Clinical trial NCT01892436
Conditions: Psoriatic Arthritis
Keywords: Extension study, psoriatic arthritis, pre-filled syringe
Sponsor: Novartis Pharmaceuticals
Start date: 2013-09-30; Completion date: 2018-01-11
Enrollment: 460 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed as a 3-year extension to the phase III core study CAIN457F2306. It aimed to provide continuous treatment with secukinumab in pre-filled syringes (PFS) for subjects who completed the core study CAIN457F2306, to obtain further long term efficacy, safety and tolerability information in subjects with active psoriatic arthritis receiving secukinumab every 4 weeks. At Week 104 of the study CAIN457F2306, eligible subjects completed the assessments associated with the core study visit and subsequently continued in this extension study on the same dose that they were receiving during the core study. The regular assessments of disease activity ensure that subjects who are experienced worsening of disease in any of the treatment groups could exit the study upon their own wish or based on the advice of the investigator at any time.

Detailed description:

Arms: arm 1: Subjects continued to receive secukinumab 75mg in PFS (same dose as that was received in core study CAIN457F2306) every 4 weeks up to Week 256. From Week 156, patients may have been escalated to 150 mg or 300 mg as judged appropriate by investigator arm 2: Subjects continued to receive secukinumab 150mg in PFS (same dose as that was received in core study CAIN457F2306) every 4 weeks up to Week 256. From Week 156, patients may have been escalated to 300 mg as judged appropriate by the investigator arm 3: Placebo (for maintaining the blind till Week 152): Placebo to secukinumab 0.5 mL solution solution for injection was provided in PFS for s.c. administration (a single use pre-filled 1mL long glass syringe). It contained a mixture of inactive excipients, matching the composition of secukinumab 75mg arm 4: Placebo (for maintaining the blind till Week 152): Placebo to secukinumab 1 mL solution for injection was provided in PFS for s.c. administration (a single use pre-filled 1mL long glass syringe). It contained a mixture of inactive excipients, matching the composition of secukinumab 150 mg
Interventions: intervention 1: Secukinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Secukinumab is a human monoclonal antibody. Monoclonal antibodies are proteins that recognize and bind to unique proteins that your body produces. Secukinumab binds and reduces the activity of a cytokine (a "messenger" protein in the body) called Interleukin 17 (IL-17). intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
Clinical Development
Secukinumab (AIN457)
Clinical Trial Protocol [CAIN457F2306E1] / NCT01892436
A three-year extension study to evaluate the long term 
efficacy, safety and tolerability of secukinumab in patients 
with active psoriatic arthritis 
Authors:
 
Document type:
Amended Protocol Version
EUDRACT number:
2013-001241-13
Version number:
v02 Clean
Development phase:
III
Release date:
22 July 2016 
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
NCDS Template Version 03-Feb-2012
 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Amendment 2 ...........................................................................................................................10
Amendment 1 ...........................................................................................................................10
Protocol synopsis...............................................................................................................14
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................18
2
Study objectives.................................................................................................................19
2.1
Primary objectives .................................................................................................19
2.2
Secondary objectives .............................................................................................19
19
3
Investigational plan ...........................................................................................................20
3.1
Study design...........................................................................................................20
3.2
Rationale of study design.......................................................................................22
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....22
3.4
Rationale for choice of comparator .......................................................................23
3.5
Purpose and timing of interim analyses/design adaptations..................................23
3.6
Risks and benefits..................................................................................................24
4
Population..........................................................................................................................24
4.1
Inclusion criteria ....................................................................................................25
4.2
Exclusion criteria...................................................................................................25
5
Treatment...........................................................................................................................26
5.1
Protocol requested treatment .................................................................................26
5.1.1
Investigational treatment.......................................................................26
5.1.2
Additional study treatment....................................................................26
5.2
Treatment arms......................................................................................................27
5.3
Treatment assignment, randomization...................................................................27
5.4
Treatment blinding.................................................................................................28
5.5
Treating the subject................................................................................................28
5.5.1
Subject numbering ................................................................................28
5.5.2
Dispensing the investigational treatment ..............................................28
 


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5.5.3
Handling of study treatment..................................................................29
5.5.4
Instructions for prescribing and taking study treatment........................29
5.5.5
Permitted dose adjustments and interruptions of study treatment ........31
5.5.6
Rescue medication ................................................................................32
5.5.7
Concomitant treatment..........................................................................32
5.5.8
Prohibited Treatment.............................................................................33
5.5.9
Discontinuation of study treatment and premature subject 
withdrawal.............................................................................................33
5.5.10
Emergency breaking of treatment assignment ......................................34
5.5.11
Study completion and post-study treatment..........................................35
5.5.12
Early study termination.........................................................................35
6
Visit schedule and assessments .........................................................................................35
6.1
Information to be collected on screening failures..................................................43
6.2
Subject demographics/other baseline characteristics.............................................43
6.3
Treatment exposure and compliance .....................................................................43
6.4
Efficacy..................................................................................................................43
6.4.1
American College of Rheumatology (ACR) response..........................44
6.4.2
Radiographic assessments.....................................................................46
47
6.4.4
DAS28 
...............................................................47
47
47
47
48
49
50
6.4.11
Physician’s global assessment of fingernail disease severity (VAS)....51
6.4.12
Appropriateness of efficacy assessments..............................................51
6.5
Safety.....................................................................................................................51
6.5.1
Physical examination ............................................................................52
6.5.2
Vital signs..............................................................................................52
6.5.3
Height and weight .................................................................................52
6.5.4
Laboratory evaluations..........................................................................52
6.5.5
Electrocardiogram (ECG) .....................................................................53
6.5.6
Pregnancy and assessments of fertility .................................................53
6.5.7
Tolerability of secukinumab .................................................................54
54
 


