except for leflunomide, 
which has to be discontinued for 8 weeks prior to randomization unless a cholestyramine 
washout has been performed.
16. Patients who have been on a TNFα inhibitor (not more than two) must have experienced 
an inadequate response to previous or current treatment given at an approved dose for at 
least 3 months prior to randomization or have been intolerant to at least one administration 
of an anti-TNFα agent
17. Patients who have previously been on a TNFα inhibitor will be allowed entry into study 
after an appropriate wash-out period prior to randomization:

4 weeks for etanercept – with a terminal half-life of 102 ± 30 hours (s.c. route)

8 weeks for infliximab – with a terminal half-life of 8.0-9.5 days (i.v. infusion)

10 weeks for adalimumab – with a terminal half-life of 10-20 days (average 2 weeks) 
(s.c. route)

10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days

10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days
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. Previous exposure to secukinumab or other biologic drug directly targeting IL-17 or IL-17 
receptor.
4. 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.
5. Ongoing use of psoriasis treatments / medications (e.g. topical corticosteroids, UV therapy) 
at randomization. The following wash out periods need to be observed:


Novartis
Confidential
Page 31
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301

Oral or topical retinoids: 4 weeks.

Photochemotherapy (e.g. PUVA): 4 weeks.

Phototherapy (UVA or UVB): 2 weeks.

Topical skin treatments (except in face, eyes, scalp and genital area during screening, 
only corticosteroids with mild to moderate potency): 2 weeks.
6. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
7. Any intramuscular or intravenous corticosteroid treatment within 4 weeks before 
randomization.
8. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
randomization.
9. Patients who have previously been exposed to more than two (2) TNF inhibitors 
(investigational or approved).
10. Patients who have ever received biologic immunomodulating agents, except those 
targeting TNFα.
11. 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).
12. 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.
13. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment and minimum 16 weeks or longer if local label requires it (e.g. 
20 weeks in EU) after stopping the study medication. Effective contraception methods 
include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least 6 weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository.

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 


Novartis
Confidential
Page 32
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential. 
14. Active ongoing inflammatory diseases other than PsA and axSpA that might confound the 
evaluation of the benefit of secukinumab therapy, including inflammatory bowel disease 
or uveitis.
15. 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.
16. 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), and uncontrolled diabetes.
17. History of clinically significant liver disease or liver injury as indicated by abnormal liver 
function tests (LFT) such as aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase (AST/SGOT), alanine aminotransferase/ serum glutamic pyruvic 
transaminase (ALT/SGPT), alkaline phosphatase, or serum bilirubin. The investigator 
should be guided by the following criteria:

Any single parameter may not exceed 2 × 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.

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).
18. 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).
19. Screening total white blood cell (WBC) count < 3000/µL, or platelets < 100000/µL or 
neutrophils < 1,500/µL or hemoglobin < 8.5 g/dL (85 g/L).
20. Active systemic infections during the last 2 weeks (exception: common cold) prior to 
randomization.
21. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis 
infection as defined by a positive QuantiFERON TB-Gold test. 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 have been initiated.
22. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at 
screening or randomization.
23. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for basal cell carcinoma or actinic 
keratoses that have been treated with no evidence of recurrence in the past 3 months, 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been 
removed).


Novartis
Confidential
Page 33
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
24. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
investigator renders the patient unsuitable for the trial.
25. Inability or unwillingness to undergo repeated venipuncture (e.g. because of poor 
tolerability or lack of access to veins).
26. 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.
27. Donation or loss of 400 mL or more of blood within 8 weeks before randomization.
28. History or evidence of ongoing alcohol or drug abuse, within the last 6 months before 
randomization.
29. Plans for administration of live vaccines during the study period or within 6 weeks 
preceding randomization.
30. Inability or unwillingness to undergo MRI of the feet (e.g., patients with pacemakers, or 
metal fragments / foreign objects in the body that are not compatible with performing an 
MRI of the feet)
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Novartis will supply the following:

Study treatment:
Secukinumab 150 mg provided in 1 ml PFS.

Placebo:
Secukinumab placebo provided in a 1 ml PFS.
The PFSs are packed in a double blinded fashion and do not need to be prepared. The study 
treatments will be labeled as follows:

Double-blind secukinumab and placebo PFS will be labeled as AIN457 
150 mg/1ml/Placebo for dosing till Week 24.

Open-label secukinumab PFS will be labeled as AIN457 150 mg/1ml.
Note: The secukinumab PFSs are packed in double-blinded fashion until Week 24 when 
open-label treatment is started and, therefore, do not need to be prepared by the study site. 
Starting at Week 24, open-label medication will be supplied until the last dose is given at 
Week 48.
For detailed instructions on the storage of the study treatments, please refer to Section 5.5.3.
5.1.2
Additional treatment
No additional treatment beyond study drug and control drug are included in this trial.
5.2
Treatment arms
Patients will be randomized to one of the following 2 treatment groups in a 1:1 ratio as 
depicted below:


Novartis
Confidential
Page 34
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301

Group 1: secukinumab 150 mg/300 mg s.c.: secukinumab as 1 (1.0 mL PFS of 150 mg 
dose) s.c. or 2 (2 × 1.0 mL PFS of 150 mg dose, 300 mg) s.c. injections at Baseline, 
Weeks 1, 2, and 3, followed by administration every 4 weeks starting at Week 4.
o
PsA patients, who have been previously exposed to TNF blockers, and/or with 
concomitant moderate to severe plaque psoriasis receive 2 (two) 1.0 mL PFS of 150 mg 
dose (i.e. 300 mg) s.c..
o
Other PsA patients and axSpA patients receive 1 (one) 1.0 mL PFS of 150 mg dose 
s.c..

Group 2: placebo s.c. followed by secukinumab 150 mg/300 mg s.c. at Baseline, Weeks 1, 
2, and 3, followed by administration every 4 weeks starting at Week 4.2
o
PsA patients, who have been previously exposed to TNF blockers, and/or with 
concomitant moderate to severe plaque psoriasis receive placebo as 2 (two) 1.0 mL 
PFS s.c..
o
Other PsA patients and axSpA patients receive placebo as 1 (one) 1.0 mL PFS s.c..
At Week 24, all patients in Group 2 will switch to their pre-assigned secukinumab 
treatment
Patients will receive study treatment at Baseline, Weeks 1, 2, and 3, followed by treatment 
every 4 weeks through Week 52 (last dose given at Week 48). At Week 24, patients originally 
randomized to placebo will switch to receive secukinumab 150 mg (1 injection of 
secukinumab 1 mL/150 mg) or secukinumab 300 mg (2 injections of secukinumab 
1 mL/150 mg) in open-label fashion without a loading regimen. Blinding to the original 
treatment assignment will be maintained until after the Week 52 database lock and analyses 
are completed (see Section 5.4). Patients will self-administer all secukinumab and placebo 
doses as described in Section 3.1 at the study site or at home at indicated study visits (see
Table 6-1) through Week 52.
5.3
Treatment assignment and randomization 
At Baseline, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to 1 of the 2 treatment arms 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, 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 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).
Patients will be stratified at randomization on the basis of PsA or axSpA disease. Based on 
enrollment target, it is planned that approximately 50% of randomized patients should be PsA 


Novartis
Confidential
Page 35
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
and approximately 50% axSpA patients to ensure a balanced patient population for the 
assessment of efficacy and safety.
Additionally, it is planned to enroll no more than 40% TNF-IR patients in the study.
The randomization scheme for patients will be reviewed and approved by a member of the 
Integrated Quantitative Sciences Randomization Group.
5.4
Treatment blinding
Patients, investigator staff and persons performing the assessments remain blinded to the 
identity of the treatment from the time of randomization until Week 52 database lock, using 
the following methods:

Up until the Week 52 database lock and analyses are completed, all original randomized 
treatment assignments will be double-blinded to patients, investigators, and site personnel.

Following the Week 24 database lock, the Sponsor will be unblinded to treatment
assignment.

After the Week 52 database lock and analyses have been completed, site personnel and 
patients may be unblinded to the original randomized treatment assignment at Baseline.
The identity of the original randomized treatments administered through Week 24 will be 
concealed up to the Week 52 database lock and analyses are completed by the use of study 
treatments in the form of PFS that are all identical in packaging, labeling, schedule of 
administration, appearance, and odor.
Patients will be instructed by site staff on how to self-administer the s.c. injection using the 
PFS containing the liquid formulation of secukinumab, based on the Instructions for Use 
(IFU). The study drug will be administered by the patient into the appropriate injection site of 
the body s.c. under the supervision of the site staff. All injections through Week 52 will be 
performed at the study site or at home (see Table 6-1).
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9), at the time 
of the interim analysis (see Section 9.7) and at the conclusion of the study.
The hsCRP results from samples collected during the treatment period will be revealed to 
everyone involved in the study only after the Week 52 database lock and analyses are 
completed.
As a primary efficacy analysis will be performed at Week 24, there will be a database lock 
when all patients have completed Week 24 assessments. 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 52 week study.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial-related
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Patient Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the investigator. Once assigned to a 
patient, the Patient Number will not be reused.


Novartis
Confidential
Page 36
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site must 
select the CRF book with a matching Patient Number from the Electronic Data Capture
system to enter data.
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
period Study Disposition eCRF.
Patients may be re-screened once and will receive a new Patient Number after they have been 
re-consented. Patients who are mis-randomized cannot be re-screened; mis-randomization 
occurs when a patient who does not meet all eligibility criteria receives a randomization 
number incorrectly.
5.5.2
Dispensing the study drug 
Each study site will be supplied with study treatment for secukinumab/placebo in packaging 
of identical appearance.
The study drug packaging has a 2-part label. A unique randomization number is printed on 
each part of this label which corresponds to 1 of the 2 treatment groups. Investigator staff will 
identify the study treatment packages to dispense to the patient by contacting the IRT and 
obtaining the medication numbers. Immediately before dispensing the package to the patient, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique patient number.
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Pharma Organization Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number.
The PFS (150 mg active/placebo) sealed in an outer box must be stored in a access 
controlled/locked refrigerator between 2°C and 8°C (36°F and 46°F) and protected from light. 
They must be carefully controlled in accordance with regulations governing study medicinal 
products and local regulations.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the next site visit, at the end of the study 
or at the time of discontinuation of study treatment.


Novartis
Confidential
Page 37
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment 
Study treatment (150 mg secukinumab and placebo) will be administered by s.c. PFSs 
throughout the study. Administration of study treatment will occur at the study site or at home 
from Baseline up to Week 52.
All study treatment kits assigned to the patient during the study will be recorded in the IRT.
The PFS with the ready-to-use study treatment solution will be provided by the site staff to the 
patient. Detailed instructions on the self-administration of the study treatment will be 
described in IFU and provided to each patient. At the Baseline visit, patients will be instructed 
by the site staff, utilizing the IFU, on how to self-inject using a PFS. Patients will be asked to 
raise questions, if they have any, and then to proceed with self-injection. The first study 
treatment administration will occur at the Baseline visit only after eligibility criteria have been 
confirmed, all study scheduled Baseline assessments have been performed and the scheduled 
blood samples have been drawn.
At the Week 1 visit, patients will be asked to refer to the IFU and to proceed directly with 
self-injection of the study drug (i.e. no prior retraining) for the remainder of the trial. However, 
if the patient is not comfortable self-injecting the study treatment, then the site staff or 
caretaker may administer it for the patient.
At each subsequent visit, all study assessments, including the completion of patient-reported 
outcomes (as applicable per Table 6-1), should be completed prior to the self-injection of 
study treatment.
The investigator must promote compliance by instructing the patient to attend the study visits 
as scheduled 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 attend a study visit as scheduled or if he/she is unable for any reason 
to take the study treatment as prescribed.
Subcutaneous administration with pre-filled syringes
Secukinumab solution for subcutaneous injection (150 mg in 1.0 mL active/placebo) will be 
provided in PFSs.
The study treatment solution must be injected into non-affected areas of the skin.
Patients will be instructed by the site staff on how to self-inject study treatment using a PFS, 
following the IFU. The injections will be self-administered into the appropriate site of the 
body (thighs, arms, abdomen), and each injection should be given at a different injection site 
to reduce the risk of reaction. Each new injection should be given at least 1 inch from the 
previously used site. If patient chooses the abdomen, a 2 inch area around the navel should be 


Novartis
Confidential
Page 38
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
avoided. Study drug should not be injected into areas where the skin is tender, bruised, red, or 
hard, or where patient has scars or stretch marks.
Single PFSs will be packaged in individual boxes. The boxes containing the PFSs with study 
treatment solution should be kept at 2°C to 8°C (36°F and 46°F) (Do Not Freeze) and 
protected from light. Prior to administration the boxes containing the PFSs with study 
treatment solution should be allowed to come to room temperature unopened for 
15 minutes-30 minutes prior to injection. Used PFSs should be disposed immediately after use 
in a sharps container OR according to the regulatory needs of the respective countries.
Any PFS for which a defect or malfunction is noticed prior to or during the injection at any of 
the study visits, must be kept at the site until guidance is received from Novartis on whether it 
should be returned to Novartis for investigation or discarded. Devices identified as defective 
should be stored according to local guidelines, until specific instruction is discussed with 
Novartis personnel. Additionally, from Baseline onwards, any noticed defect, malfunction, 
problem during the injections or product complaints with the PFS should be recorded in the 
source document and the Use of Device electronic case report form (eCRF). Sites should 
detail the issue, the date, the kit number and the visit number. Site will be asked to record 
based on their judgment whether the observed issue was primarily related to the device or to 
the user. Device malfunctions should also be immediately reported to Novartis personnel as a 
necessary replacement kit may need to be provided.
Home administration
Up to Week 24, all doses of study treatment will be self-administered by the patient at the 
study site, after the study assessments for the visit have been completed. After Week 24 , the 
patients will be allowed to self-administer the study treatment at home during the optional 
visits in which there are no scheduled site assessments. Optional site visits are included in the 
assessment table for Treatment Period 2 of the study (Table 6-1) and between visits in which 
trial-related procedures are to be conducted. Patients will be allowed to self-administer the 
study treatment via PFS at home or to visit the site during the optional visits to self-administer 
study treatment under the supervision of the site staff. If the patient opts for home 
administration of study treatment and is unable or unwilling to self-administer the treatment 
via PFS, a caregiver may administer the study treatment after Week 24 during Treatment 
Period 2 only. Caregivers should be trained on the IFU prior to administering the study 
treatment to the patient. Information about self-administration i.e. whether the patient
self-administered the study treatment at home or at the site and if a caregiver administered the 
treatment should be recorded on the Dose Administration Record eCRF. Prior to 
self-administration at home, patients should contact the investigator/site staff in case they are 
experiencing any AE/SAEs, or have any concerns. All dates and times of self-administrations 
by the patient during the study must be recorded on the Dosage Administration Record eCRF. 
Immediately before dispensing the package to the patient, site staff will detach the outer part 
of the label from the packaging and affix it to the source document (Drug Label Form) for that 
patient’s unique patient number.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments are not permitted. Study treatment interruption should be 
avoided with the following exceptions:


Novartis
Confidential
Page 39
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Study treatment interruption is only permitted if, in the opinion of the investigator, a patient 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 Dosage Administration Record CRF.
5.5.6
Rescue medication
Rescue medication is defined as medication used to control symptoms that are not adequately 
controlled on study treatment. 
Rescue medication must not be used before completion of Week 24 assessments as previously 
outlined in Section 3.1. Please see Section 5.5.7 and Section 5.5.8 for details on concomitant 
and prohibited medication for this study. Although no patient will be restricted from receiving 
necessary rescue medications for lack of benefit or worsening of disease, if rescue with 
prohibited treatments (as described in Section 5.5.8) occurs prior to completion of Week 24 
assessments, patients will be discontinued from the study.
Use of rescue medication must be recorded on the Concomitant medications in the eCRF page.
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.
Changes in NSAIDs concomitant therapy is permitted after Week 24 assessments as per the 
investigator’s clinical judgment.
Patients taking MTX (7.5 mg/week to 25 mg/week) or sulfasalazine (only in case of axSpA, 
≤3 g/day) are allowed to continue their medication and must have taken it for at least 
3 months and have to be on a stable dose for at least 4 weeks prior to randomization and 
should remain on a stable dose up to Week 24. Any changes in dose or initiation after 
Week 24 must be recorded in the Concomitant medications eCRF page.
After Week 24, the dose and regimen of other concomitant medications may be adjusted 
slowly at the investigator’s discretion and recorded appropriately on the Concomitant 
medications eCRF page.
5.5.7
Concomitant medication 
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.


Novartis
Confidential
Page 40
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
The effect of secukinumab on live vaccines is unknown; therefore live vaccines should not be 
administered during participation in the study. In case a live vaccine has been administered 
due to a medical urgency, study treatment should be interrupted for 12 weeks.
Guidelines for the use of specific medications are provided below:
Methotrexate
Patients taking MTX (up to 25 mg/week) must be on a stable dose for at least 4 weeks before 
randomization and maintained stable until Week 24.
Folic acid
Patients on MTX must be taking folic acid supplementation at randomization and during the 
trial to minimize the likelihood of MTX associated toxicity. 
Sulfasalazine
Patients taking sulfasalazine (≤3 g/day) must be on a stable dose for at least 4 weeks before 
randomization and maintained stable until Week 24. Any changes in dose or initiation after 
Week 24 must be recorded in the Prior/Concomitant medications eCRF page.
Leflunomide wash-out with cholestyramine
In case of leflunomide treatment, a drug wash-out of 8 weeks has to be performed. However, 
another wash-out procedure might be considered. Cholestyramine could be given orally to 
wash-out the drug at a dose of 8 g t.i.d. Cholestyramine has been shown to reduce plasma 
levels of the active leflunomide metabolite by approximately 40% in 24 hours and by 49% to 
65% in 48 hours in 3 healthy volunteers. The administration of cholestyramine is 
recommended in patients who require a drug elimination procedure. If a patient receives 8 g 
t.i.d. for 11 days he/she could be safely randomized 4 weeks after the beginning of the 11-day 
treatment period.
Systemic corticosteroids
Treatment with systemic corticosteroids is permitted up to a maximum daily dosage of 
≤10 mg prednisone equivalent and if the dose was stable within the 2 weeks preceding 
randomization. The patient should remain on a stable dose until Week 24.
Corticosteroid dose reductions below 10 mg prednisone equivalent are permitted after 
Week 24 although the corticosteroid dose should not be reduced more than 1 mg prednisone 
equivalent every 4 weeks.
Any change in the dose of systemic corticosteroids during the trial must be recorded on the 
corresponding eCRF page.
Intra-articular corticosteroids are not permitted within the 4 weeks preceding randomization 
and up to Week 24. After Week 24, no more than 1 joint per 24-week period may be injected. 
No single injection should exceed 40 mg of triamcinolone (or equivalent) and the total dose of 
intra-articular corticosteroid may not exceed 80 mg of triamcinolone (or equivalent) during 
any 52-week period.
Non-steroidal anti-inflammatory drugs (including COX-1 or COX-2 inhibitors), low 
strength opioids and acetaminophen/paracetamol


Novartis
Confidential
Page 41
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Patients should have been on NSAIDs at the highest recommended dose for at least 1 month 
prior to randomization with an inadequate response or failure to respond, or less if therapy had 
to be withdrawn due to intolerance, toxicity or contraindications.
Patients regularly using NSAIDs, low strength opioids, or paracetamol/acetaminophen should 
be on stable dose for at least 2 weeks before randomization to allow inclusion. They should 
remain on a stable dose in the study up to Week 24. However, they have to refrain from any 
intake during at least 24 hours before a visit with disease activity assessment.
After Week 24 assessments are completed, a change in the NSAIDs, low strength opioids, or 
paracetamol/acetaminophen treatment regimen as well as PRN use are permitted.
Any change of the NSAIDs, low strength opioids, or paracetamol/acetaminophen treatment 
during the trial should be recorded in the Prior/Concomitant medications eCRF page.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-1 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 5-1
Prohibited medication
Prohibited medication
Washout period
(before randomization)
Etanercept* 
4 weeks
Infliximab* 
8 weeks
Adalimumab, golimumab, certolizumab* 
10 weeks
Biological immunomodulating agents* except TNF inhibitors as 
described above
Never
Unstable dose of MTX or sulfasalazine (until Week 24)
4 weeks
Other DMARD (incl. apremilast, except MTX and – in case of axSpA -
sulfasalazine)
4 weeks
Leflunomide 
8 weeks
Leflunomide with cholestyramine washout 
4 weeks
Unstable doses of NSAIDs (COX1 or COX2 inhibitors), low strength 
opioids, paracetamol/acetaminophen (until Week 24). After week 24, use 
PRN is allowed.
2 weeks
Analgesics, other than NSAIDs or paracetamol/acetaminophen or low 
strength opioids as described above
2 weeks
Systemic corticosteroids > 10 mg prednisone equivalent** (until Week 
52)
2 weeks
Unstable dose of systemic corticosteroids ≤10 mg prednisone 
equivalent (until Week 24)
2 weeks
Intra-articular injections (until Week 24)
4 weeks
Intramuscular or intravenous corticosteroid treatment
4 weeks
Any cell-depleting therapies including but not limited to anti-CD20 or 
investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, 
anti-CD19)
Never
Any investigational treatment or participation in any interventional Trial
4 weeks or 5 half-lives 
(whichever is longer)


Novartis
Confidential
Page 42
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Prohibited medication
Washout period
(before randomization)
Live vaccines (and until 12 weeks after last study treatment 
administration, see above)
6 weeks
Oral or topical retinoids 
4 weeks
Photochemotherapy (e.g. PUVA) 
4 weeks
Phototherapy (UVA or UVB) 
2 weeks
Topical skin treatments (except in face, eyes, scalp and
genital area during screening, only corticosteroids with mild
to moderate potency)
2 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); PUVA
= psoralen and ultraviolet A; UVA = ultraviolet A; UVB = ultraviolet B: TNF = tumor necrosis factor.
* These agents fall under the category of biologic immunomodulators and are prohibited medications. 
Administration of these agents requires study treatment discontinuation (see Section 5.6.2).
** See details about corticosteroid management in Section 5.5.7.
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un -
blinding can be performed at any time.
Study drug must be discontinued after emergency unblinding.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol i.e. Visit 18/Week 52 (see Table 6-1).
Information on the patient’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the appropriate Study Phase Completion 


Novartis
Confidential
Page 43
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
eCRF page. In any case, the investigator or site staff must contact the IRT as soon as possible 
to record the patient’s study completion and/or discontinuation.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from or complete the study or must refer them for appropriate ongoing care. This 
care may include initiating another treatment outside of the study as deemed appropriate by 
the investigator. Based on the individual risk/benefit profile of a patient, treatment may be any 
non-biologic DMARD. In case of a biologic treatment, a waiting period of 3 months before 
initiating the treatment is recommended.
nr-axSpA patients with objective signs of inflammation at Screening, evident by either MRI 
with sacroiliac joint inflammation (according to source documentation) and/or hsCRP > ULN 
(as defined by central lab) who successfully complete the 1 year trial duration and were 
benefiting from secukinumab 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

Emergence of the following AEs:

Any severe 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 on balance, he/she thinks that continuation 
would be detrimental to the patient’s well-being. While PsA and axSpA are multifaceted 
diseases and the assessment of responder status should be based on the global clinical picture 
and not on a single efficacy parameter; not achieving an improvement (e.g. in the TJC or SJC 


Novartis
Confidential
Page 44
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
of ≥20% [PsA patients]) or BASDAI of ≥20% or ≥1 unit (0-10 scale) (axSpA patients,
Pavy et al 2005) at Week 36 may be considered as a guidance for considering a patient 
inadequate responder to secukinumab treatment.
For patients who discontinue study treatment, a Dosage Administration Record eCRF 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.
Patients who prematurely discontinue during Treatment Period 1 (secukinumab/placebo 
treatment from Baseline through Week 24) should return for assessments associated with 
Week 24 visit (4 weeks after the last study treatment in Treatment Period 1). Patients who 
prematurely discontinue during Treatment Period 2 (secukinumab treatment from Week 24 
through Week 52) should return and complete assessments associated with Week 52 visit 
(4 weeks after the last study treatment in Treatment Period 2, see Table 6-1). 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

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 the 
assessment Table 6.1 below.


Novartis
Confidential
Page 45
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
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 period of the study from Screening to Week 52 (Treatment Periods 1 and 2), the 
assessments must be performed as indicated in Table 6-1.
Preferably, patients should be seen for all visits on the designated day, or within the 
recommended visit window to the original planned visit.

For visits scheduled through Week 4, the study treatment should not be administered less 
than 7 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.
Note: Missed or rescheduled visits should not lead to automatic discontinuation of patients.
Recommended visit windows:

± 2 days for Baseline, Week 1, Week 2, Week 3 and Week 4, Week 24 and Week 52

± 2 days for all study drug home administrations

± 5 days for all other study visits
Patients who prematurely discontinue during a specific treatment period should return for the 
final visit within that treatment period (4 weeks after the last study treatment administration). 
At this final visit, all dispensed study product should be reconciled with the source documents 
including the AE and concomitant medications reconciled on the eCRF.
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 informed consent form (ICF). 
Once patient signs the ICF, he will be screened for eligibility criteria. Screening will be 


Novartis
Confidential
Page 46
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
flexible in duration based on the time required to washout prior antirheumatic and other 
medications and will have a duration of up to 8 weeks (see Section 5.5.5). During Screening 
Visit, initial assessments will be performed as outlined in Table 6-1. At that visit (Screening), 
the duration of the washout period will be determined.
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.
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.


Novartis
Confidential
Page 47
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Table 6-1
Assessment schedule
Screening
Treatment Period 1
Treatment Period 2
Unscheduled visita
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Week
≤ -10
BSL
1
2
3
4
8
12
16
20
24*
TD/PPD
28
32
36
40
44
48
52* 
TD/PPD
Day
≤ -70
1
8
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Recommended visit 
window (± days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
± 5
± 2
± 2
± 2
± 5
± 2
± 2
± 2
± 2
Optional site visit 
because of home 
administration
X
X
X
X
X
Administration of s.c. 
study treatment via PFS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Obtain informed 
consent 
X
Inclusion & Exclusion 
criteriab
X
X
Hepatitis B, C or HIV 
serology (only in 
countries where it is 
required)c
S
Relevant medical 
history/current medical 
condition
X
Washout evaluation/
instruction
S
Smoking history 
X
Cardiovascular medical 
X


Novartis
Confidential
Page 48
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Screening
Treatment Period 1
Treatment Period 2
Unscheduled visita
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Week
≤ -10
BSL
1
2
3
4
8
12
16
20
24*
TD/PPD
28
32
36
40
44
48
52* 
TD/PPD
Day
≤ -70
1
8
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Recommended visit 
window (± days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
± 5
± 2
± 2
± 2
± 5
± 2
± 2
± 2
± 2
history
Demography
X
PsA/axSpA medical 
history and previous 
therapies
X
Physical exam
S
S
S
S
S
S
S
S
Height
X
Weight
X
Vital signsd
X
X
S
S
X
S
X
S
X
X
X
X
QuantiFERON TB-Gold 
test
X
X
Chest X-ray/MRIe
S
Serum pregnancy test
X
X
Urine pregnancy test
X
X
X
X
X
X
X
Xf
Xf
X
Xf
Xf
Xf
X
X
Rheumatoid factor
X
Anti-CCP
X
Electrocardiogramg
X
X
X


Novartis
Confidential
Page 49
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Screening
Treatment Period 1
Treatment Period 2
Unscheduled visita
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Week
≤ -10
BSL
1
2
3
4
8
12
16
20
24*
TD/PPD
28
32
36
40
44
48
52* 
TD/PPD
Day
≤ -70
1
8
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Recommended visit 
window (± days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
± 5
± 2
± 2
± 2
± 5
± 2
± 2
± 2
± 2
Randomization via IRT
X
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
X
X
X
X
Assessments only in PsA patients
CASPAR criteria 
X
Assessments only in axSpA patients
ASAS 
criteria/modified New 
York criteriah
X


Novartis
Confidential
Page 50
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Screening
Treatment Period 1
Treatment Period 2
Unscheduled visita
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Week
≤ -10
BSL
1
2
3
4
8
12
16
20
24*
TD/PPD
28
32
36
40
44
48
52* 
TD/PPD
Day
≤ -70
1
8
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Recommended visit 
window (± days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
± 5
± 2
± 2
± 2
± 5
± 2
± 2
± 2
± 2
Assessments for all patients
Heel pain
X
X
X
X
X
X
X
X
X
X
X
X
X
MRI of the affected 
foot
X
X
X
X
Prior/Concomitant 
medication/non-drug 
therapy
X
X
X
X
X
X
X
X
X
X
X
Xi
Xi
X
Xi
Xi
Xi
X
X
AEs/SAEsj (including 
injection site 
reactions)
X
X
X
X
X
X
X
X
X
X
X
Xk
Xk
X
Xk
Xk
Xk
X
X
LEI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s assessment 
of heel enthesiopathy 
activity
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician’s 
assessment of heel 
enthesiopathy activity
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s global 
assessment of 
disease activity
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician`s global 
assessment of 
X
X
X
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 51
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Screening
Treatment Period 1
Treatment Period 2
Unscheduled visita
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Week
≤ -10
BSL
1
2
3
4
8
12
16
20
24*
TD/PPD
28
32
36
40
44
48
52* 
TD/PPD
Day
≤ -70
1
8
15
22
29
57
85
113
141
169
197
225
253
281
309
337
365
Recommended visit 
window (± days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
± 5
± 2
± 2
± 2
± 5
± 2
± 2
± 2
± 2
disease activity
SF-36 v2
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, blood 
chemistry, urinalysism
X
X
X
X
X
X
X
X
X
X
X
X
HLA-B27
X
Treatment period 1 
completion form 
X
Treatment period 2 
completion form
X
X = assessment to be recorded on clinical database.
S = assessment to be recorded on source documentation only.
* Patients who prematurely discontinue during Treatment Period 1 should return for assessments associated with Week 24 visit (4 weeks after the last study treatment in 
Treatment Period 1). Patients who prematurely discontinue during Treatment Period 2 should return and complete assessments associated with Week 52 visit (4 weeks 
after the last study treatment in Treatment Period 2).
a Unscheduled visit – assessments at discretion of the investigator.
b Eligibility assessments are conducted at Screening and at BSL. The data for both visits should be recorded on the corresponding eSource/eCRF available at SV.