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6.5.9
Additional parameters...........................................................................54
6.5.10
Appropriateness of safety measurements..............................................54
6.6
Other assessments..................................................................................................55
6.6.1
Health-related Quality of Life...............................................................55
6.6.2
Pharmacokinetics ..................................................................................56
7
Safety monitoring..............................................................................................................56
7.1
Adverse events.......................................................................................................56
7.2
Serious adverse event reporting.............................................................................58
7.3
Liver safety monitoring .........................................................................................59
7.4
Pregnancy reporting...............................................................................................59
8
Data review and database management.............................................................................60
8.1
Site monitoring ......................................................................................................60
8.2
Data collection.......................................................................................................60
8.3
Database management and quality control............................................................60
8.4
Data Monitoring Committee..................................................................................61
8.5
Adjudication Committee........................................................................................61
9
Data analysis......................................................................................................................61
9.1
Analysis sets ..........................................................................................................62
9.2
Subject demographics and other baseline characteristics......................................62
9.3
Treatments .............................................................................................................62
9.4
Analysis of the primary variable(s) .......................................................................63
9.4.1
Variable(s).............................................................................................63
9.4.2
Statistical model, hypothesis, and method of analysis..........................63
9.4.3
Handling of missing values/censoring/discontinuations.......................63
9.4.4
Supportive analyses...............................................................................63
9.5
Analysis of secondary and exploratory variables ..................................................64
9.5.1
Efficacy variables..................................................................................64
9.5.2
Safety variables .....................................................................................64
66
9.5.4
Pharmacokinetics ..................................................................................66
67
9.6
Interim analyses.....................................................................................................67
9.7
Sample size calculation..........................................................................................67
10 Ethical considerations........................................................................................................67
10.1
Regulatory and ethical compliance........................................................................67
10.2
Informed consent procedures.................................................................................67
10.3
Responsibilities of the investigator and IRB/IEC..................................................68
 


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10.4
Publication of study protocol and results...............................................................68
11 Protocol adherence ............................................................................................................68
11.1
Protocol Amendments ...........................................................................................69
12 References .........................................................................................................................69
13 Appendices ........................................................................................................................72
13.1
Appendix 1: Clinically notable laboratory values and vital signs .........................72
13.2
Appendix 2: Blood collection logs ........................................................................73
74
13.4
Appendix 4: American College of Rheumatology (ACR) Measures and 
Criteria of Response ..............................................................................................75
13.5
Appendix 5: Disease Activity Score 28(DAS28)..................................................77
79
81
83
13.9
Appendix 9: Health Assessment Questionnaire (HAQ) © .....................................84
13.10 Appendix 10: Guidelines for administering the PRO questionnaires....................86
13.11 Appendix 11: Study design of core study CAIN457F2306...................................89
List of tables
Table 5-1
Prohibited treatment..............................................................................33
Table 6-1
Assessment schedule (Week 104E1 to Week 156)...............................37
Table 6-2
Assessment schedule (Week 160 to Week 208) ...................................39
Table 6-3
Assessment Schedule (Week 212 to Week 260 and Follow-up) ..........41
48
49
Table 6-6
Score for percent of nail with onycholysis or oil-drop dyschromia......50
Table 6-7
Score for number of pits........................................................................50
Table 6-8
Score for percent of nail with crumbling present..................................51
Table 13-1
Safety Analyses: Expanded Limits and Notable Criteria......................72
73
Table 13-3
Blood collection log for pharmacokinetics ...........................................73
83
83
List of figures
Figure 3-1
Extension Study (CAIN457F2306E1) design....................................................... 22
 


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Figure 13-1
Core Study (CAIN457 F2306) Design ................................................................. 90
List of abbreviations
ACR
American College of Rheumatology 
AE
Adverse event
ALT
Alanine aminotransferase/Serum Glutamic Pyruvate Transaminase (SGPT)
ANA
Anti-nuclear antibodies
ANCOVA
Analysis of covariance
Anti-CCP
Anti-cyclic citrullinated peptide antibodies
AS
Ankylosing Spondylitis
AST
Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase
(SGOT)
ATC
Anatomical Therapeutic Classification
BMI
Body Mass Index
BSL
Baseline
BUN
Blood Urea Nitrogen
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CRO
Contract Research Organization
CRP (hsCRP)
(high sensitivity) C-Reactive Protein
DAS
Disease Activity Score
DMARD
Disease Modifying Anti-rheumatic Drug
DMC
Data Monitoring Committee 
DNA
Desoxyribonucleic acid
DS&E
Drug Safety & Epidemiology
dsDNA Ab
Anti-double stranded DNA antibodies
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked Immunosorbent Assay
EMA/EMEA
European Medicnices (Evaluation) Agency
 


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EoS
End of Study
ESR 
Erthrocyte Sedimentation Rate 
FACIT-Fatigue© Functional Assessment of Chronic Illness Therapy - Fatigue
FAS
Full Analysis Set
FDA
Food and Drug Administration
FSH
Follicle-stimulating Hormone
GCP
Good Clinical Practice
GGT 
Gamma Glutamyl Transferase
GTL
Global Trial Leader
HAQ-DI©
Health Assessment Questionnaire – Disability Index
hCG
Human Chorionic Gonadotropin
HDL
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC/EC
Independent Ethics Committee
IFU
Instructions for Use
IL
Interleukin
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra Uterine Device
IUS
Intra Uterine System
i.v.
intravenous
LDL
Low Density Lipoprotein
LLN
Lower limit of normal
 


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LLOQ
Lower Limit of Quantification
LOCF
Last observation carried forward
MedDRA 
Medical Dictionary for Regulatory Activities
mmHG
Millimeter mercury 
MTX
Methotrexate
NSAID
Non-Steroidal Anti-Inflammatory Drug
NovDTD
Novartis Drug/Therapy Dictionary
PASI
Psoriasis Area and Severity Index
PFS
Pre-filled Syringe
PK
Pharmacokinetic
PoC
Proof of Concept
PRO
Patient Reported Outcome
PsA
Psoriatic Arthritis
QoL
Quality of Life
RA
Rheumatoid Arthritis
RBC
Red blood cells
RDC
Remote Data Capture
RF
Rheumatoid Factor
SAE
serious adverse event
s.c.
Subcutaneous
 
SJC
Swollen joint count
SpA
Spondyloarthritides
SUSAR
Suspected Unexpected Serious Adverse Reaction
TJC
Tender joint count
TNF
Tumor Necrosis Factor 
TNFα-IR
TNFα Inhibitor Incomplete/Inadequate Responders 
ULN
Upper Limit of Normal
UPT
Urine Pregnancy Test
VAS
Visual Analog Scale 
WBC
White blood cells
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Epoch 
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after treatment 
has ended.
Investigational drug
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as approved drugs 
used outside of their indication/approved dosage or tested in a fixed 
combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage
Medication number
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system
Subject Number 
A number assigned to each patient who enrolls into the study 
Part 
A subdivision of a single protocol into major design components. These 
parts often are independent of each other and have different populations or 
objectives. For example, a single dose design, a multiple dose design that 
are combined into one protocol, or the same design with different patient 
populations in each part.
Period
A subdivision of a cross-over study
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up)
Randomization number
A unique identifier assigned to each randomized patient, corresponding to 
a specific treatment arm assignment
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as part 
of the required study procedures; includes investigational drug (s), active 
drug run-ins or background therapy 
Study/investigational treatment 
discontinuation
Point/time when patient permanently stops taking study/investigational 
treatment for any reason; may or may not also be the point/time of 
premature patient withdrawal
Variable
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points
 


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Amendment 2
Amendment rationale 
This protocol amendment is primarily issued for the following reasons:
1. Removing Week 260 X-Ray (hands/wrists + feet) assessment
Due to limited scientific value of the week 260 X-Rays beyond which is provided by the week 
208 X-Rays, business priorities and initiation of an additional PsA study that will evaluate 
skeletal X-Rays, the Week 260 X-Rays included in the current study are now being deleted in 
this Amendment 2.
2. Introducing updated Novartis standard language for SAE reporting
3. Adding further specifications with respect to statistical analysis
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 “Study objectives” (Section 2),”Visit Schedule and 
Assessments” (Section 6), “Safety monitoring” (Section 7) and “Data Analysis” (Section 9) 
have been amended to reflect the rationale given above.
Additionally, this protocol amendment includes the correction of typographical and 
formatting errors and editorial changes for increased clarity of the text. Consequently, changes 
were implemented throughout the protocol.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation. 
Amendment 1
Amendment rationale 
This protocol amendment is primarily issued for the following reasons:
1. Allowing dose escalation of secukinumab administered sc every 4 weeks from 75 mg 
to 150 mg or 300 mg, and from 150 mg to 300 mg
75 mg sc dose of secukinumab provides insufficient exposure:
Phase 3 studies in patients with active PsA (CAIN457F2306 and CAIN457F2312) 
demonstrated the superior efficacy of secukinumab 150 mg sc and 300 mg sc 
 


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(CAIN457F2312 only) regimens over placebo. Secukinumab 150 mg sc and 300 mg sc 
regimens had a rapid onset of response and similar magnitude of efficacy across several 
endpoints.
In contrast, based on the results of CAIN457F2312, secukinumab 75 mg sc is considered an 
inadequate dose, as the primary endpoint was met but overall, when evaluated against the 150 
and 300 mg sc doses, 75 mg sc did not provide clinically meaningful responses in arthritic 
signs and symptoms, skin clearance and physical function:

ACR20 response rates at Week 24 were 54%, 51%, 29.3% and 15.3% with 300mg, 
150mg, 75mg and placebo respectively. 

PASI75 response rates at Week 24 were 63.4%, 48.3%, 28% and 16.3% with 300mg, 
150mg, 75mg and placebo respectively. 

PASI90 response rates at Week 24 were 48.8%, 32.8%, 12% and 9.3% with 300mg, 
150mg, 75mg and placebo respectively. 

DAS-28 CRP mean change from baseline at Week 24 was -1.61, -1.58, -1.12 and -0.96  
with 300mg, 150mg, 75mg and placebo respectively. 

SF36-PCS mean change from baseline at Week 24 was 7.25, 6.39, 4.38 and 1.95 with 
300mg, 150mg, 75mg and placebo respectively. 
This trend from CAIN457F2312 is reflected in the week 104 results of CAIN457F2306, 
indicating that in the present longer term efficacy extension study, a higher dose could be
more beneficial to patients. Secukinumab 150mg had clinically superior ACR50 and 
PASI75/90 response rates compared to 75mg at Week 104:

ACR50 response rates at Week 104 were 46.4 % and 35.5% with 150mg and 75mg 
respectively.

PASI75 response rates at Week 104 were 82.9 % and 70.2% with 150mg and 75mg 
respectively.

PASI90 response rates at Week 104 were 69.5 % and 50.0% with 150mg and 75mg 
respectively.
As a conclusion, there is strong evidence that the 75 mg dose administered every 4 weeks in 
PsA patients provides insufficient exposure to achieve optimal, clinically relevant 
improvements in all subgroups and across multiple domains in this debilitating multifaceted 
chronic disease.
300 mg sc dose of secukinumab offers increased benefit for TNFα-inadequate responder 
patients and in patients with moderate to severe plaque psoriasis:
While secukinumab 150 mg sc and 300 mg sc regimens are both more efficacious than 
placebo regardless of TNFα inhibitor status, the 300 mg sc regimen provided the greatest 
efficacy across multiple PsA domains including ACR20, ACR50, ACR70, HAQ-DI, PASI 75, 
PASI 90, SF-36 PCS, and presence of dactylitis and enthesitis in TNF-IR patients.
Evidence of dose response was shown in TNF-IR patients favoring secukinumab 300 mg sc 
over 150 mg sc at the Week 24 efficacy endpoint used for the primary and secondary efficacy 
analyses of CAIN457F2312, while the 75 mg sc dose showed overall lower efficacy. Indeed, 
ACR20/50/70 response rates at Week 24 in TNF-IR patients were higher with secukinumab 
 