Novartis
Confidential
Page 52
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
C Tests performed during screening period only if required as per local regulators prior to initiation of therapy.
d For Vitals, blood pressure will be measured 3 times and its mean will be analyzed.
e 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
f For home administration test kits will be provided by central lab and test will be performed at home.
g Clinically relevant abnormalities should be recorded on the relevant medical history/Current medical conditions eCRF page for the Baseline ECG. Clinically relevant 
abnormalities noted after the Baseline ECG should be reported as AEs on the Adverse Event eCRF page.
h The following eCRFs are to be completed: axSpA disease background eCRF, modified New York criteria for AS eCRF and history of extra-axial involvement eCRF 
(Extra-axial involvement such as uveitis, psoriasis, inflammatory bowel disease, dactylitis, enthesitis, peripheral arthritis).
i Update as necessary
j 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 84 days after the patient has stopped study participation (whichever is later) must be reported to Novartis within 24 hours of learning of its occurrence.
K Update as necessary
m Kits for urinalysis will be provided by central lab and test is performed locally.
AE = adverse event, Anti-CCP = anti-cyclic citrullinated peptide, ASAS=assessment of spondyloarthritis international society, axPsA =axial psoriatic arthritis (i.e. psoriatic 
arthritis with axial involvement),
,
, BSL = baseline, CASPAR=classification criteria 
for psoriatic arthritis, 
,
, HLA-B27 = human leukocyte antigen B27, 
, IRT= interactive response technology, LEI = leeds enthesitis index, MRI = magnetic resonance imaging, PFS = prefilled 
syringe, PPD = premature patient discontinuation, RF = rheumatoid factor, SAE = serious adverse event, SF-36 v2 = medical outcome short form (36) health survey, TD = 
treatment discontinuation, VAS = visual analog scale.


Novartis
Confidential
Page 53
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
6.1
Information to be collected on screening failures 
Patient may discontinue from the study prior to randomization. These patients are considered 
screening failures.
If a patient discontinues before entering the double-blind treatment period at Baseline, IRT 
must be notified within 2 days and the reason for not being randomized will be entered on the 
Screening Phase Disposition eCRF page. In addition, only the following eCRFs should be 
completed: Demography eCRF, Informed Consent eCRF, Inclusion/Exclusion eCRF, and the 
Adverse Event eCRF should be completed for any SAEs that occurred during the Screening 
period.
Adverse events that are not serious will be followed by the investigator and collected only in 
the source data.
All patients who have signed informed consent and are randomized into the 
Treatment Period 1 of the study will have all AEs occurring after informed consent is 
signed recorded in the Adverse Event eCRF.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and Baseline characteristic data to be collected on all patients and 
recorded in the eCRF include:

Date of birth, age, sex, race, and source of patient referral.

Relevant PsA/axSpA and general medical history/current medical condition data until the 
ICF is signed, such as date of diagnosis of PsA/axSpA, previous PsA/axSpA therapies, 
AS/axSpA functional status, history of extra-axial involvement (uveitis, psoriasis, 
inflammatory bowel disease, dactylitis, enthesitis, peripheral arthritis), date of onset of 
inflammatory back pain, number of previous DMARDs used, cardiovascular medical 
history, smoking history and surgical sterilization for females if applicable.
Whenever possible, diagnoses and not symptoms will be recorded.
6.3
Treatment exposure and compliance 
All dates and times of study treatment administration will be recorded in the appropriate 
eCRF page.
Drugs administered prior to start of treatment and other drugs/procedures continuing or started 
during the study treatment period will be entered in the Prior/Concomitant medications or 
Significant non-drug therapies eCRF page.
Compliance is expected to be 100%, unless temporary interruption is needed for safety 
reasons as described in (Section 5.5.5). Compliance will also be assessed by a Novartis
monitor using information provided by the authorized site personnel.


Novartis
Confidential
Page 54
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
6.4
Efficacy
All efficacy assessments should be performed prior to administration of study treatment.

Assessments in all patients:

Resolution of Achilles tendon enthesitis as assessed by the respective subcomponent 
of the Leeds enthesitis index (LEI).

Enthesitis assessment (LEI).

Heel pain (NRS).

Physician`s global assessment of disease activity (VAS).

Patient’s global assessment of disease activity (VAS).

Physician`s global assessment of heel enthesiopathy activity (VAS).

Patient’s global assessment of heel enthesiopathy activity (VAS).

Magnetic Resonance Imaging (MRI) including subcomponents of the Psoriatic 
arthritis magnetic resonance imaging scoring system (PsAMRIS).
Details relating to the administration of all PROs are provided in Appendix 8.
6.4.1
Assessments in all patients
6.4.1.1
Enthesitis assessment
The LEI is a validated enthesitis index that uses 6 sites for evaluation of enthesitis: lateral 
epicondyle humerus L + R, proximal Achilles L + R and medial condyle femur L + R. 
Tenderness on examination is recorded as either present (1) or absent (0) for each of the 6 
sites, for an overall score range of 0–6. Higher count represents greater enthesitis burden.
The LEI demonstrated substantial to excellent agreement with other scores in the indication of 
PsA (Healy and Helliwell 2008) and axSpA (Landewé and van Tubergen 2015).
Resolution of Achilles tendon enthesitis
Resolution of Achilles tendon enthesitis will be assessed by the respective subcomponent of 
the LEI.


Novartis
Confidential
Page 55
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
6.4.1.2
Heel pain
The patient’s assessment of heel pain will be performed using a 10-point numeric rating scale 
(NRS) ranging from ‘no pain’ to ‘unbearable pain’ after the question ‘Please indicate with a 
cross ( X ) at the respective number the most pain you had from your heel today’. 
6.4.1.3
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.
6.4.1.4
Patient’s global assessment of disease activity
The patient’s global assessment of disease activity will be performed using a 100 mm VAS 
ranging from ‘not severe ’ to ‘very severe ’ after the question ‘How active was your disease 
on average during the last week? , Please indicate your response with a vertical mark ( | ) 
through the horizontal line.’
6.4.1.5
Physician’s global assessment of heel enthesiopathy activity
The physician`s global assessment of heel enthesiopathy activity will be performed using 100 
mm VAS ranging from no activity to maximal activity, after the question ‘Considering all the 
ways the heel enthesitis 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 heel enthesiopathy activity, when performing his own 
assessment on that patient.
6.4.1.6
Patient’s global assessment of heel enthesiopathy activity
The patient’s global assessment of heel enthesiopathy activity will be performed using a 
100 mm VAS ranging from ‘not severe’ to ‘very severe ’ after the question ‘How active was 
your heel enthesitis on average during the last week? Please indicate your response with a 
vertical mark ( | ) through the horizontal line.’
6.4.1.7
Magnetic resonance imaging
Disease severity and activity of PsA and axSpA can be evaluated by a variety of modalities, 
including magnetic resonance imaging (MRI). MRI has been frequently used to measure 
outcome of PsA because of its sensitivity in detecting changes in both bone and soft tissues 
(Yanaba et al 2015).
Effects on inflammation in the affected foot at Baseline will be assessed by MRI image 
analysis throughout the trial compared to pre-treatment including the following parameters
(Feydy et al 2012):


Novartis
Confidential
Page 56
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301

Bone marrow oedema in the insertion of the Achilles tendon in the upper part of the 
calcaneus and/or in the insertion of the plantar aponeurosis in the lower part of the 
calcaneus.
 

Periarticular inflammation.

Resolution of signs of active inflammation.

Bone erosions.
MRI analysis will be performed at 3 time points i.e., during pre-treatment, Week 24, and 
Week 52. For patients who discontinue before or at Week 24, a MRI will be performed at the 
time of discontinuation. MRI machines should have field strength of 1.5 Tesla. The MRI 
protocol and required sequences will be described in the imaging acquisition manual.
Except for the local reading of the eligibility scan for trial participation, the readings and 
scoring will be performed centrally. Readers will be blinded to clinical information and to the 
sequence of the images.
Psoriatic arthritis magnetic resonance imaging scoring system 
The PsAMRIS has been developed by the Outcome Measures in Rheumatology Clinical Trial 
(OMERACT, Ostergaard et al 2009, McQueen et al 2009) and was based on the OMERACT 
rheumatoid arthritis
(RA) MRI scoring system (RAMRIS) (Ostergaard et al 2003, 
Haavardsholm et al 2005). The PsAMRIS has shown high inter- and intraobserver reliability 
(Bøyesen et al 2011) and it is thought that this scoring system will be useful in measuring
outcomes in the treatment of PsA. It is composed of the following six subcomponents that are 
assessed by a defined grading scale: synovitis, tenosynovitis, periarticular inflammation, bone 
oedema, bone erosions, bone proliferation.
The PsAMRIS has been originally developed for the hands (Ostergaard et al 2009) but it has 
recently been applied in feet MRI image analysis (Yanaba et al 2015).
Feet MRI images will be assessed for the PsAMRIS subcomponents periarticular 
inflammation, bone oedema and bone erosion by their respective grading scale 
(Ostergaard et al 2003, Ostergaard et al 2009).
Table 6-2
PsAMRIS scoring of MRIs of PsA feet
Periarticular inflammation
Score 0 or 1 
0 = absent
1 = present
Bone oedema
Score 0 to 3*
0 = no oedema 
1 = 1–33% of bone oedematous
2 = 34–66% 
3 = 67–100% 
Bone erosion
Score 0 to 10**
0 = no erosion
1 = 1-10% of bone eroded
2 = 11-20%
3 = 21-30%
4 = 31-40%
5 = 41-50%


Novartis
Confidential
Page 57
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
6 = 51-60%
7 = 61-70%
8 = 71-80%
9 = 81-90%
10 = 91-100%
* The scale is 0–3 based on the proportion of bone with oedema, compared to the “assessed bone 
volume”, judged on all available images.
** The scale is 0–10, based on the proportion of eroded bone compared to the “assessed bone 
volume”, judged on all available images.


Novartis
Confidential
Page 58
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301


Novartis
Confidential
Page 59
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
6.4.4
Appropriateness of efficacy assessments 
The efficacy outcome measures used in this study are the standard measures used across many 
PsA and axSpA trials.
6.5
Safety 

Evaluation of AE/SAEs.

Physical examination.

Vital signs.

Height and weight.

QuantiFERON TB-Gold test.

Laboratory evaluations (hematology, clinical chemistry, urinalysis).

Electrocardiogram.

Pregnancy and assessment of fertility.

Tolerability of secukinumab.
All blood draws and safety assessments should be done prior to study treatment 
administration. Appropriate safety assessments (e.g. evaluation of AEs and SAEs including 
injection site reactions) should be repeated after the dose is administered.
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 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 Adverse Event eCRF page.
6.5.2
Vital signs 
Vital signs (including blood pressure and pulse measurements) will be assessed as indicated in
Table 6-1. After the patient has been sitting for 5 minutes, with back supported and both feet 
placed on the floor, systolic blood pressure (SBP) and diastolic blood pressure (DBP) will 
be measured thrice (1 to 2 minutes apart) using a validated device with an appropriately 
sized cuff (Mancia et al 2007); each BP measurement will be recorded in the source and mean 
of the three measurement will be considered for analysis. In case the cuff sizes available are 


Novartis
Confidential
Page 60
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
not large enough for the patient’s arm, a sphygmomanometer with an appropriately sized cuff 
may be used.
If possible, assessments should be performed per patient by the same study center staff 
member throughout the study.
Normal blood pressure will be defined as a SBP of 90 to < 120 mmHg, and a DBP of 60 to 
< 80 mmHg under the measurement conditions outlined above. Notable blood pressure will be 
hypertension (SBP of ≥ 140 mmHg and/or DBP of ≥ 90 mmHg) or hypotension (SBP of 
< 90 mmHg and/or a DBP of < 60 mmHg). A blood pressure indicative of pre-hypertension 
(SBP of 120 to < 140 mmHg and/or DBP 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 centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but 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 
to 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.


Novartis
Confidential
Page 61
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
6.5.5.1
Hematology
Hemoglobin, platelet, red blood cell, WBC and differential WBC counts will be measured at 
scheduled visits.
6.5.5.2
Clinical chemistry
Serum chemistries will include glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, 
total protein, albumin, and uric acid.
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.
6.5.6
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as indicated in Table 6-1. All ECGs must be 
performed on the ECG machines provided for the study.
All ECGs will be independently reviewed. Instructions for the collection and transmission of 
the ECGs to the independent reviewer will be provided in the ECG investigator manual.
Clinically relevant abnormalities should be recorded on the relevant medical history/Current 
medical conditions eCRF page for the Baseline ECG.
Clinically relevant abnormalities noted after the Baseline ECG should be reported as AEs on 
the Adverse Event eCRF page (see Section 7).
6.5.7
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
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 Screening. All women 
who are not surgically sterile or post-menopausal (as defined in Section 4.2) 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.
6.5.8
Tolerability of secukinumab
Tolerability will be assessed by AEs, laboratory values and injection site reactions.
6.5.9
Additional parameters
Blood will be obtained at Screening (Visit 1) for anti-CCP antibodies and the RF assessment 
(see Table 6-1).


Novartis
Confidential
Page 62
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
6.5.10
Appropriateness of safety measurements 
The safety measures used in this study are reliable and relevant standard measures for a 
biologic in PsA and axSpA. The radiation exposure that results from the chest X-ray safety 
measurements at screening 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. 
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments

Medical outcome short form (36) health survey (SF-36 v2).

Human leukocyte antigen B27 (HLA-B27).
6.6.1
Medical outcome short form (36) health survey
The SF-36 is a widely used and extensively studied instrument to measure HRQoL among 
healthy subjects and patients with acute and chronic conditions. It consists of 8 subscales that 
can be scored individually: physical functioning, role- physical, bodily pain, general health, 
vitality, social functioning, role-emotional, and mental health (Ware et al 1993). Two overall 
summary scores, the PCS and the Mental Component Summary also can be computed 
(Ware et al 1994). The SF-36 has proven useful in monitoring general and specific 
populations, comparing the relative burden of different disease, differentiating the health 
benefits produced by different treatments, and in screening individual patients.
The purpose of the SF-36 in this study is to assess the HRQoL of patients. Given the acute 
nature of this disease, version 2, with a 1-week recall period, will be used in this study.


Novartis
Confidential
Page 63
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
6.6.5
Human leukocyte antigen B27
A blood sample to analyze Human leukocyte antigen-B27 (HLA-B27) will be obtained from 
all patients at Screening.
Details on the collection, handling and shipment of the sample to the central laboratory will be 
provided to investigators in the laboratory manual.
6.6.6
Resource utilization 
Not applicable.
6.6.7
Pharmacokinetics 
Not applicable.
6.6.8
Other biomarkers 
Not applicable.
7
Safety monitoring 
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.


Novartis
Confidential
Page 64
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the Adverse Events eCRF 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 (Yes/No)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of SAE) 
and which seriousness criteria have been met.

action taken regarding study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

study treatment dosage adjusted/temporarily interrupted 

study treatment permanently discontinued due to this adverse event

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the patient informed consent and should 


Novartis
Confidential
Page 65
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
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 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 adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to 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


Novartis
Confidential
Page 66
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to 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 84 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 is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to 
be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
7.3
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 


Novartis
Confidential
Page 67
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
The following two categories of abnormalities/adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation or 
resolution.
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. 
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
To date, there has been no safety signal for nephrotoxicity with secukinumab in over 12,000 
patients and healthy subjects exposed, and from a mechanism of action standpoint there is no 
known effect of blocking IL-17A on the kidney. All subjects with laboratory tests resulting in 
clinically significant abnormal values (see Appendix 1 for notable laboratory values) are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 


Novartis
Confidential
Page 68
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
related AE, is defined. Standard renal function tests (blood urea nitrogen, serum creatinine) 
will be obtained at regular intervals, but special measures for renal safety monitoring are not 
planned.
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 DAR (dose administration record) 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
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in Adverse 
Event eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes, 
Yes, even if not associated 
with a SAE
7.6
Pregnancy reporting 
All women who are not surgically sterile or post-menopausal at Screening will have local 
urine pregnancy tests. A positive urine pregnancy test requires immediate interruption of 
study drug until serum β-hCG is performed and found to be negative.
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.