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300 mg sc compared to 150 mg sc (45.5% vs 29.7%, 27.3% vs 18.9%% and 15.2% vs 10.8% 
respectively), while 75 mg sc failed to differentiate from placebo in all ACR endpoints. This 
trend was maintained up to week 52.
Furthermore, secukinumab 300 mg sc was more efficacious than 150 mg sc in achieving 
clinically meaningful improvements in skin disease, particularly with respect to clear/almost 
clear skin (PASI 90, IGA mod 2011 0/1) in patients with moderate to severe psoriasis (defined 
as ≥ 10% BSA). There was a clear dose response favoring secukinumab 300 mg sc in the 
higher thresholds of skin clearance. The difference between 300 mg sc and 150 mg sc 
regimens was more pronounced in the more difficult-to-achieve PASI 90 and IGA mod 2011 
0/1 endpoints, with 21.9% and 27.4% more patients with ≥ 10% BSA compared to 8.2% and 
3.3% more patients with < 10 % BSA reaching PASI 90 and IGA mod 2011 0/1 responses, 
respectively, at Week 24. Therefore, secukinumab 300 mg sc afforded greater improvement in 
plaque psoriasis than 150 mg sc, particularly in the achievement of clear/almost clear skin, in 
patients with moderate to severe psoriasis (≥ 10% BSA).
In addition, pertaining to safety assessments, there were no clinically meaningful differences
among the secukinumab doses of 300 mg sc, 150 mg sc and 75 mg sc in the exposure adjusted 
incidences rates of the key risks over the entire treatment period in the 2 phase 3 trials in PsA 
patients. The overall safety in the PsA population was consistent with prior extensive 
experience in psoriasis, and shows that secukinumab 300 mg sc and 150 mg sc are acceptable 
for chronic use in adult patients with active PsA.
Thus, given all the results outlined above, and in order to maintain a high proportion of 
clinically meaningful response during the entire duration of the extension study, the dosing 
options available, at the investigator's discretion, are:
1. The dose of secukinumab should be escalated from 75 mg sc every 4 weeks to 150 mg sc 
every 4 weeks for patients whose signs and symptoms are not fully controlled  with 
the current dose of 75 mg, and may improve with higher dose as judged by the 
investigator.
2. Further, the dose should also be escalated to 300 mg sc every 4 weeks for patients 
currently on 75 mg or 150 mg dose whose signs and symptoms are not fully controlled,
and may improve further with an increase in dose as judged by investigator.
3. Dose escalation from secukinumab 75 mg to 300 mg can be done either in one step or in 
two steps (first 150 mg then 300 mg based on investigator’s judgement).
2.
Clarification on the duration of contraception
According to protocol exclusion criterion #4 women of child-bearing potential, currently 
defined as all women physiologically capable of becoming pregnant and unwilling to use 
effective contraception during the study and for 16 weeks after stopping treatment, should not 
be considered eligible for the study. However, there are approved secukinumab labels for the 
psoriasis indication that indicate a specific time window for the use of effective contraception 
after stopping treatment.  There is currently no evidence to indicate that a specific duration of 
post-treatment contraception is required for patient safety. However, to align with these 
specifications in local prescribing information, protocol exclusion criterion #4 is changed to 
 


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“Women of child-bearing potential (WoCBP), defined as all women physiologically capable 
of becoming pregnant, unless they are using effective methods of contraception during the 
entire study or longer if required by locally approved prescribing information (e.g. 20 weeks 
in EU).”
3.
Data monitoring committee review no longer required
Based on the safety results of studies CAIN457F2306 and CAIN457F2312, the DMC review 
will no longer be required.
None of the changes described in this amended protocol are due to evidence-based safety 
concerns.
At the time of this amendment, enrolment into the extension study was complete with 460 
patients enrolled and 432 patients still under treatment as of September 6, 2015.
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 “Study objectives” (Section 2) “Investigational Plan” 
(Section 3), “Population” (Section 4), “Treatment” (Section 5), “Data analysis” (Section 9), 
“ Data Monitoring Committee” (Section 8.4) and “Appendix 4” (Section 13.4) have been 
amended to reflect the rationale given above.
Additionally, this protocol amendment includes the correction of typographical and 
formatting errors and editorial changes for increased clarity of the text. Consequently, changes 
were implemented throughout the protocol.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
 


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Protocol synopsis
Protocol number
CAIN457F2306E1
Title
A three year extension study to evaluate the long term efficacy, safety and 
tolerability of secukinumab in subjects with active psoriatic arthritis
Brief title
Extension study up to 3 years for secukinumab in psoriatic arthritis
Sponsor and Clinical 
Phase
Novartis, Phase III
Investigation type
Drug / Biological
Study type
Interventional
Purpose and rationale
The extension study CAIN457F2306E1 is designed as a 3-year extension 
to the phase III core study CAIN457F2306. It aims to provide continuous 
treatment with secukinumab in pre-filled syringes (PFS) for subjects who 
completed the core study CAIN457F2306, to obtain further long term 
efficacy, safety and tolerability information in subjects with active psoriatic 
arthritis receiving secukinumab every 4 weeks.
Primary Objective
To evaluate the long-term efficacy of secukinumab (provided as pre-filled 
syringes) with respect to ACR20, ACR50 and ACR70 response over time 
up to Week 260 in subjects with active psoriatic arthritis and who complete 
the phase III study CAIN457F2306
Secondary Objectives
1. To evaluate the long-term efficacy of secukinumab with respect to:
a.
Changes in HAQ-DI relative to baseline over time up to Week 260
b.
The proportion of subjects with improvements from baseline in 
HAQ-DI meeting or exceeding minimal clinically important 
difference (MCID)
c.
The changes in DAS28 (utilizing hsCRP) relative to baseline over 
time up to Week 260
d.
The proportion of subjects achieving low disease activity (DAS28 ≤ 
3.2) and disease remission as defined by DAS28 (DAS28 < 2.6) 
over time up to Week 260
2. To evaluate the long term safety and tolerability of secukinumab as 
assessed by vital signs, clinical laboratory variables, and adverse events 
monitoring over time up to Week 260
Study design
This study will employ a parallel group, double blind design for the first 
year (up to and excluding Week 156) followed by an open-label design for 
the next two years (Week 156 onwards). Investigators will use their clinical 
judgment to decide if it is beneficial for subjects to enter the extension 
study based upon overall improvement and response to therapy during the 
2 year period of the core study CAIN457F2306. The total combined 
duration of treatment for the core study and this extension study is five 
years. At Week 104 of the core study CAIN457F2306, eligible subjects will 
 


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complete the assessments associated with the core study visit and will 
subsequently continue in the extension study on the same dose (every 4 
weeks) that they were receiving during the core study.
Population
The study population will consist of male or female subjects of at least 18 
years of age. All subjects who completed the core study CAIN457F2306, 
who comply with the inclusion and exclusion criteria of this study, who are 
deemed by investigators to benefit from continued secukinumab therapy 
and provide a new informed consent are eligible to enter into this 
extension study. Approximately 460-520 subjects will be eligible for 
enrollment in study CAIN457F2306E1.
Inclusion criteria
1.
Subjects must be able to understand and communicate with the 
investigator and comply with the requirements of the study and must 
give a written, signed and dated informed consent before any study 
assessment is performed
2.
Subjects must have participated in core study CAIN457F2306, and 
must have completed the entire treatment period
3.
Subjects who are deemed by the investigator to benefit from 
continued secukinumab therapy
Exclusion criteria
1.
Any subject taking other concomitant biologic immunomodulating 
agent(s) except secukinumab 
2.
Any subject who is deemed not to be benefiting from the study drug 
based upon lack of improvement or worsening of their symptoms
Investigational and 
reference therapy
All subjects will continue to receive the same dose of secukinumab they 
were receiving during the treatment period of the core study. No re-
randomization is planned. The two treatment groups are: 
Till Week 152

Group 1: secukinumab 75mg plus placebo matching high dose once 
every four weeks till Week 152

Group 2: secukinumab 150mg plus placebo matching low dose once 
every four weeks till Week 152
Starting with Week 156 (open label period of study)

Group 1: secukinumab 75mg once every four weeks till (and including) 
Week 256, or escalated to secukinumab 150mg or 300mg once every 
four weeks till and including Week 256, after implementation of 
Amendment 1

Group 2: secukinumab 150mg once every four weeks till (and 
including) Week 256, or escalated to secukinumab 300 mg once every 
four weeks till and including Week 256, after implementation of 
Amendment 1
Efficacy assessments

ACR20, 50, 70

HAQ-DI

hsCRP/ESR

DAS28 response/remission
 


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Safety assessments

Evaluation of all AEs and SAEs including injection site reactions and 
infections

Laboratory evaluations (Hematology, Clinical Chemistry, Lipid Panel, 
Urinalysis)

ECG, physical examination, vital signs
Other assessments

Pharmacokinetics

 

Data analysis
The primary efficacy variable is the clinical response to treatment 
according to ACR20, ACR50 and ACR 70 improvement in disease activity 
over time up to Week 260. The analysis of the primary variables will be 
based on the FAS. No formal hypotheses are planned for this study. The 
proportion of subjects meeting the ACR criteria (ACR20, ACR50, and 
ACR70) will be descriptively summarized for each treatment.
Summary statistics for continuous variables will include the number of 
subjects (N), minimum, lower quartile, mean, median, upper quartile, and 
maximum. For categorical or binary variables, the number and percent of 
subjects in each category will be presented. 95% confidence intervals will 
be provided in order to assess the magnitude of treatment efficacy.
Key words
Secukinumab, psoriatic arthritis, long term extension study
 


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1
Introduction
1.1
Background
Psoriatic arthritis (PsA) is an immune-mediated chronic inflammatory disease belonging to 
the spectrum of conditions commonly referred to as spondyloarthritides (SpA). The scientific 
community is split over the question whether to view these conditions together or consider 
them as separate entities (Nash 2005). For example, inflammatory back pain associated with 
psoriasis fits two classifications (1) AS with psoriasis or (2) psoriatic spondylitis (Gladman 
2007). However, while diverse in their clinical presentations, common environmental as well 
as genetic factors associated with susceptibility to SpA are suspected (Turkiewicz 2007). This 
latter notion was recently corroborated by findings in a large-scale single nucleotide 
polymorphism (SNP) scan study, where IL23R variants that were previously linked to 
Crohn`s disease and psoriasis (diseases that may both co-exist with spondylarthritides) 
conferred risk to developing ankylosing spondylitis (Barrett 2008). Together, a common 
pathway including the IL-23/IL-17 axis may play a role in seronegative SpA including PsA.
PsA 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. Recent efforts were aimed at defining more stringent classification criteria for 
standardized recruitment into clinical trials (Taylor 2006). PsA is associated with significant 
morbidity and disability, and thus constitutes a major socioeconomic burden. It is not only 
more common but also more severe than previously thought (Gladman 2004). The majority of 
patients will have psoriasis prior to the occurrence of the associated arthritis and are typically 
under treatment for their skin disease. For musculoskeletal disease manifestations initially 
NSAIDs are used to alleviate symptoms. Typically disease modifying anti-rheumatic drugs 
(DMARDs) are used for PsA including methotrexate (MTX), sulfasalazine, cyclosporine, and 
leflunomide, however, these are often inadequate because they only partially control 
established disease (Mease 2008). 
Several lines of evidence support the notion of prominent T cell involvement in the 
pathogenesis of PsA. Memory CD4+ and CD8+ cells are present in skin lesions as well as the 
inflamed synovium that express activation markers and have characteristics of oligoclonal 
expansion. (Curran 2004, Tassiulas 1999) Clinical trials demonstrated efficacy of T cell 
targeted therapy in PsA (cyclosporine A, CTLA4 Ig, alefacept). TNF blocking therapy was 
successfully introduced to the treatment of patients with PsA (Mease 2000). Despite these 
efforts, an unmet clinical need exists for patients with PsA for better disease control and long 
term prevention of structural damage beyond mere abrogation of inflammatory processes. 
Thus, current treatment options for patients with intolerance or an inadequate response to anti-
TNFα agents are limited. 
IL-17 antagonism represents a novel therapeutic approach aimed at interference with the 
chronic inflammatory process by selectively targeting the predominant pro-inflammatory 
cytokine of the T helper 17 cell subset. Additional effects of anti-IL17 on bone homoeostasis 
via RANKL and IL-1, upstream of TNFα, can be inferred from animal studies (Koenders 
2005). Assuming a potential role of IL-17 cells in the inflammatory infiltrate in PsA, it can be 
speculated that locally disturbed homeostasis of osteoclastogenic and osteoblastogenic 
 