Novartis
Confidential
Page 69
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
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 eCRFs, the 
adherence to the protocol and to GCP, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization, 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (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 eCRF 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 eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients/subjects will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained.
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the eCRFs are complete and accurate. After database lock, the 
investigator will receive copies of the patient data for archiving at the investigational site. 
8.3
Database management and quality control 
Novartis staff [or CRO working on behalf of Novartis] review the data entered into the eCRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 


Novartis
Confidential
Page 70
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and 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).
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
MRI image analysis will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
All patient questionnaires will be completed using an electronic device, processed centrally 
and sent electronically to Novartis (or a designated CRO).
Randomization codes and data about study drug dispensed to the patient and all dosage 
changes will be tracked using an 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.
8.4
Data Monitoring Committee 
Not required.
8.5
Adjudication Committee 
Not required.
9
Data analysis 
The analysis will be conducted on all patient data after data base lock for the respective trial 
periods. Any data analysis carried out independently by the investigator should be submitted 
to Novartis before publication or presentation.


Novartis
Confidential
Page 71
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
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, miss-randomized patients (miss-randomized in IRT) will be 
excluded from the randomized set.
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. For patients 
randomized erroneously into the wrong stratum, the actual stratum will be used for analyses.
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.
9.2
Patient 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.
9.3
Treatments 
Study treatment
The analysis of study treatment data will be based on the safety set. 
The duration of exposure to study treatment will be summarized by treatment group. In 
addition, the number of patients with exposure of certain thresholds will be displayed. 
Compliance will be calculated based on documented study drug administrations and syringe 
counts and displayed by treatment group.
Prior and concomitant treatment
Prior and concomitant treatments and non-drug therapies will be summarized by treatment 
group in separate tables.
Prior treatments are defined as treatments taken and stopped prior to first dose of study 
treatment. Any treatment given at least once between the day of first dose of randomized 
study treatment and the last day of study visit will be a concomitant treatment, including those 
which were started pre-baseline and continued into the treatment period.
Treatments will be presented in alphabetical order, by Anatomical Therapeutic Classification 
codes and grouped by anatomical main group. Tables will also show the overall number and 
percentage of patients receiving at least one treatment of a particular Anatomical Therapeutic 
Classification.


Novartis
Confidential
Page 72
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
9.4
Analysis of the primary variable
9.4.1
Variable
The primary endpoint variable is the percentage of patients with resolution of Achilles tendon 
enthesitis as assessed by the respective subcomponent of the LEI at 24 weeks. This resolution 
is referred to as ‘response’ below.
9.4.2
Statistical model, hypothesis, and method of analysis
The null hypothesis to be rejected is that the odds of response Week 24 are equal in both 
treatment groups. The corresponding alternative hypothesis is that the odds of response at 
Week 24 are higher under secukinumab compared to placebo.
Let pj denote the proportion of responders at Week 24 for treatment group j, j=0, 1, where

0 corresponds to placebo

1 corresponds to secukinumab
The following hypotheses will be tested:
H0: (p1 / (1- p1)) / (p0 / (1- p0)) = 1 versus HA: (p1 / (1- p1)) / (p0 / (1- p0)) ≠1
In other words:
HA: The odds ratio of achieving a response at Week 24 for secukinumab vs Placebo is 
different from 1.
The primary analysis will be performed comparing treatments with respect to the primary 
efficacy variable in a logistic regression model with the factors treatment, TNFα inhibitor 
status and stratification factor diagnosis (PsA or axSpA). The odds ratio and its 95% 
confidence interval and p-value will be given.
9.4.3
Handling of missing values/censoring/discontinuations
This study aims to estimate the magnitude of treatment effects that are obtainable under the 
respective treatments. The disease activity is expected to decrease in the course of treatment. 
If a patient drops out or discontinues the trial prematurely, the last observed value of that 
patient seems to be a proper estimate for the effect achieved in that patient.
For the primary endpoint, a patient with a missing assessment will be considered as a 
responder if he/she has met the response criterion already at the time of drop-out. Otherwise 
he/she will be considered as a non-responder.
For the confirmatory analyses of secondary endpoints related to physician’s/patient’s global 
assessment and SF-36, missing values will be replaced by the last observed value in that 
patient (Last Observation Carry Forward). In case of a substantial number of missing values, 
alternative approaches (RMREM, MI) may be additionally calculated as sensitivity analyses.
9.4.4
Sensitivity analyses 
A possible effect modification of patient characteristics will be explored by subgroup analyses 
for sex, age class, TNFα inhibitor status and disease severity at Baseline. The primary model 


Novartis
Confidential
Page 73
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
may also be recalculated with these factors included as well as with respective terms for a 
subgroup*treatment interaction. In case of a substantial number of missing values, alternative 
approaches to handle missing values (RMREM, MI) may be additionally calculated as 
sensitivity analyses.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
9.5.1.1
Heel pain 
The mean change from Baseline of heel pain at 24 weeks, measured on a 10-point NRS will 
be analyzed using an Analysis of covariance (ANCOVA)-model with factors treatment, 
country and diagnosis (PsA or axSpA) and with covariate baseline heel pain. The adjusted 
(LS-) mean difference will be calculated as a point estimate together with its corresponding 
95% confidence interval and p-value.
9.5.1.2
Percentage of patients with an improvement of bone marrow oedema
The percentage of patients with an improvement of bone marrow oedema will be analyzed 
using a logistic regression model analogous to the one described above for the primary 
endpoint.
9.5.1.3
Physician’s/patient’s global assessment
Physician’s/patient’s global assessment, measured on a VAS scale will be analyzed using an 
ANCOVA model analogous to that used for heel pain.
9.5.1.4
SF-36
The score of the SF-36 will be analyzed using an ANCOVA model analogous to that used for 
heel pain.
9.5.1.5
Time courses of primary and secondary endpoints
The time courses of primary and secondary endpoints (percentage of patients with resolution 
of Achilles tendon enthesitis, heel pain NRS and Physician’s / patient’s global assessment, 
VAS) will be summarized descriptively for all visits from Baseline until Week 52. Summary 
statistics will include relative and absolute frequencies for the binary variable ‘resolution of 
enthesitis’, and the number of patients (N), minimum, mean, median and maximum for the 
NRS/VAS variables. Additionally, these time courses will be displayed graphically.
9.5.1.6
Preplanned subgroup analyses
The primary endpoint (percentage of patients with resolution of Achilles tendon enthesitis) 
will additionally be analyzed separately for the subgroups of patients with PsA or axSpA as 
well as TNFα inhibitor status, using the same model as for the respective pooled, overall 
population tests. Those subgroup analyses within PsA or axSpA patients are included in the 
confirmatory testing strategy (see below). Additional subgroup analyses may be conducted 
post-hoc as required as exploratory evaluations only.


Novartis
Confidential
Page 74
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
9.5.1.7
Confirmatory testing strategy
The primary endpoint will be confirmatorily tested in the pooled, overall population as well as 
in the two complementary subgroups of patients with PsA or axSpA.
If the null hypotheses has been rejected for the overall population, it will then be tested for 
both subgroups simultaneously, both at the significance level 0.05. If the null-hypothesis is 
false for the overall population, it can logically not be true for both complementary subgroups. 
Therefore both subgroups can be tested at the same significance level α = 0.05 without any 
further adjustments for multiplicity of subgroups. This procedure provides strong control of 
the familywise type-I-error at α = 0.05.
All secondary endpoints will be tested exploratively outside the confirmatory framework.
9.5.2
Safety variables 
9.5.2.1
Adverse events
Treatment emergent adverse events (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.
Adverse events 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 adverse event 
with the same preferred term, the adverse event with the greatest severity will be presented. If 
a patient reported more than one adverse event 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.


Novartis
Confidential
Page 75
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
These summaries may be presented separately by study periods, i.e., Weeks 1-24 and after 
Week 24.
Separate summaries will be provided for death, serious adverse event, other significant 
adverse events leading to discontinuation and adverse events leading to dose adjustment 
(including study treatment discontinuation).
9.5.2.2
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 assessments.
For each parameter, the maximum change from Baseline within each study period will be 
analyzed analogously.
9.5.2.3
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from 
Baseline for each Post-Baseline visit will be performed. These descriptive summaries will be 
presented by vital sign and treatment group. Change from Baseline will only be summarized 
for patients with both Baseline and Post-Baseline values.
9.7
Interim analyses
Once all data until/including Week 24 (containing the primary and secondary endpoints) are 
complete and clean, the database for that study period may be locked and analyzed. The 
results may be published or made available to personnel involved in data collection of this 
study prior to database lock of the complete study period until Week 52.
9.8
Sample size calculation
The primary endpoint of this trial is the percentage of patients with resolution of Achilles 
tendon enthesitis assessed by application of firm pressure with the pulp of the thumb by the 
physician at Week 24. The sample size calculation is based on the same enthesitis assessment 
we performed within the FUTURE 2 PsA trial (CAIN457F2312) in the form of the LEI which 
is composed of three different enthesial sites (Lateral epicondyle, left and right; Medial 
femoral condyle, left and right; Achilles tendon insertion, left and right). Within this trial, the 
resolution of enthesitis amongst those patients with these symptoms at Baseline has been 
assessed for Week 24:


Novartis
Confidential
Page 76
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Week 24, the end of the placebo-controlled phase:

Secukinumab (300 mg): 48.2% of patients.

Secukinumab (150 mg): 42.2% of patients.

Placebo: 21.5% of patients.
In addition to these clinical data we can make the following assumptions:

There is no difference in response to secukinumab between the different enthesial sites 
assessed as part of the LEI in the FUTURE 2 trial. Therefore we do not expect a different 
response when we only assess the Achilles tendon insertion.

There is no difference in secukinumab response rates regarding resolution of enthesitis 
between PsA and axPsA patients. Therefore we pool the analysis for both diseases.
A total of 89 patients per arm are required to achieve 90% power to detect a difference on a 
two-sided, 5% significance level, if the true response rates are 45% under secukinumab and 
21% under placebo. To account for some drop-outs and other protocol violations, 100 patients 
per arm = 200 patients total should be recruited into this trial.
For the comparison within the 2 subgroups of PsA and axSpA patients, which will consist of 
approximately 50% of the total study population each, the trial will have about 58% power 
with regard to the primary endpoint.
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/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 


Novartis
Confidential
Page 77
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential 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 informed consent form, consent form updates, 
subject recruitment procedures (e.g., advertisements) and any other written information to be 
provided to patients/subjects. Prior to study start, the investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
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/subjects
should be administered as deemed necessary on a case by case basis. Under no circumstances 


Novartis
Confidential
Page 78
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the Clinical 
Study Report.
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/subjects may be implemented immediately provided the health authorities
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any 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 
References are available upon request
Amor B, Dougados M, Mijiyawa M (1990) Criteria of the classification of 
spondylarthropathies. Rev Rhum Mal Osteoartic; 57:85-9.
Baraliakos X and Braun J (2011) Spondyloarthritides. Best Pract Res Clin Rheumatol; 
25:825-42.
Benham H, Rehaume LM, Hasnain SZ et al (2014) Interleukin-23 mediates the intestinal 
response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in 
SKG mice. Arthritis Rheumatol; 66:1755-67.
Bøyesen P, McQueen FM, Gandjbakhch F, et al (2003) The OMERACT Psoriatic Arthritis 
Magnetic Resonance Imaging Score (PsAMRIS) is reliable and sensitive to change: results 
from an OMERACT workshop. J Rheumatol; 38:2034-8.
Callhoff J, Sieper J, Weib A,et al (2014) Efficacy of TNFα blockers in patients with 
ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann 
Rheum Dis; 0:1-8.
Chobanian AV, Bakris GL, Black HR (2003) Seventh report of the joint national committee 
on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension; 42: 
1206-52.
 


Novartis
Confidential
Page 79
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
D’Agostino MA, Breban M, Said-Nahal R et al (2002) Refractory inflammatory heel pain in 
spondylarthropathy: a significant response to infliximab documented by ultrasound. Arthritis 
Rheum; 46:840-1.
D’Agostino MA, Olivieri I (2006) Enthesitis. Best Pract Res Clin Rheumatol; 20:473–86.
Dadoun S, Geri G, Paternotte S et al (2011) Switching between tumour necrosis factor 
blockers in spondyloarthritis: a retrospective monocentre study of 222 patients. Clin Exp 
Rheumatol; 29:1010-3.
Dougados M, Combe B, Braun J et al (2010) A randomised, multicentre, double-blind, 
placebocontrolled trial of etanercept in adults with refractory heel enthesitis in 
spondyloarthritis: the HEEL trial. Ann Rheum Dis; 69:1430-5.
Ebihara S, Date F, Dong Y et al (2015) Interleukin-17 is a critical target for the treatment of 
ankylosing enthesitis and psoriasis-like dermatitis in mice. Autoimmunity; 48:259-66.
EMA guidance document (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 (2006) 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
FDA guidance document:
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M071579.pdf
Feydy A, Lavie-Brion MC, Gossec L, et al (2012) Comparative study of MRI and power 
Doppler ultrasonography of the heel in patients with spondyloarthritis with and without heel 
pain and in controls. Ann Rheum Dis; 71:498-503.
 
Gladman DD (2004) Psoriatic arthritis. In: Harris ED, Budd RC, Firestein GS, et al, eds. 
Kelly’s Textbook of Rheumatology. 7th ed. Philadelphia: Saunders, p. 1154-64.
Haavardsholm EA, Ostergaard M, Ejbjerg BJ, et al (2005) Reliability and sensitivity to 
change of the OMERACT rheumatoid arthritis magnetic resonance imaging score in a 
multireader, longitudinal setting. Arthritis Rheum; 52:3860–7.
Haibel H, Rudwaleit M, Braun J et al (2005) Six months open label trial of leflunomide in 
active ankylosing spondylitis. Ann Rheum Dis; 64:124-6.
Haibel H, Brandt HC, Song IH et al (2007) No efficacy of subcutaneous methotrexate in 
active ankylosing spondylitis: a 16-week open-label trial Ann Rheum Dis; 66:419-21.
Haibel H, Sieper J (2015) Enthesitis under spondyloarthritides. The Orthopedist; 44:395-406.


Novartis
Confidential
Page 80
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Healy PJ, Helliwell PS (2008) Measuring clinical enthesitis in psoriatic arthritis: assessment 
of existing measures and development of an instrument specific to psoriatic arthritis. Arthritis 
Rheum; 59:686-91.
ICH E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited 
Reporting.
Kavanaugh A, McInnes I, Mease P et al (2009) Golimumab, a new human tumor necrosis 
factorantibody, administered every four weeks as a subcutaneous injection in Psoriatic 
Arthritis. Arthritis Rheum; 60:976-86.
Landewé R, Braun J, Deodhar A, et al (2014) Efficacy of certolizumab pegol on signs and 
symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a 
double-blind randomized placebo-controlled Phase 3 study. Ann Rheum Dis; 73:39-47.
Landewé R, van Tubergen A (2015) Clinical tools to assess and monitor spondyloarthritis. 
Curr Rheumatol Rep; 17:47.
Lories RJ, McInnes IB (2012) Primed for inflammation: enthesis-resident T cells. Nat Med; 
18:1018-9.
 
Mancia G, De Backer G, Dominiczak A, 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.
McQueen F, Lassere M, Duer-Jensen A, et al (2009) Testing an OMERACT MRI Scoring 
System for Peripheral Psoriatic Arthritis in Cross-sectional and Longitudinal Settings. J 
Rheumatol; 36:1811-5.
Mease PJ, Fleischmann R, Deodhar AA et al (2014) Effect of certolizumab pegol on signs and 
symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind 
randomized placebo-controlled study (RAPID-PsA). Ann Rheum Dis; 73:48-55.
Moll JM and Wright V (1973) Psoriatic arthritis. Semin Arthritis Rheum; 3:55-78.
Ostergaard M, Peterfy C, Conaghan P, et al (2003). OMERACT Rheumatoid Arthritis 
Magnetic Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology 
definitions, and the OMERACT RA-MRI scoring system. J Rheumatol; 30(6):1385–1386.
Ostergaard M, McQueen F, Wiell C, et al (2009) The OMERACT psoriatic arthritis magnetic 
resonance imaging scoring system (PsAMRIS): Definitions of key pathologies, suggested 
MRI sequences, and preliminary scoring system for PsA Hands. J Rheumatol; 36:1816–1824.
Pavy S, Brophy S, Calin A (2005) Establishment of the minimum clinically important 
difference for the bath ankylosing spondylitis indices: a prospective study. J Rheumatol; 
32:80-5.


Novartis
Confidential
Page 81
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
Rudwaleit M, Landewé R, van der Heijde D, et al (2009) The development of Assessment of 
SpondyloArthritis international Society classification criteria for axial spondyloarthritis 
(part I): classification of paper patients by expert opinion including uncertainty appraisal. Ann 
Rheum Dis; 68:770-6.
Ritchlin CT, Kavanaugh A, Gladman DD et al (2009) Treatment recommendations for 
psoriatic arthritis. Ann Rheum Dis; 68:1387-94.
Sherlock JP, Joyce-Shaikh B, Turner SP et al (2012) IL-23 induces spondyloarthropathy by 
acting on ROR-γt+ CD3+CD4–CD8– entheseal resident T cells. Nat Med; 18:1069-76.
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:ii1-44.
Taylor W, Gladman D, Helliwell P et al (2006) Classification criteria for psoriatic arthritis: 
development of new criteria from a large international study. Arthritis Rheum; 54:2665-73.
Turkiewicz AM, Moreland LW (2007) Psoriatic Arthritis: Current Concepts on Pathogenesis-
Oriented Therapeutic Options. Arthritis Rheum; 56: 1051-66.
van der Heijde D, Kivitz A, Schiff MH et al (2006) Efficacy and safety of adalimumab in 
patients with Ankylosing Spondylitis. Arthritis Rheum; 54:2136-46.
Ware J, Kosinki M, Gandeck B. (1993) SF-36 Health Survey manual and interpretation guide. 
Boston: The Health Institute, New England Medical Center.
Ware J, Kosinki M, Gandeck BS (1994) F-36 Health Survey manual and interpretation guide. 
Update. Boston: The Health Institute, New England Medical Center.
Yanaba K, Sadaoka A, Yonenaga T et al (2015) Adalimumab markedly improves enthesitis in 
patients with psoriatic arthritis: Evaluation with a magnetic resonance imaging scoring system. 
J Dermatol; 42:1153-9.
Zochling J, van der Heijde D, Burgos-Vargas R et al (2006) ASAS/EULAR recommendations 
for the management of ankylosing spondylitis. Ann Rheum Dis; 65:442-52.


Novartis
Confidential
Page 82
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
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


Novartis
Confidential
Page 83
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT/AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*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)


Novartis
Confidential
Page 84
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
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.


Novartis
Confidential
Page 85
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
15
Appendix 3: The classification criteria for psoriatic arthritis 
(CASPAR)
To meet the Classification of Psoriatic Arthritis (CASPAR) criteria for diagnosis of psoriatic 
arthritis according to (Taylor et al 2006), a patient must have inflammatory articular disease 
(joint, spine or entheseal) and at least 3 points (out of 6) from the following 5 categories:
1. Evidence of current psoriasis, a personal history of psoriasis, or a family history of 
psoriasis: 

Current psoriasis is defined as psoriatic skin or scalp disease present today as judged 
by a rheumatologist or dermatologist.* (2 points)

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. (1 points, only if current psoriasis is NOT present)

A family history of psoriasis is defined as a history of psoriasis in a first- or second-
degree relative according to patient report. (1 points, only if current psoriasis or 
personal history of psoriasis is NOT present)
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 patient. If the total score ≥3, the patient meets CASPAR criteria for PsA 
diagnosis).
*Current psoriasis is assigned a score of 2; all other features are assigned a score of 1.


Novartis
Confidential
Page 86
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
16
Appendix 4: ASAS Classification Criteria for Axial 
Spondyloarthritis (axSpA)
In patients with ≥3 months back pain and age at onset < 45 years:
Sacroiliitis on imaging*
plus
≥1 SpA feature
OR
HLA-B27
plus
≥2 other SpA features
*Sacroiliitis on imaging:
Active (acute) inflammation on 
MRI highly suggestive of 
sacroiliitis associated with SpA
Definite radiographic sacroilitis 
according to the modified NY 
criteria
SpA features:
Inflammatory back pain
Arthritis
Enthesitis (heel)
Uveitis
Dactylitis
Psoriasis
Crohn’s/colitis
Good response to NSAIDs
Family history for SpA
HLA-B27
Elevated CRP
17
Appendix 5: Modified New York criteria
Clinical criteria:

Low back pain and stiffness for more than 3 months that improves with exercise, but is not 
relieved by rest.

Limitation of motion of the lumbar spine in the sagittal and frontal planes.

Limitation of chest expansion relative to normal values correlated for age and sex.
Radiological criterion:

Sacroiliitis grade ≥2 bilaterally or grade 3–4 unilaterally.
Definite AS if the radiological criterion is associated with at least one clinical criterion. 


Novartis
Confidential
Page 87
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301


Novartis
Confidential
Page 88
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
20
Appendix 8: Guidelines for administering the questionnaires 
for patient reported outcomes
Before trial start
Study coordinators should familiarize themselves with the PRO questionnaire(s) in the trial 
and identify any items where a patient’s response might highlight issues of potential concern.
For example, one question in the SF-36 asks ‘How much of the time in the past 4 weeks- have 
you felt downhearted and blue?’ If a patient responds ‘most or all of the time’, then the study 
coordinator should inform the study investigator.
Before completion
1. Patients should be provided with the correct questionnaire at the appropriate visits and in 
the appropriate language.
2. Patients should have adequate space and time to complete the forms.
3. Questionnaire should be administered before the clinical examination.
During completion
1. Administrator may clarify the questions but should not influence the response.
2. Only one response for each question.
3. Also see “Addressing Problems and Concerns”.
After completion
1. Check for completeness and not for content*.
2. Check for multiple responses that were made in error.
*However, any response which may directly impact or reflect the patient’s medical condition 
(e.g. noting of depression) should be communicated by the study coordinator to the 
investigator).
Addressing problems and concerns
Occasionally a patient may have concerns or questions about the questionnaires administered. 
Guidance related to some of the most common concerns and questions are given below.
The patient does not want to complete the questionnaire(s)
Tell the patient that completion of the questionnaire(s) is voluntary. The goal is to better 
understand the physical, mental and social health problems of patients. Emphasize that such 
information is as important as any other medical information and that the questionnaire(s) is 
simple to complete. Suggest that the questionnaire(s) may be different from anything the 
respondent has filled in the past. If the patient still declines, retrieve the questionnaires. 
Record the reason for the decline and thank the patient.


Novartis
Confidential
Page 89
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
The patient is too ill or weak to complete the questionnaire(s)
In these instances, the coordinator may obtain patient responses by reading out loud each 
question, followed by the corresponding response categories, and entering the patient’s 
response. No help should be provided to the patient by any person other than the designated 
study coordinator. The coordinator should not influence patient responses. The study 
coordinator cannot translate the question into simpler language and has to be read verbatim.
The patient wants someone else to complete the questionnaire(s)
In no case should the coordinator or anyone other than the patient provide responses to the 
questions. Unless specified in the study protocol, proxy data are not an acceptable substitute 
for patient self-report. Patients should be discouraged from asking a family member or friend 
for help in completing a questionnaire.
The patient does not want to finish completing the questionnaire(s)
If non-completion is a result of the patient having trouble understanding particular items, ask 
the patient to explain the difficulty. Re-read the question for them verbatim but do not 
rephrase the question. If the respondent is still unable to complete the questionnaire, accept it 
as incomplete. Thank the patient.
The patient is concerned that someone will look at his/her responses
Emphasize that all responses are to be kept confidential. Point out that their names do not 
appear anywhere on the questionnaire, so that their results will be linked with an ID number 
and not their name. Tell the patient that his/her answers will be pooled with other patients’ 
answers and that they will be analyzed as a group rather than as individuals. Tell the patient 
that completed forms are not routinely shared with treating staff and that their responses will 
only be seen by you (to check for completeness) and by the investigator. Any response which 
may directly impact on or reflect their medical condition (e.g. noting of severe depression) 
will be communicated by the coordinator to the physician.
The patient asks the meaning of a question/item
While completing the questionnaire, some patients might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the patient by rereading the 
question for them verbatim. If the patient asks to interpret the meaning of an item, do not try 
to explain it, but suggest that he/she use his/her own interpretation of the question. Patients 
should answer the questions based on what they think the questions mean.
General information about all questionnaire(s):
All questionnaires have 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 
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 


Novartis
Confidential
Page 90
Amended Clinical Trial Protocol Version 03 clean
Protocol No. CAIN457F3301
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.

SAP_001.pdf: 
Clinical Development
AIN457/Secukinumab / NCT02771210
[A randomized, double-blind, placebo-controlled 
multicenter study of subcutaneous secukinumab to 
demonstrate efficacy in the treatment of enthesitis at the 
Achilles tendon up to 1 year in adult patients with active 
Psoriatic Arthritis (PsA) and axial Spondyloarthritis (axSpA) 
(ACHILLES)]
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final Version 1
Release date:
23-Jun-2016
Number of pages:
38
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP
AIN457F3301
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
23-
Jun-
2016
Prior 
to 
DB 
lock
Final 
version 
created


Novartis
For business use only
Page 3
SAP
AIN457F3301
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
Figure 1: Study design.........................................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
Table 1.2-1
Objectives and related endpoints ............................................................9
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................14
2.3.2
Demographics and other baseline characteristics .................................14
2.3.3
Medical history......................................................................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.4.1
Study treatment / compliance................................................................15
2.4.2
Prior, concomitant and post therapies ...................................................16
2.5
Analysis of the primary objective..........................................................................17
2.5.1
Primary endpoint...................................................................................17
2.5.2
Statistical hypothesis, model, and method of analysis..........................17
2.5.3
Handling of missing values/censoring/discontinuations.......................18
19
2.6
Analysis of the key secondary objective ...............................................................19
2.7
Analysis of secondary efficacy objective(s) ..........................................................19
2.7.1
Secondary endpoints .............................................................................19
2.7.2
Statistical hypothesis, model, and method of analysis..........................19
2.7.3
Handling of missing values/censoring/discontinuations.......................21
2.8
Safety analyses.......................................................................................................21
2.8.1
Adverse events (AEs)............................................................................22
Table  2.8-1   Overview of analyses on some safety endpoints.............................23
2.8.2
Deaths....................................................................................................23
2.8.3
Laboratory data .....................................................................................23
Table 2.8-2 CTCAE grades for laboratory parameters to be analyzed..................24
Table 2.8-3 Liver-related events............................................................................25


Novartis
For business use only
Page 4
SAP
AIN457F3301
2.8.4
Other safety data ...................................................................................26
Table 2.8-4
Criteria for notable vital sign abnormalities....................................27
2.9
Pharmacokinetic endpoints....................................................................................27
2.10
PD and PK/PD analyses.........................................................................................27
2.11
Patient-reported outcomes .....................................................................................27
2.12
Biomarkers.............................................................................................................28
28
2.14
Interim analysis......................................................................................................29
3
Sample size calculation .....................................................................................................29
4
Change to protocol specified analyses ..............................................................................30
5
Appendix ...........................................................................................................................30
5.1
Imputation rules.....................................................................................................30
5.1.1
Study drug .............................................................................................30
5.1.2
AE date imputation ...............................................................................30
5.1.3
Concomitant medication date imputation .............................................32
5.2
AEs coding/grading ...............................................................................................33
5.3
Laboratory parameters derivations ........................................................................33
5.4
Statistical models...................................................................................................33
5.4.1
Primary analysis ....................................................................................33
5.4.2
Key secondary analysis .........................................................................34
5.4.3
Secondary analysis ................................................................................34
Rule of exclusion criteria of analysis sets..............................................................34
5.5
34
6
Reference...........................................................................................................................38


Novartis
For business use only
Page 5
SAP
AIN457F3301
List of abbreviations
ACR
American College of Rheumatology
AE
Adverse event
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
axSpA
axial Spondyloarthritis
BASDAI
Bath ankylosing spondylitis disease activity index
CASPAR
Classification criteria for Psoriatic Arthritis
CRP
C-reactive protein
CSR
Clinical Study report
CTC
Common Toxicity Criteria
DMARD
Disease Modifying Anti-rheumatic Drug
DMC
Data Monitoring Committee 
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
hCG
human chorionic gonadotropin
hsCRP
High sensitivity C-Reactive Protein
IVR
Interactive Voice Response
IWR
Interactive Web Response
LEI
Leeds Enthesitis Index
LFT
Liver function test (raised serum transaminases and/or bilirubin levels)
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI
Magnetic resonance imaging
MTX
Methotrexate
NRS
Numerical rating scale
PCS
Physical Component Summary
PFS
Prefilled syringe
PRO
Patient Reported Outcome
PsA
Psoriatic arthritis
PsAMRIS
Psoriatic Arthritis Magnetic Resonance Imaging Score
RA
Rheumatoid arthritis
RF
Rheumatoid factor
SAE
Serious adverse event
SAP
Statistical Analysis Plan
s.c.
Subcutaneous(ly)
SF-36
Medical Outcome Short Form (36) Health Survey


Novartis
For business use only
Page 6
SAP
AIN457F3301
SJC
Swollen Joint Count
SmPC
Summary of Product Characteristics
SpA
Spondyloarthritis
SUSAR
Suspected Unexpected Serious Adverse Reactions
TJC
Tender Joint Count
TNF
Tumor necrosis factor
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
White blood cell
WHO
World Health Organization


Novartis
For business use only
Page 7
SAP
AIN457F3301
1
Introduction
This SAP module describes the planned statistical methods for all safety and efficacy analyses.
Any changes made to the statistical plan and methodology after the clinical database lock will 
be documented as an addendum.
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 according to the data analysis section 9 of the clinical study 
protocol. 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.
This SAP describes the planned statistical methods. It is structured as

A draft of the Clinical Study Report (CSR) Section 9.7 (statistical methods planned in 
the protocol and determination of sample size) and 

A draft of CSR Appendix 16.1.9 (documentation of statistical methods). Appendix 
16.1.9 text will contain details of statistical methods and issues that are too long to 
include in the CSR text.
Please refer to the following document:

Clinical Protocol CAIN457F3301
1.1
Study design
This is a 52-week, randomized, parallel-group, double-blind, multicenter, international study 
consisting of an 8-week screening period, a 24-week, placebo-controlled, double-blind 
treatment period and a 28-week open-label treatment period in patients with PsA and axSpA.
The dosing of secukinumab will be applied according to the approved European Summary of 
Product Characteristics (SmPC) in PsA and AS disease. According to SmPC, patients with AS 
and PsA (with concomitant none-to-mild psoriasis) will receive 150 mg secukinumab or 
placebo (1 PFS) where as only PsA patients with concomitant moderate-to-severe-psoriasis
will receive 300 mg of secukinumab or placebo (2 PFS). In case of axSpA patients with 
objective signs of inflammation at screening, evident by either MRI with Sacroiliac joint 
inflammation (according to source documentation) and/or hsCRP > upper limit of normal 
(ULN, as defined by central lab) , secukinumab/placebo will be applied as 1 (1.0 mL pre-
filled syringe (PFS) of 150 mg dose) s.c. injection.
The study design is given in Figure 1.