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mechanisms characteristic of PsA might be affected by IL-17 blockade thus potentially 
providing a therapeutic advancement to prevent structural damage in PsA. 
Secukinumab (AIN457) is a high-affinity fully human monoclonal anti-human antibody that 
neutralizes IL-17A activity. IL-17A is the key cytokine in the newly discovered Th17 
pathway which is thought to be an important mediator of autoimmunity. Neutralization of IL-
17A has strong pre-clinical and clinical target validation and documentation of efficacy in a 
proof of concept study (CAIN457A2101) and a phase II study (CAIN457F2201) in 
Rheumatoid Arthritis (RA). IL-17A has been shown to play a pivotal direct pathogenic role in 
both inflammatory and destructive joint tissue manifestations of RA and has direct effects on 
matrix metalloprotease (MMP) activation and stimulation of osteoclast-mediated bone 
resorption (Stamp 2004; Witowski 2004; Moseley 2003). A proof-of concept study conducted 
in subjects with PsA (CAIN457A2206; n=42) suggests that a clinically meaningful response 
for signs and symptoms is induced as early as 2 weeks after start of secukinumab treatment, 
with further improvement up to Week 6 and maintenance of response up to Week 16. 
Therefore, treatment with secukinumab may also reduce loss of cartilage and erosion of bone 
in PsA and may result in improvement of symptoms and functional joint manifestations in 
afflicted patients. Furthermore, in a completed proof of concept study (CAIN457A2102), the 
effects of secukinumab administered at 3 mg/kg as a single intravenous infusion were 
compared with that of placebo in thirty-six subjects with active chronic plaque-type psoriasis. 
The study demonstrated efficacy at the 4- week endpoint and continuous efficacy at 12 weeks 
based on Psoriasis Area and Severity Index (PASI) and Investigator’s Global Assessment mod 
(IGA mod 2011) endpoints.
As of January 2013, approximately 7400 subjects have been enrolled into the secukinumab 
clinical program, of which approximately 6000 subjects have received secukinumab. Overall, 
healthy volunteers and patients across various indications (psoriasis, RA, AS, PsA, multiple 
sclerosis, uveitis, Crohn’s disease, dry eye, polymyalgia rheumatica) have received 
secukinumab at doses ranging from single and multiple doses of 0.1 mg/kg to 30 mg/kg i.v. 
and 25mg to 300mg s.c. In total, 606 PsA patients have been enrolled into the core study
(CAIN457F2306) with secukinumab. Safety results from all completed studies show 
comparable numbers of adverse events in subjects treated with secukinumab compared to 
placebo without indication of any specific organ toxicity. Please refer to the Investigator 
Brochure for a more detailed review of the pre-clinical and clinical information on 
secukinumab.
1.2
Purpose 
Study CAIN457F2306 is a 2 year Phase III study which enrolled 606 patients with active PsA.
The study CAIN457F2306E1 is designed as a 3-year extension to the core study 
CAIN457F2306. It aims to provide continuous treatment with secukinumab in pre-filled 
syringes (PFS) for subjects who completed the core study CAIN457F2306 in order to obtain 
further longer term efficacy, safety and tolerability information.
 


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2
Study objectives
2.1
Primary objectives
To evaluate the long-term efficacy of secukinumab (provided as pre-filled syringes) with 
respect to ACR20, ACR50 and ACR70 response over time up to Week 260 in subjects with 
active PsA and who complete the phase III study CAIN457F2306
2.2
Secondary objectives
1. To evaluate the long-term efficacy of secukinumab with respect to:
a. Changes in HAQ-DI relative to baseline over time up to Week 260
b. The proportion of subjects with improvements from baseline in HAQ-DI meeting or 
exceeding minimal clinically important difference (MCID) over time up to Week 260
c. The changes in DAS28 (utilizing hsCRP) relative to baseline over time up to Week 
260
d. The proportion of subjects achieving low disease activity (DAS28 ≤ 3.2) and disease 
remission as defined by DAS28 (DAS28 < 2.6) over time up to Week 260
2. To evaluate the long term safety and tolerability of secukinumab as assessed by vital signs, 
clinical laboratory variables, and adverse events monitoring over time up to Week 260
 


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3
Investigational plan
3.1
Study design
Core study (CAIN457F2306) design is provided in Appendix 11.
This extension study will employ a parallel group, double blind design for the first year (up 
to and excluding Week 156) followed by an open-label design for the next two years
(Week 156 onwards). The blinding during first year of this extension study is required to 
ensure that 52-week data from the core study are cleaned and locked before unblinding the 
subjects in the extension study.
Investigators will use their clinical judgment to decide if it is beneficial for subjects to enter 
the extension study based upon overall improvement and response to therapy during the 2-
year period of the core study CAIN457F2306.
The total combined duration of treatment for the core study and this extension study is 5 years. 
As this long-term study extends the pivotal registration study CAIN457F2306 by an 
additional 3 years it may be affected by an agency's review or potential product approval 
considerations. If the product is approved during study conduct, dose groups in this extension 
study may be amended (via a future protocol amendment) based on agency recommendations 
for product usage in this indication.
At Week 104 of the study CAIN457F2306, eligible subjects will complete the assessments
associated with the core study visit and will subsequently continue in the extension study on 
the same dose (secukinumab 75mg or secukinumab 150mg every 4 weeks) that they were 
receiving during the core study.
At each study treatment time point till Week 152, two s.c. injections in the form of PFS 
will be administered. This is necessary to maintain the blind, as secukinumab is available in 
either 0.5 ml (75 mg) PFS or 1.0 ml (150 mg) PFS. Placebo to secukinumab is also available 
in 0.5 ml and 1.0 ml PFS to match the active drug.

Group 1: secukinumab 75 mg (0.5mL) plus placebo (1mL) once every four weeks till (and 
including) Week 152

Group 2: secukinumab 150 mg (1mL) plus placebo (0.5mL) once every four weeks till 
(and including) Week 152
At each study treatment time point starting at Week 156, one or two s.c. injections in the 
form of PFS will be administered. This will be open label treatment.

Group 1: secukinumab 75 mg (0.5mL) once every four weeks till (and including) Week 
256. After approval and implementation of Amendment 1, patients may be escalated to 
150 mg or 300 mg as judged appropriate by the investigator. 

Group 2: secukinumab 150 mg (1mL) once every four weeks till (and including) Week 
256. After approval and implementation of Amendment 1, patients may be escalated to 
300 mg as judged appropriate by the investigator.
Study treatment dose adjustments are not permitted until Week 156.
 


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Starting from Week 156 (i.e. during the open label study period), after approval and 
implementation of Amendment 1, the secukinumab dose should be escalated from 75 mg 
to 150 mg for patients whose signs and symptoms are not fully controlled with the 
current dose of 75 mg, and may improve with higher dose as judged by the investigator.
Further, the dose should also be escalated to 300 mg for patients currently on 75 mg or 
150 mg, and whose signs and symptoms are not fully controlled and may improve 
further with an increase in dose as judged by the investigator.
Dose escalation from secukinumab 75 mg to 300 mg can be done either in one step or in 
two steps (first 150 mg, then 300 mg based on investigator’s judgement).
For patients escalated to 150 mg or 300 mg, no dose reduction can be performed at a 
later stage.
Subjects will continue to be on background methotrexate (MTX) (if they  were already taking 
MTX at the start of core study CAIN457F2306) throughout the study. The dose of MTX may 
be adjusted as deemed appropriate by the investigator. 
In addition subjects will be allowed to start or adjust the dose of corticosteroids and non-
steroidal anti-inflammatory drugs (NSAIDs) as  deemed appropriate by the investigator. 
Before enrolment in this extension study, all subjects electing to continue will sign an 
Informed Consent form. After approval and implementation of Amendment 1, all subjects 
electing to continue will sign a new version of the Informed Consent form. Detailed 
instructions for self-administration of the s.c injection using the PFS formulation will be 
provided to each subject. Each injection will be administered into an appropriate injection site 
of the body. For the first 6 months of the extension study (up to Week 128), all injections will 
be performed at site. Starting from Week 132 subjects will have the choice of self-
administration at home or continuing with administration at site, based on personal 
preference and the investigator’s clinical judgment. Site staff or caregiver (once trained) will 
administer the injection to subjects who are not able or feel insecure to self-administer the 
PFS injection.
On-site visits to assess safety and efficacy will be scheduled at 4-16 week intervals during the 
study. Assessments for safety, efficacy, PK 
 will be performed according 
to the assessment schedule.
Efficacy assessments will be performed at regular intervals in this study, and after careful 
evaluation of disease status/activity, investigators should discontinue subjects who are 
deemed not to be benefiting from the study treatment, based on lack of improvement or 
worsening of their symptoms. Moreover, subjects are free to discontinue participation in the 
study at any time for lack of efficacy or for any other reason.
 