Novartis
For business use only
Page 8
SAP
AIN457F3301
Figure 1: Study design
Planned number of patients and randomization
At Baseline approximately 200 patients will be randomized. Randomization will occur to one
of the following two treatment groups in a ratio of 1:1.

Group 1 (secukinumab): secukinumab as 1 (1.0 mL pre-filled syringe (PFS) of 150 mg 
dose) s.c. or 2 (2 × 1.0 mL PFS of 150 mg dose, 300 mg) s.c. injections according to 
axSpA or PsA disease at Baseline, Weeks 1, 2, and 3, followed by administration 
every 4 weeks starting at Week 4.

Group 2 (placebo): placebo as 1 (1.0 mL PFS) or 2 (2 × 1.0 mL PFS) s.c. injections 
according to axSpA or PsA disease at Baseline, Weeks 1, 2, 3, followed by 
administration every 4 weeks starting at Week 4.
Patients will receive study treatment at Baseline, Weeks 1, 2, and 3, followed by treatment
every 4 weeks through Week 52 (last dose given at Week 48). At Week 24, patients originally
randomized to placebo will switch to receive secukinumab 150 mg (1 injection of
secukinumab 1 mL/150 mg) or secukinumab 300 mg (2 injections of secukinumab 1 mL/150 
mg) in open-label fashion without a loading regimen.
Blinding to the original treatment assignment will be maintained until after the Week 52 
database lock and analyses are completed. However, original randomized treatment 
assignment to secukinumab or placebo will remain double-blinded to all patients, 
investigators, and site personnel, whereas the Sponsor (including the Region Europe Clinical 
Team, statisticians and data management) will be unblinded after the Week 24 database lock 
(protocol Section 3.5) and analyses are completed (protocol Section 9.7).


Novartis
For business use only
Page 9
SAP
AIN457F3301
Patients will be stratified at randomization on the basis of PsA or axSpA disease.
Based on enrollment target, it is planned that approximately 50% of randomized patients 
should be PsA and approximately 50% axSpA patients to ensure a balanced patient population 
for the assessment of efficacy and safety.
Primary analysis time point 
The primary analyses will be performed at Week 24.
Interim analyses
No interim analysis is planned for this study.
Once all data until/including Week 24 (containing the primary and secondary endpoints) are 
complete and clean, the database for that study period will be locked and analyzed. The 
results may be published or made available to personnel involved in data collection of this 
study prior to database lock of the complete study period until Week 52.
1.2
Study objectives and endpoints
The following objectives will be evaluated in patients with active PsA and axSpA.
Table 1.2-1 Objectives and related endpoints
Objective
Endpoint
Primary objective
To demonstrate the superiority of 
secukinumab to placebo based on the 
respective subcomponent of LEI at 24 weeks 
in patients with active PsA and axSpA
Percentage of patients with resolution of 
Achilles tendon enthesitis as assessed by the 
respective subcomponent of the LEI at 
24 weeks
Secondary objectives
To demonstrate the superiority of 
secukinumab to placebo at Week 24 based on 
the 10-point NRS
Mean change from baseline of heel pain 
measured on the 10-point NRS at Week 24
To demonstrate the superiority of 
secukinumab to placebo at Week 24 based on 
the respective subcomponent of PsAMRIS  
Percentage of patients with an improvement of 
bone marrow oedema in the insertion of the 
Achilles tendon in the upper part of the 
calcaneus and/or in the insertion of the plantar 
aponeurosis in the lower part of the calcaneus as 
assessed by the respective subcomponent of the 
PsAMRIS at Week 24 in the affected foot at 
Baseline
To demonstrate the superiority of 
secukinumab to placebo at Week 24 based on 
the LEI
Percentage of patients with resolution of 
enthesitis as assessed by the LEI at Week 24


Novartis
For business use only
Page 10
SAP
AIN457F3301
To demonstrate the superiority of 
secukinumab to placebo at Week 24 based on 
the physician’s global assessment of disease 
activity
Mean change from baseline in physician’s 
global assessment of disease activity at Week 
24
To demonstrate the superiority of 
secukinumab to placebo at Week 24 based on 
the patient’s global assessment of disease 
activity
Mean change from baseline in patient’s global 
assessment of disease activity at Week 24
To demonstrate the superiority of 
secukinumab to placebo at Week 24 based 
on physician’s global assessment of heel 
enthesiopathy
Mean change from baseline in physician’s 
global assessment of heel enthesiopathy activity
at Week 24
To demonstrate the superiority of 
secukinumab to placebo at Week 24 based on 
patient’s global assessment of heel 
enthesiopathy.
Mean change from baseline in patient’s global 
assessment of heel enthesiopathy activity at 
Week 24
To demonstrate the improvement in 
secukinumab to placebo at Week 24 based on 
SF-36 PCS or SF-36v2 
Change from Baseline in SF-36 PCS or SF-
36v2
To describe the improvement in resolution of 
Achilles tendon enthesitis after switching 
from placebo to secukinumab at Week 24.
Percentage of patients with resolution of 
Achilles tendon enthesitis in patients switching 
from placebo to secukinumab at Week 24.
To demonstrate the improvement of heel 
pain after switching from placebo to 
secukinumab at Week 24.
Mean change of heel pain in patients switching 
from placebo to secukinumab at Week 24
The overall 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


Novartis
For business use only
Page 11
SAP
AIN457F3301


Novartis
For business use only
Page 12
SAP
AIN457F3301
2
Statistical methods
2.1
Data analysis general information
The analysis will be conducted by Novartis on all patient data after database lock for the 
respective trial periods. Any data analysis carried out independently by the investigator should 
be submitted to Novartis before publication or presentation.
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).
Following the Week 24 database lock, the Sponsor will be unblinded to treatment assignment. 
Once all data until/including Week 24 (containing the primary and secondary endpoints) are 
complete and clean, the database for that study period may be locked and analyzed.
Continuous variables will be summarized by number of patients, mean, standard deviation, 
minimum, median and maximum. Categorical variables will be summarized by absolute and 
relative frequencies. Summary statistics will also be presented graphically wherever 
applicable.
If not otherwise specified, p-values and confidence intervals will be two-sided. Unless 
otherwise stated, the level of significance will be set to 5% (two-sided, family-wise type-I-
error).
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.


Novartis
For business use only
Page 13
SAP
AIN457F3301
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 two treatment periods for this study defined as :
Treatment Period 1 is defined as a 24 Week placebo-controlled, double-blind treatment period
starting from baseline till Week 24.
Treatment Period 2 is a 28 Week open-label treatment period starting from Week 28 (end of 
Week 24) 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 treatment group 1) for secukinumab,
and 24 weeks of on-treatment period for placebo and 28 weeks of on treatment for 
secukinumab  (for treatment group 2). 
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, miss-randomized patients (miss-randomized in IRT) will be 
excluded from the randomized set.
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IVR prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given.
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. For patients 
randomized erroneously into the wrong stratum, the actual stratum will be used for analyses.
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.


Novartis
For business use only
Page 14
SAP
AIN457F3301
2.2.1
Subgroup of interest
The main subgroup of interest for this study are the PsA set of patients and axSpA set of 
patients. The two subgroups of PsA and axPsA patients will consist of approximately 50% in 
each of the total study population.
All (baseline, efficacy and safety) summaries will be performed based on this subgroup and 
overall.
A possible effect modification of patient characteristics will be explored by subgroup analyses 
for sex, age class and disease severity at Baseline.  
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 who are screened will be presented. In addition, the 
reasons for screen failures will be provided.
The number and percentage of patients who are enrolled, and who completed each treatment 
period and who discontinued the study will be summarized by treatment group at the end of 
each treatment period. In addition, for those patients who discontinued, the summary will be 
broken down by primary reason for study discontinuation. 
The number and percentage of patients who took the rescue medication and hence 
discontinued at week 24 will be presented. For each protocol deviation (PD), the number and 
percentage of patients for whom the PD applies will be tabulated.
2.3.2
Demographics and other baseline characteristics
The following common background, demographics and baseline characteristics data will be 
analyzed as described below:
Continuous variables:

Age (which is derived from date of birth and the screening assessment date)

Height

Weight

Body mass index (BMI) = (body weight in kilograms) / (height in meters)2
Categorical variables:

Age categories (<65 years, 65 – 74 years, 75 years and older)

Gender

Race

Source of patient referral 


Novartis
For business use only
Page 15
SAP
AIN457F3301
The following disease specific baseline characteristics and history of disease will be 
summarized as well:

CASPAR, 

Smoking status at baseline

Disease background fo PsA/ axSpA, including time since diagnosis, etc

Previous PsA/axSpA therapies

PsA/axSpA functional status

History of extra-axial involvement (uveitis, psoriasis, inflammatory bowel 
disease, dactylitis, enthesitis, peripheral arthritis) 

Time since onset of inflammatory back pain

Number and proportions of previous DMARDs used
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.
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 medical history and psoriasis and psoriatic arthritis history will 
be provided as well.
Smoking history will be summarized by treatment group.
Unless otherwise specified, 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 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.
Duration of exposure
The duration of exposure to study treatment will 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.


Novartis
For business use only
Page 16
SAP
AIN457F3301
Duration of exposure will be 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 (whichever 
is first). For patients who discontinue, this will be the subject’s last visit in the corresponding 
treatment period.
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 subject years) = duration of exposure (years) / 100
The analyses of duration of exposure described above will be done for both the study 
treatment periods.
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
Concomitant medications and significant non-drug therapies prior to and after enrolling into 
the study will be summarized by preferred term and ATC class of the World Health 
Organization (WHO)  Drug Reference List.
Concomitant or prior medications entered into the database will be coded using the WHO 
Drug Reference List. Medical history/current medical conditions and AEs will be coded using 
MedDRA terminology.
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 psoriatic arthritis 
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 psoriatic arthritis therapies previously.
Prior or concomitant medication will be identified by comparing recorded or imputed start 
and end dates of medication taken to the reference start date. 


Novartis
For business use only
Page 17
SAP
AIN457F3301
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 benefir 
or worsening of disease, if rescue with prohibited treatments occurs prior to completion of 
Week 24 assessments, patients will be discontinued from the study.
Rescue medication will be summarized similarly to concomitant medication.
2.5
Analysis of the primary objective
The primary objective is to demonstrate that the efficacy of secukinumab is superior to 
placebo based on the percentage of patients with resolution of Achilles tendon enthesitis as 
assessed by the respective subcomponent of the Leeds enthesitis index (LEI) at 24 weeks in 
patients with active PsA and axSpA.
2.5.1
Primary endpoint
The primary endpoint is the percentage of patients with resolution of Achilles tendon 
enthesitis as assessed by the respective subcomponent of the LEI at Week 24. This resolution 
is referred to as ‘response’ below.
The analysis of the primary efficacy variable will be based on the FAS.
2.5.2
Statistical hypothesis, model, and method of analysis
The null hypothesis to be rejected is that the odds of response Week 24 are equal in both 
treatment groups. The corresponding alternative hypothesis is that the odds of response at 
Week 24 are higher under secukinumab compared to placebo.
In other words: Let pj denote the proportion of responders at Week 24 for treatment group j, 
j=0, 1, where

0 corresponds to placebo

1 corresponds to secukinumab
The following hypotheses will be tested:
H0: (p1 / (1- p1)) / (p0 / (1- p0)) = 1 versus H1: (p1 / (1- p1)) / (p0 / (1- p0)) ≠1
In other words, H1: The odds ratio of achieving a response at Week 24 for secukinumab vs 
Placebo is different from 1.
The hypothses can also be re-written as a difference of proportions as follows:
In statistical terms, H0: p1 = p0, H1: p1 ≠p0, i.e.
H1: The difference of porportions at Week 24 for secukinumab vs Placebo is different from 0.
The primary analysis will be performed comparing treatments with respect to the primary 
efficacy variable in a logistic regression model with the factors treatment, country and 


Novartis
For business use only
Page 18
SAP
AIN457F3301
stratification factor diagnosis (PsA or axSpA). The odds ratio and its 95% confidence interval 
(CI) and p-value will be presented comparing secukinumab to placebo at Week 24.
The study is said to be positive/declared as success if the lower limit of 95% CI of odds ratio 
is greater than 1.
The primary endpoint (percentage of patients with resolution of Achilles tendon enthesitis) 
will additionally be analyzed separately for the subgroups of patients with PsA or axSpA, 
using the same model as for the respective pooled, overall population tests (except for the 
stratification factor). Those two subgroup analyses are included in the confirmatory testing 
strategy. The  primary  model  will  also  be recalculated with the stratification factor
included as well as with respective term for a strata*treatment interaction. 
Testing strategy
The primary endpoint will be confirmatorily tested in the pooled, overall population as well as 
in the two complementary subgroups of patients with PsA or axSpA.
If the null hypotheses has been rejected for the overall population, it will then be tested for 
both subgroups simultaneously, both at the significance level 0.05. If the null-hypothesis is 
false for the overall population, it can logically not be true for both complementary subgroups.
Therefore both subgroups can be tested at the same significance level α = 0.05 without any 
further adjustments for multiplicity of subgroups. This procedure provides strong control of 
the familywise type-I-error at α = 0.05.
2.5.3
Handling of missing values/censoring/discontinuations
This study aims to estimate the magnitude of treatment effects that are obtainable under the 
respective treatments. The disease activity is expected to decrease in the course of treatment. 
If a patient drops out or discontinues the trial prematurely, the last observed value of that 
patient seems to be a proper estimate for the effect achieved in that patient.
For the primary endpoint, a patient with a missing assessment will be considered as a 
responder if he/she has met the response criterion already at the time of drop-out. Otherwise 
he/she will be considered as a non-responder.


Novartis
For business use only
Page 19
SAP
AIN457F3301
2.6
Analysis of the key secondary objective
Not applicable
2.7
Analysis of secondary efficacy objective(s)
Secondary objectives
Refer to Table 1-1 of Section 1 for the list of secondary objectives.
2.7.1
Secondary endpoints
Secondary efficacy evaluation will be performed on FAS. 
Refer to Table 1-1 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 the secondary objectives. All secondary endpoints 
will be tested exploratively outside the confirmatory framework:
H2: Secukinumab is not different to placebo regimen with respect to 10-point numerical 
rating scale (NRS) at Week 24.
H3: Secukinumab is not different to placebo regimen with respect to the respective 
subcomponent of the Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) in 
the affected foot at baseline at Week 24.
H4: Secukinumab is not different to placebo regimen with respect to resolution of enthesitis as 
assessed by the LEI at Week 24.
H5: Secukinumab is not different to placebo regimen with respect to physician’s global 
assessment of disease activity at Week 24.
H6: Secukinumab is not different to placebo regimen with respect to patient’s global 
assessment of disease activity at Week 24.
H7: Secukinumab is not different to placebo regimen with respect to physician’s global 
assessment of heel enthesiopathy activity at Week 24.
H8: Secukinumab is not different to placebo regimen with respect to patient’s global 
assessment of heel enthesiopathy acitivity at Week 24.


Novartis
For business use only
Page 20
SAP
AIN457F3301
H9: The improvement in Secukinumab is not different to placebo regimen with respect to
from Baseline in Short Form-36 Physical Component Summary (SF-36 PCS) or SF-36v2 at 
Week 24.
Analysis of secondary efficacy variables

Heel pain
The mean change from Baseline of heel pain at 24 weeks, measured on a 10-point NRS will 
be analyzed using an Analysis of covariance (ANCOVA) model with factors treatment, 
country and diagnosis (PsA or axSpA) and with covariate baseline measuremenet of heel pain. 
The adjusted (LS) mean difference will be calculated as a point estimate together with its 
corresponding 95% confidence interval and p-value.

Bone marrow oedema (PsAMRIS)
The percentage of patients with an improvement of bone marrow oedema will be analyzed 
using a logistic regression model with factors treatment, country and diagnosis (PsA or 
axSpA). The odds ratio and its 95% confidence interval (CI) and p-value will be presented 
comparing secukinumab to placebo at Week 24.

Enthesitis Assessment (LEI)
The 4-site LEI (i.e. score with the four correct sites: lateral epicondyle humerus L + R and 
proximal achilles L + R) will be analyzed using a logistic regression model with factors 
treatment, country and diagnosis (PsA or axSpA). The odds ratio and its 95% confidence 
interval (CI) and p-value will be presented comparing secukinumab to placebo at Week 24.

Physician’s global assessment of disease activity
Physician’s assessment, measured on a VAS scale will be analyzed using an ANCOVA model  
with factors treatment, country and diagnosis (PsA or axSpA) and with covariate baseline 
value of global assessment of disease activity. The adjusted (LS-) mean difference will be 
calculated as a point estimate together with its corresponding 95% confidence interval and p-
value.

Physician’s global assessment of heel enthesiopathy activity
Physician’s assessment, measured on a VAS scale will be analyzed using an ANCOVA model 
with factors treatment, country and diagnosis (PsA or axSpA) and with covariate baseline 
measurement of the global assessment of heel enthesiopathy. The adjusted (LS-) mean 
difference will be calculated as a point estimate together with its corresponding 95% 
confidence interval and p-value.

Patient’s global assessment of disease and heel enthesiopathy activity
Refer to section 2.11 for analyses details.

SF-36 or SF-36v2
Refer to section 2.11 for analyses details
The time courses of secondary endpoints (percentage of patients with resolution of enthesitis
as assessed by LEI, mean change from baseline for heel pain in NRS, Physician’s / patient’s 


Novartis
For business use only
Page 21
SAP
AIN457F3301
global assessment in VAS, etc.) will be summarized descriptively for all visits by treatment 
group, subgroup (PsA, axSpA) and overall from Baseline until Week 52.
Summary statistics will include relative and absolute frequencies for the binary variable 
‘resolution of enthesitis’, and the number of patients (N), minimum, mean, median and 
maximum for the NRS/VAS variables. Additionally, these time courses will be displayed 
graphically.
Switching from placebo to secukinumab at Week 24
At Week 24, patients originally randomized to placebo will switch to receive secukinumab 
150 mg (1 injection of secukinumab 1 mL/150 mg) or secukinumab 300 mg (2 injections of 
secukinumab 1 mL/150 mg) in open-label fashion without a loading regimen.
Summary statistics will be provided for:

Number and percentage of patients with resolution of Achilles tendon enthesitis after 
switching from placebo to secukinumab at Week 24. 

Mean change of heel pain in patients after switching from placebo to secukinumab at 
Week 24.
2.7.3
Handling of missing values/censoring/discontinuations
This study aims to estimate the magnitude of treatment effects that are obtainable under the 
respective treatments. The disease activity is expected to decrease in the course of treatment. 
If a patient drops out or discontinues the trial prematurely, the last observed value of that 
patient seems to be a proper estimate for the effect achieved in that patient.
For the confirmatory analyses of secondary endpoints related to physician’s/patient’s global 
assessment and SF-36, missing values will be replaced by the last observed value in that 
patient (Last Observation Carry Forward). In case of a substantial number of missing values, 
alternative approaches (RMREM, MI) may be additionally calculated as sensitivity analyses.
2.8
Safety analyses
For all safety analyses, the Safety set will be used.
Summaries will be performed separately for first (Week 1-24) and entire treatment periods. 
Use of data up to and including the last visit before rescue provides and unbiased comparison 
between secukinumab and placebo; data collected beyond week 24 are included in analyses 
which summarize the entire treatment period. 
Safety analyses will be performed by PsA and AxSpA patients 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 received not the treatment randomized, 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.


Novartis
For business use only
Page 22
SAP
AIN457F3301
2.8.1
Adverse events (AEs)
The crude incidence 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) will be summarized by primary system organ 
class and preferred term. Confidence intervals for the crude rate will be derived as described 
in Section 
In addition, exposure time-adjusted rates (incidence rate) including 95% confidence intervals 
will be provided for the entire treatment period to adjust for differences in exposure between 
treatment groups.Graphical displays of the crude incidence and exposure-adjusted rates will 
be presented for all AEs and serious AEs by system organ class.
Treatment  emergent  adverse  events  reported  will  be  presented  by  preferred  term  in 
descending frequency according to its incidence in total secukinumab group (combining all 
secukinumab treatment groups) starting from the most common event. Summaries (crude 
incidences only) will also be presented for AEs by severity and for study treatment related 
AEs. If a particular AE ‘severity’ is missing, this variable will be listed as missing and treated 
as missing in summaries. If a subject reported more than one adverse event with the same 
preferred term, the adverse event with the greatest severity will be presented. If a subject 
reported more than one adverse event within the same primary system organ class, the subject 
will be counted only once with the worst 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 will also be reported separately by MedDRA SMQ.
For all adverse event summaries, the MedDRA version used for reporting the study will be 
described in a footnote.
Adverse event summaries will also be provided for the follow-up period for all patients
(completers and early discontinuations).
A listing of non-treatment emergent adverse events will be provided.  These cover adverse 
events that occurred before the first dose of the study treatment.  The crude incidence will be 
provided without treatment information.
Algorithms for date imputations will be provided in Programming Specifications.
For SAEs that occurred during screening a listing will be prepared for all patients screened 
including screening failures.


Novartis
For business use only
Page 23
SAP
AIN457F3301
Table  2.8-1  Overview of analyses on some safety endpoints
Analy
sis 
period
AEs & SAEs
AEs by 
severity
Study
drug 
related
AEs
AEs-SMQ
Risk
Notables for
(vitals/
ECG), lab 
criteria
Day 1 –
Week 24

crude
incidence
• crude
incidence
• crude
incidence

crude
incidence
• crude
incidence
• crude
incidence
Day 1
–
Week
24

exposure 
time 
adjusted
incidence*
Entire
Treatment
(up to week
52)

crude
incidence

exposure time 
adjusted 
incidence*
• crude
incidence
• crude
incidence

exposure
timeadjust
ed 
incidence
• crude
incidence
exposure 
time adjusted 
incidence
• crude
incidence
*Exposure-adjusted incidence rates will be done for the following:

at the PSOC for AE and SAE 

at the PT level for common AEs, which is 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

at Level 1 for Risks and SMQ analyses
2.8.1.1
Adverse events of special interest / grouping of AEs
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.
The crude incidence and exposure-adjusted incidence rates for SPP risks will be summarized. 
In addition, listings will be provided presenting which subjects experienced which risk.
Important note: For the evaluation of SPP risks primary and secondary system organ classes 
of the MedDRA dictionary will be considered.
2.8.2
Deaths
Separate summaries and listings will be provided for deaths for each treatment period.
2.8.3
Laboratory data
The summary of laboratory evaluations will be presented by patient sub-population 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 in 
tabular and graphical fashion.


Novartis
For business use only
Page 24
SAP
AIN457F3301
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 assessments.
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 subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was 
normal, low, or high for each visit value relative to whether or not the baseline value was 
normal, low, or high. If appropriate, the shifts to the most extreme laboratory test value within 
a treatment phase (either initial or entire) 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: 
Hematology will include hemoglobin, platelets, red blood cells (RBC), white blood cells 
(WBC), differential WBC counts. Serum chemistry will include glucose, cholesterol, 
triglycerides (TG), urea, creatinine, total bilirubin (TBL), AST (SGOT), ALT (SGPT), 
gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), sodium, potassium, 
bicarbonate, calcium, phosphorous, total protein, albumin, and uric acid. The urinalysis results 
for standard parameters such as protein, glucose, blood and WBCs will be recorded in the 
appropriate eCRF page.
These summaries will be split into hematology and chemistry for study level reports and the 
pooled summary of clinical safety.
Table 2.8-2 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


Novartis
For business use only
Page 25
SAP
AIN457F3301
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
Hypertriglyceridem
ia
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:
Table 2.8-3 Liver-related events
Parameter
Criterion
ALT
AST
ALT or AST
TBL
ALP
ALT or AST & TBL
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
>1.5xULN, >2xULN, >3xULN,
>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


Novartis
For business use only
Page 26
SAP
AIN457F3301
ALT or AST & TBL & 
ALP
  
ALT or AST>3xULN & TBL >2xULN & ALP<2xULN     
(Hy’s Law)
Note: elevated ALP may suggest obstruction as a 
consequence of gall bladder or bile duct disease; ALP may 
also be increased in malignancy. FDA therefore terms Hy’s 
Law cases as indicators of pure hepatocellular injury. This 
does not mean that cases of ALT or AST >3xULN & 
TBL >2xULN & ALP ≥2xULN may not result in severe 
DILI.
Notes:
1) In studies which enroll 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.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
The following quantitative variables will be summarized: ventricular rate, RR interval, PR 
interval, QRS duration, QT interval, and corrected QT interval (QTc). Both Bazett (QTcB) 
and Fridericia (QTcF) corrections will be presented for QTc.
QTc will be summarized by computing the number and percentage of patients (including 
95%confidence intervals for pooled analyses, e.g. DMC or SCS) with:

QTc > 500 msec

QTc > 480 msec

QTc > 450 msec

QTc changes from baseline > 30 msec

QTc 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.


Novartis
For business use only
Page 27
SAP
AIN457F3301
2.8.4.2
Vital signs
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed. These descriptive summaries will be 
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 2.8-4
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Pulse (bpm)
>= 140 mmHg or < 90 mmHg
>=90 mmHg or <60 mmHg
> 100 bpm or <60 bpm
2.8.4.3
Physical examination
Summary statistics will be provided for physical examination by visit.
2.8.4.4
Height and weight
Summary statistics will be provided for height and weight captured at screening.
2.8.4.5
Pregnancy and assessment of fertility
A serum β-hCG test will be performed in all women at Screening.
Urine pregnancy test will be performed at various visits as indicated in the assessment 
schedule
Summaries will be provided for both the above tests as other safety measures.
2.8.4.6
Tolerability of secukinumab
Tolerability will be assessed by AEs, laboratory values and injection site reactions and 
summarized accordingly.
2.9
Pharmacokinetic endpoints
Not applicable
2.10
PD and PK/PD analyses
Not applicable
2.11
Patient-reported outcomes
Patient’s global assessment of disease activity
Patient’s global assessment od disease activity, measured on a VAS scale will be analyzed 
using an ANCOVA model with factors treatment, country and diagnosis (PsA or axSpA) and 


Novartis
For business use only
Page 28
SAP
AIN457F3301
with covariate baseline measurement of the global assessment of disease activity. The 
adjusted (LS-) mean difference will be calculated as a point estimate together with its 
corresponding 95% confidence interval and p-value.
Patient’s global assessment of heel enthesiopathy activity
Patient’s global assessment of heel enthesiopathy, measured on a VAS scale will be analyzed 
using an ANCOVA model with factors treatment, country and diagnosis (PsA or axSpA) and 
with covariate baseline measurement of the global assessment of heel enthesiopathy. The 
adjusted (LS-) mean difference will be calculated as a point estimate together with its 
corresponding 95% confidence interval and p-value.
Short Form-36 Physical Component Summary (SF-36 PCS) or SF-36v2
The score of the SF-36 or SF-36v2 will be analyzed using an ANCOVA model with factors 
treatment, country and diagnosis (PsA or axSpA) and with covariate baseline value of SF-36
or SF-36v2. The adjusted (LS-) mean difference will be calculated as a point estimate together 
with its corresponding 95% confidence interval and p-value.
 
Bath ankylosing spondylitis disease activity index (BASDAI)
BASDAI wil be summarized descriptively for axSpA patients. Summary statistics will include 
relative and absolute frequencies.
2.12
Biomarkers
Not applicable


Novartis
For business use only
Page 29
SAP
AIN457F3301
2.14
Interim analysis
Once all data until/including Week 24 (containing the primary and secondary endpoints) are 
complete and clean, the database for that study period will be locked and analyzed. The 
results may be published or made available to personnel involved in data collection of this 
study prior to database lock of the complete study period until Week 52.
The details of the Week 24 analyses will be mentioned in TFL Shells. Additional SAP for 
Week 24 analyses will be written if required.
3
Sample size calculation
The primary endpoint of this trial is the percentage of patients with resolution of Achilles 
tendon enthesitis assessed by application of firm pressure with the pulp of the thumb by the 
physician at Week 24. The sample size calculation is based on the same enthesitis assessment 
we performed within the FUTURE 2 PsA trial (CAIN457F2312) in the form of the LEI which 
is  composed  of  three  different enthesial  sites  (Lateral epicondyle,  left  and  right;  medial 
femoral condyle, left and right; Achilles tendon insertion, left and right). Within this trial, the 
resolution of enthesitis amongst those patients with these symptoms at Baseline has been 
assessed for Week 24:


Novartis
For business use only
Page 30
SAP
AIN457F3301
Week 24, the end of the placebo-controlled phase:

Secukinumab (300 mg): 48.2% of patients.

Secukinumab (150 mg): 42.2% of patients.

Placebo: 21.5% of patients.
In addition to these clinical data we can make the following assumptions:

There is no difference in response to secukinumab between the different enthesial sites 
assessed as part of the LEI in the FUTURE 2 trial. Therefore we do not expect a 
different response when we only assess the Achilles tendon insertion.

There is no difference in secukinumab response rates regarding resolution of enthesitis 
between PsA and axPsA patients. Therefore we pool the analysis for both diseases.
A total of 89 patients per arm are required to achieve 90% power to detect a difference on a 
two-sided, 2.5% significance level, if the true response rates are 45% under secukinumab and
21% under placebo. To account for some drop-outs and other protocol violations, 100 patients 
per arm = 200 patients total should be randomized into this trial.
For the comparison within the 2 subgroups of PsA and axPsA patients, which will consist of 
50% of the total study population each, the trial will have about 46% power with regard to the 
primary endpoint.
No sample size justification is provided for secondary analyses, hence results from secondary 
analyses should be interpreted carefully.
4
Change to protocol specified analyses
Not applicable
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).