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Figure 3-1
Extension Study (CAIN457F2306E1) design
3.2
Rationale of study design
This 3 year extension study will offer continuous secukinumab therapy to eligible subjects 
from the core study CAIN457F2306 and will provide sufficient long-term efficacy and safety 
data that could be used at the time of initial licensing submission or later reports to the health 
authority agencies. The regular assessments of disease activity ensure that subjects who are 
experiencing worsening of 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.
The first year of this extension study was kept blinded to allow sufficient time for cleaning
and locking of the 52-week data from the core study.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
The doses and regimen selected for secukinumab phase III study (CAIN457F2306) were
projected to deliver efficacy while at the same time ensuring subject safety. The proposal to 
continue treatment with s.c. doses of 75 mg and 150 mg administered every four weeks, as 
well as the additional treatment duration of up to 156 weeks (leading to an overall treatment 
period [core plus extension] of 260 weeks) was based on the need for long-term treatment 
exposure in subjects suffering from a chronic illness such as psoriatic arthritis.
The extension study initially continued to evaluate two doses (75mg and 150mg) using PFS in 
order to characterize the long-term safety profile for a higher and a lower secukinumab dose.
Week
104  108  112  116            128               140                   156                            256   260       F268
E1 
E1
Group 1
secukinumab 75 mg 
+ placebo 150 mg
(for blinding up to 
Week 156)
Group 2
secukinumab 150 mg 
+ placebo 75 mg
(for blinding up to 
Week 156)
Secukinumab administration (75 or 150mg s.c.) via PFS + placebo
Secukinumab administration (75 or 150mg s.c.) via PFS transitioned, after implementation 
of Amendment 1, to Secukinumab administration of:
Group 1: 75 mg, 150mg or 300 mg s.c. 
Group 2: 150 mg or 300 mg s.c.
Site personnel and subject unblinded
Start of extension phase
 


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The analysis of the 2 Phase III studies conducted in PsA patients (see Rationale for 
Amendment 1) led to the conclusion that to maintain a clinically meaningful response during 
the entire duration of the extension study, the dose of secukinumab should be escalated from 
75 mg sc every 4 weeks to 150 mg sc every 4 weeks for patients whose signs and symptoms 
may be improved with a higher dose, as judged by the investigator. Further, the dose should 
also be escalated to 300 mg sc every 4 weeks for patients currently on 75 mg or 150 mg dose, 
as judged by investigator. 
The dose escalation from secukinumab 75 mg sc to 300 mg sc can be done either in one step 
or in two steps (first 150 mg sc and then 300 mg sc). These dose modifications are 
implemented through Amendment 1.
Secukinumab can be currently administered by intravenous infusion or by subcutaneous 
injection by reconstitution of lyophilisate. Drug delivery using this formulation either for 
intravenous infusion or subcutaneous injection requires commitment to regular clinic or 
hospital visits to allow for reconstitution and administration by allied health professionals. 
Subcutaneous injection through PFS offers the option of self-administration by the patient and 
is likely to provide a better treatment experience and added convenience. Patients with 
chronic diseases who are able to self-inject their medication gain control of their treatment 
schedule and their treatment setting, thus allowing greater independence, better adherence, 
improved therapeutic outcomes and freedom in their social, domestic, and professional lives, 
which can result in economic benefits to both patients and the healthcare system (Kivitz 
2006); (Chilton 2008).
Self-injection may also offer psychological benefits over 
administration by healthcare professionals, including improved self-esteem (Hamm 2000).
Bioequivalence between the secukinumab lyophilisate and pre-filled syringe formulation has 
been established in study CAIN457A2106 in 150 healthy volunteers in which the 
pharmacokinetics, safety and tolerability of a PFS and the lyophilisate formulation were 
compared. The confidence intervals for geometric mean ratios of Cmax, AUClast and AUCinf 
for the two formulations were within the 0.8-1.25 boundaries and therefore, the PFS met the 
standard criteria for assuming bioequivalence. The use of the PFS was safe and well- tolerated. 
Therefore, in study CAIN457F2306E1, it is considered appropriate to use secukinumab in 
PFS for the administration of secukinumab in the same doses and regimen as in the core study 
(CAIN457F2306) which used the lyophilisate formulation.
3.4
Rationale for choice of comparator
There is no placebo control group or active comparator in this study given the purpose and 
main objectives. However, the current design will allow assessment of multiple doses in 
terms of long term efficacy and safety.
3.5
Purpose and timing of interim analyses/design adaptations
Interim analyses are planned in order to support regulatory filing and for purposes of 
publication after subjects complete year 1 (Treatment period 3), and year 2 (Treatment period 
4) of treatment in this extension study. Additional analyses may be performed to support 
heath authority interactions, as necessary.
 