Novartis
For business use only
Page 31
SAP
AIN457F3301
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 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


Novartis
For business use only
Page 32
SAP
AIN457F3301
5.1.3
Concomitant medication date imputation
Concomitant medication (CMD) date imputation uses both a comparison of the partial CMD 
start date to the treatment start date, and the value of the CMDTYP1C flag (1, 2, or 3).  Event 
date comparisons to treatment start date are made based on the year and month values only 
(any day values are ignored) in Table 1-3 below.
1. If the CMD start date year value is missing, the date will be imputed based on the 
CMDTYP1C flag value.  If the flag value is 1 or 3, the imputed CMD start date is set to 
one day before the treatment start date.  Else, if the flag value is missing or 2, the imputed 
CMD start date is set to one day after the treatment start date.  (Note that for some legacy 
data, the CMDTYP1C variable may not exist in the data.  When this happens and the 
CMD start date year value is missing, the imputed date value will be NULL.)
2. If the CMD start date year value is less than the treatment start date year value, the CMD 
started before treatment.  Therefore:
a.
if the CMD year is less than the treatment year and the CMD month is missing, the 
imputed CMD start date is set to the mid-year point (01JulYYYY).
b. Else if the CMD year is less than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the mid-month point 
(15MONYYYY).
If the CMD start date year value is greater than the treatment start date year value, the CMD 
started after treatment. Therefore:
a.
If the CMD year is greater than the treatment year and the CMD month is missing, 
the imputed CMD start date is set to the year start point (01JanYYYY).
b. Else if the CMD year is greater than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the month start point 
(01MONYYYY).
3. If the CMD start date year value is equal to the treatment start date year value:
a.
and the CMD month is missing or the CMD month is equal to the treatment start 
month,
i.
If the flag value is 1 or 3, the imputed CMD start date is set to one day 
before the treatment start date.
ii.
Else, if the flag value is missing or 2, the imputed CMD start date is set to 
one day after the treatment start date.
a.
Else if the CMD month is less than the treatment start month, the imputed CMD 
start date is set to the mid-month point (15MONYYYY).
b. Else if the CMD month is greater than the treatment start month, the imputed 
CMD start date is set to the start month point (01MONYYYY).
Table 5.1-3:  CMD date imputation
MON MISSING
MON < CFM
MON = CFM
MON > CFM
YYYY 
MISSING (F)
(F)
(F)
(F)
Uncertain
Uncertain
Uncertain
Uncertain


Novartis
For business use only
Page 33
SAP
AIN457F3301
YYYY < 
CFY
(D)=01JULYYYY
(C)=15MONYY
(C)=15MONYY
(C)=15MONYY
Before Treatment Start
Before Treatment Start Before Treatment Start
Before Treatment Start
YYYY = 
CFY
(B)
(C)=15MONYY
(B)
(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)
IF CMDTYP1C IN (1,3) THEN TRTSTD-1
     ELSE IF CMDTYP1C in(. , 2) THEN TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
(F)
IF CMDTYP1C IN (1,3) THEN TRTSTD-1
    ELSE IF CMDTYP1C in  (. , 2) THEN TRTSTD+1
5.1.3.1
Prior therapies date imputation
Not applicable
5.1.3.2
Post therapies date imputation
Not applicable
5.1.3.3
Other imputations
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 to SAP
5.4
Statistical models
5.4.1
Primary analysis
The primary analysis will be performed comparing treatments with respect to the primary
efficacy variable in a logistic regression model with the factors treatment, country and 
stratification factor diagnosis (PsA or axSpA).


Novartis
For business use only
Page 34
SAP
AIN457F3301
Proc logistic data=aaa;
Class TRT OCUNTRY STRATA / param=glm;
Model AVAL = TRT COUNTRY 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 24, 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.
SAS Code for Logistic model:
Proc logistic data=aaa exactonly;
Class TRT STRATA / param=glm;
Model AVAL = TRT STRATA;
Exact TRT / estimate=both;
Ods output exactoddsratio=exactoddsratio;
Run;
For subgroup analysis, the above code will be used for each stratification factor.
The primary model will also be recalculated with the above factors included as well as with 
respective tersm for a subgroup*treatment interaction. 
5.4.2
Key secondary analysis
Not applicable
5.4.3
Secondary analysis
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, country 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 COUNTRY STRATA;
model response = TRT STRATA COUNTRY BASE / s;
lsmeans TRT / diff;
run;
5.5
Rule of exclusion criteria of analysis sets 
Table 5.1-4
Protocol deviations that cause subjects to be excluded


Novartis
For business use only
Page 35
SAP
AIN457F3301
Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
INCL01A
ICF is not signed or missing or date of signing ICF is 
missing
EXCLUDE FROM FAS 
AND SAF
3
INCL01B
ICF date is after visit or assessment date
INCLUDE IN 
EVERYTHING
0
INCL02A
Pregnant or lactating female patients
INCLUDE IN 
EVERYTHING
0
INCL02B
Age is less than 18 years
INCLUDE IN 
EVERYTHING
0
INCL03A
Diagnosis of PsA classified by CASPAR criteria with
no symptoms or symptoms for less than 6 months
INCLUDE IN 
EVERYTHING
0
INCL03B
Active PsA as not assessed by greater than 1/78 
tender joints and greater than 1/76 swollen joints at 
Baseline.
INCLUDE IN 
EVERYTHING
0
INCL04A
No objective signs of inflammation at Screening, no 
evident of Sacroiliac joint inflammation or 
radiographic sacroilitis and hsCRP less than ULN
INCLUDE IN 
EVERYTHING
0
INCL04B
Total BASDAI < 4 (0–10) at Baseline
INCLUDE IN 
EVERYTHING
0
INCL05
Subject with no diagnosis of Achilles tendon 
enthesitis
INCLUDE IN 
EVERYTHING
0
INCL06
Onset of heel pain < 1 month or > 5 years at 
baseline
INCLUDE IN 
EVERYTHING
0
INCL07
Heel enthesitis is not MRI-positive according to the 
investigator`s judgement.
INCLUDE IN 
EVERYTHING
0
INCL08
Subject is intolerable or toxified or contraindicated to 
NSAIDs standard treatment for heel enthesitis
INCLUDE IN 
EVERYTHING
0
INCL09
Rheumatoid factor (RF) or anti-cyclic citrullinated 
peptide (anti-CCP) antibodies is positive at 
Screening
INCLUDE IN 
EVERYTHING
0
INCL10A
Subject are inadequate response to NSAIDs at the 
highest recommended dose at least 1 month prior to 
randomization to enroll into study.
INCLUDE IN 
EVERYTHING
0
INCL10B
Subject is inadequate response or failure to 
respond, or less than 1 month if therapy
INCLUDE IN 
EVERYTHING
0
INCL11A
Subject is unstable to remain on regular dose of 
NSAIDs as part of PsA or axSpA therapy for 2 
weeks before study randomization
INCLUDE IN 
EVERYTHING
0
INCL11B
Subject is unable to remain up to Week 24 on stable 
regular dose of NSAIDs as part of PsA or axSpA 
therapy 
INCLUDE IN 
EVERYTHING
0
INCL12A
Patient taking corticosteroid is unable to remain on 
stable dose of less than or equal of 10 mg/day 
prednisone for 2 weeks before randomization
INCLUDE IN 
EVERYTHING
0
INCL12B
Patient taking corticosteroid is unable to remain on 
stable dose up to week 24
INCLUDE IN 
EVERYTHING
0
INCL13A
Patient taking MTX or axSpA-sulfasalazine is not 
taken it for atleast 3 months
INCLUDE IN 
EVERYTHING
0
INCL13B
Patient taking MTX or axSpA-sulfasalazine is unable 
to remain on stable dose for at least 4 weeks prior to
randomization
INCLUDE IN 
EVERYTHING
0
INCL13C
Patient taking MTX or axSpA-sulfasalazine is unable 
INCLUDE IN 
0


Novartis
For business use only
Page 36
SAP
AIN457F3301
Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
to remain on stable dose for up to Week 24
EVERYTHING
INCL14
Patient is on MTX but not on folic acid 
supplementation at randomization
INCLUDE IN 
EVERYTHING
0
INCL15A
Patient who is on DMARD other than MTX or - only 
in case of axSpA - sulfasalazine is not discontinued 
the DMARD for 4 weeks prior to randomization.
INCLUDE IN 
EVERYTHING
0
INCL15B
Patients who are on leflunomide, has not been 
discontinued for 8 weeks unless a cholestyramine
washout has been performed prior to randomization 
to randomized into study.
INCLUDE IN 
EVERYTHING
0
INCL16
Patients are not TNFα inhibitor-naïve
INCLUDE IN 
EVERYTHING
0
EXCL01
Chest X-ray or chest MRI with evidence of ongoing 
infectious or malignant process
INCLUDE IN 
EVERYTHING
0
EXCL02
Patient took high potency opioid analgesics (e.g. 
methadone, hydromorphone, morphine).
INCLUDE IN 
EVERYTHING
0
EXCL03
Previous exposure to secukinumab or other biologic 
drug directly targeting IL-17 or IL-17 receptor
INCLUDE IN 
EVERYTHING
0
EXCL04
Patient used any of investigational drug and/or 
devices within 4 weeks before randomization or a
period of 5 half-lives of the investigational drug.
INCLUDE IN 
EVERYTHING
0
EXCL05A
Patient is using Oral or topical retinoids of psoriasis 
treatments / medications
INCLUDE IN 
EVERYTHING
0
EXCL05B
Patient is using Photochemotheraphy of psoriasis 
treatments / medications and not undergone 4 
weeks of washout treatment
INCLUDE IN 
EVERYTHING
0
EXCL05C
Patient is using Phototheraphy of psoriasis 
treatments / medications and not undergone 2 
weeks of washout treatment
INCLUDE IN 
EVERYTHING
0
EXCL05D
Patient is using Topical skin treatments of psoriasis 
treatments / medications and not undergone 2 
weeks of washout treatment
INCLUDE IN 
EVERYTHING
0
EXCL06
History of hypersensitivity to any of the study drugs 
or its excipients or to drugs of similar
chemical classes
INCLUDE IN 
EVERYTHING
0
EXCL07
Any intramuscular or intravenous corticosteroid 
treatment within 4 weeks before
randomization
INCLUDE IN 
EVERYTHING
0
EXCL08
Any therapy by intra-articular injections (e.g. 
corticosteroid) within 4 weeks before
randomization.
INCLUDE IN 
EVERYTHING
0
EXCL09
Patients previously have been treated with TNF 
inhibitors
INCLUDE IN 
EVERYTHING
0
EXCL10
Patients have received biologic immunomodulating
agents
INCLUDE IN 
EVERYTHING
0
EXCL11
Previous treatment with any cell-depleting therapies 
including but not limited to anti-CD20, investigational 
agents
INCLUDE IN 
EVERYTHING
0
EXCL12
Pregnant or nursing (lactating) women, confirmed by 
a positive human chorionic gonadotropin (hCG) 
laboratory test
INCLUDE IN 
EVERYTHING
0
EXCL13
Women of childbearing potential, defined as all 
women physiologically capable of becoming 
pregnant, unless they are using effective methods of 
contraception before 3 months during dosing of 
study treatment
INCLUDE IN 
EVERYTHING
0
EXCL14
Active ongoing inflammatory diseases or including 
INCLUDE IN 
0


Novartis
For business use only
Page 37
SAP
AIN457F3301
Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
inflammatory bowel disease or uveitis.
EVERYTHING
EXCL15
Patient unacceptable risk for participation in the 
opinion of the investigator fior underlying metabolic, 
hematologic, renal, hepatic, pulmonary, neurologic, 
endocrine, cardiac, infectious or gastrointestinal 
conditions in the opinion of the investigator
INCLUDE IN 
EVERYTHING
0
EXCL16
Significant medical problems or diseases, including 
but not limited to the following:
uncontrolled hypertension or congestive heart failure 
or uncontrolled diabetes.
INCLUDE IN 
EVERYTHING
0
EXCL17A
Any single parameter (AST/SGOT, ALT/SGPT, 
alkaline phosphatase) exceeded 2 × ULN.
INCLUDE IN 
EVERYTHING
0
EXCL17B
Total bilirubin concentration is increased above 2 × 
ULN and serum bilirubin exceeding the value of 1.6 
mg/dL (27 μmol/L).
INCLUDE IN 
EVERYTHING
0
EXCL18
History of renal trauma, glomerulonephritis, or 
patients with 1 kidney only, or a serum
creatinine level exceeding 1.5 mg per dL
INCLUDE IN 
EVERYTHING
0
EXCL19
Screening total white blood cell (WBC) count less 
than 3000/μL, or platelets less than 100000/μL or 
neutrophils less than 1,500/μL or hemoglobin less 
than 8.5 g per dL (85 g per L).
INCLUDE IN 
EVERYTHING
0
EXCL20
Active systemic infections during the last 2 weeks 
(exception: common cold) prior to randomization.
INCLUDE IN 
EVERYTHING
0
EXCL21
Patient is having history of ongoing, chronic or 
recurrent infectious disease or evidence of 
tuberculosis infection
INCLUDE IN 
EVERYTHING
0
EXCL22
Known infection with human immunodeficiency virus 
(HIV) or hepatitis B or hepatitis C at screening or 
randomization
INCLUDE IN 
EVERYTHING
0
EXCL23
History of lymphoproliferative disease or any known 
malignancy or history of malignancy of any organ 
system within the past 5 years.
INCLUDE IN 
EVERYTHING
0
EXCL24
Current severe progressive or uncontrolled disease 
which in the judgment of the clinical
investigator renders the patient unsuitable for the 
trial
INCLUDE IN 
EVERYTHING
0
EXCL25
Inability or unwillingness to undergo repeated 
venipuncture
INCLUDE IN 
EVERYTHING
0
EXCL26
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.
INCLUDE IN 
EVERYTHING
0
EXCL27
Donation or loss of 400 mL or more of blood within 8 
weeks before randomization
INCLUDE IN 
EVERYTHING
0
EXCL28
History or evidence of ongoing alcohol or drug 
abuse within the last 6 months before
randomization.
INCLUDE IN 
EVERYTHING
0
EXCL29
Plans for administration of live vaccines during the 
study period or within 6 weeks preceding 
randomization.
INCLUDE IN 
EVERYTHING
0
WITH01
Patient becomes pregnant, while taking study 
medication.
INCLUDE IN 
EVERYTHING
0
OTH01
Pregnancy test not performed as required per 
protocol
INCLUDE IN 
EVERYTHING
0
OTH02
Pregnancy not reported within 24 hrs to Novartis 
while patient is on study treatment
INCLUDE IN 
EVERYTHING
0
WITH02
ICF withdrawn but patient continuing in the study
INCLUDE IN 
EVERYTHING (Delete 
0


Novartis
For business use only
Page 38
SAP
AIN457F3301
Deviation ID
Description of Deviation
Exclusion in Analyses
Severity code
post withdrawal data)
WITH03
Pregnant patient not withdrawn from study
INCLUDE IN 
EVERYTHING
0
WITH04
Pregnant patient not withdrawn from study as  local 
workup cannot exclude definite pregancy
INCLUDE IN 
EVERYTHING
0
TRT01
Dosing error in comparative dosing phase
INCLUDE IN 
EVERYTHING
0
OTH03
Rescue medication used
INCLUDE IN 
EVERYTHING
0
COMD01
Prohibited medication consumed during study or 
washout period not observed.
INCLUDE IN 
EVERYTHING
0
EXCL30
Inability or unwillingness to undergo MRI of the feet 
preceding but enrolled in study
INCLUDE IN 
EVERYTHING
0
OTH04
Leeds Enthesitis Index assesment is missing but 
treatment period 1 completed
INCLUDE IN 
EVERYTHING
0
Table 5.1-5 Analysis set exclusions based on population codes
Analysis set 
Population codes that cause a subject to be 
excluded
RAN 
NA
SAF 
2, 3, 6
FAS 
1, 3
Table 5.1-6 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
6
Reference
Not applicable