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3.6
Risks and benefits
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring, and extensive guidance for the investigators provided in the 
Investigator’s Brochure (IB).
As of July 2014, up to 10900 subjects have been enrolled into the secukinumab clinical 
program, of which over 8600 subjects have received secukinumab. Overall, healthy volunteers
and patients across various indications (psoriasis, RA, AS, PsA, multiple sclerosis, uveitis, 
Crohn’s disease, dry eye, polymyalgia rheumatica) have received secukinumab at doses 
ranging from single and multiple doses of 0.1 mg/kg to 30 mg/kg i.v. and 25mg to 300mg s.c..
Key results from the larger completed Phase II and III studies support a favorable benefit-risk 
profile for secukinumab in PsA patients.
Secukinumab has shown either preliminary or confirmed efficacy in several inflammatory
diseases. The safety profile of secukinumab is primarily based on the aggregate safety data
from 10 large completed phase II/III psoriasis trials. The evaluation of safety data from
completed PsA trials did not show additional safety concerns. Secukinumab was generally 
safe and well-tolerated. The most frequently reported adverse events are infections, especially 
upper respiratory tract with secukinumab relative to placebo. There was an increase in 
mucosal or cutaneous candidiasis with secukinumab compared to placebo, but the cases were 
mild or moderate in severity, non-serious, and responsive to standard treatment.
There was a small increase in mild neutropenia cases with secukinumab compared to placebo.
Common Toxicity Criteria (CTC) AE grade 3 neutropenia (<1.0-0.5x109/L) was uncommonly
observed with secukinumab, most were transient and reversible without a temporal
relationship to serious infections. Hypersensitivity reactions include urticarial and rare event 
of anaphylactic reaction to secukinumab were also observed in clinical studies.
Taking into account the available safety data for the individual risks outlined in the IB, the 
expected risk profile of secukinumab from a mechanism of action perspective is anticipated to 
be similar or improved compared to approved cytokine targeting therapies. The risk to 
subjects in this trial will be minimized by compliance with the eligibility criteria, close 
clinical monitoring and extensive guidance to the investigators, provided in the current 
version of the Investigator’s Brochure (IB).
From the standpoint of the overall risk-benefit assessment, the current trial with secukinumab 
is justified.
4
Population
Eligible subjects are those who complete the full study treatment period of the core study
(CAIN457F2306) and comply with the eligibility criteria of this extension study. These 
criteria include signed Informed Consent and/or Amended Informed Consent specific to 
CAIN457F2306E1 and the subject being deemed by the investigator to benefit from 
continued secukinumab therapy.
In total, 460 patients were enrolled in study CAIN457F2306E1.
 


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4.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1. Subjects must be able to understand and communicate with the investigator and 
comply with the requirements of the study and must give a written, signed and dated 
informed consent before any study assessment is performed
2. Subjects must have participated in core study CAIN457F2306, and must have 
completed the entire treatment period
3. Subjects must be deemed by the investigator to benefit from continued secukinumab 
therapy
4.2
Exclusion criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study
population will be representative of all eligible patients.
1. Any subject taking other concomitant biologic immunomodulating agent(s) except 
secukinumab 
2. Any subject who is deemed not to be benefiting from the study treatment based upon lack 
of improvement or worsening of their symptoms
3. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test 
4. Women of child-bearing potential (WoCBP), defined as all women physiologically 
capable of becoming pregnant, unless they are using effective methods of contraception 
during the entire study or longer if required by locally approved  prescribing information 
(e.g. 20 weeks in EU). Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment

Male partner sterilization (at least 6 m prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception. In case of use 
of oral contraception women should have been stable on the same pill for a minimum 
of 3 months before taking study treatment

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
 


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NOTE: Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks 
ago. In the case of oophorectomy alone, only when the reproductive status of the woman
has been confirmed by follow up hormone level assessment is she considered not of child 
bearing potential.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
Novartis will provide the following study treatment

Investigational treatment: Secukinumab 75mg/0.5mL solution or 150 mg/1mL solution 
for injection is provided in PFS for s.c. administration (a single use pre-filled 1mL long 
glass syringe).

Placebo (for maintaining the blind till Week 152): Placebo to secukinumab 0.5mL 
solution or 1 mL solution for injection is provided in PFS for s.c. administration (a single 
use pre-filled 1mL long glass syringe). It contains a mixture of inactive excipients, 
matching the composition of secukinumab 75mg/150 mg.
At enrolment, subjects will be provided with detailed Instructions for Use (IFU) for self-
administration of the PFS injection. The investigational treatment will be administered by the 
subject into the appropriate injection site of the body. The site staff or caregiver (once trained) 
will administer the PFS injection to subjects who are not able or feel insecure to self-
administer the injection.
Note: The pre-filled syringes (for use till Week 152) are packed in a double blinded fashion 
and do not need to be prepared at the site. Secukinumab and placebo PFS are labeled as –

AIN457 150mg/1mL/Placebo

AIN457 75mg/0.5mL/Placebo
Note: The pre-filled syringes (for use starting at Week 156) are packed in an open label 
fashion and do not need to be prepared at the site. Secukinumab PFS are labeled as –

AIN457 75mg/0.5mL

AIN457 150mg/1mL
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial.
 


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5.2
Treatment arms
All subjects will initially continue to receive the same dose of secukinumab they were 
receiving during the treatment period of the core study (CAIN457F2306). No re-
randomization is planned.
Subjects from the two treatment arms will receive following treatments: 
Till Week 152

Group 1: secukinumab 75 mg plus placebo 1mL once every four weeks till (and including) 
Week 152

Group 2: secukinumab 150 plus placebo 0.5mL mg once every four weeks till (and 
including) Week 152 
Starting with Week 156, after approval and implementation of Amendment 1, the allowed 
doses within both treatment arms will be modified as described below.

Group 1: secukinumab 75 mg once every four weeks till (and including) Week 256. After 
implementation of Amendment 1: secukinumab 75 mg, 150 mg or 300 mg.

Group 2: secukinumab 150 mg once every four weeks till (and including) Week 256. After  
implementation of Amendment 1: secukinumab 150 mg or 300 mg.
The dose should be escalated from 75 mg to 150 mg sc for patients whose signs and 
symptoms are not fully controlled, as judged by the investigator, with the current 75 mg. 
Further the dose should also be escalated to 300 mg for patients currently on 75 mg or 150 mg 
dose, and whose signs and symptoms are not controlled well, as judged by investigator. The 
dose escalation from secukinumab 75 mg sc to 300 mg sc can be done either in one step or in 
two steps (first 150 mg sc and then 300 mg sc based on investigator’s judgement). These dose 
modifications are implemented through Amendment 1.
As this long term study extends the pivotal registration study CAIN457F2306 by an additional 
3 years it may be affected by agency review or potential product approval considerations. If 
the product is approved during study conduct, dose groups in this extension study may be 
amended (via a future protocol amendment) based on eventual agency recommendations for 
product usage in this indication.
5.3
Treatment assignment, randomization
There is no re-randomization in this extension study. At Week 104E1, all eligible subjects 
from core study will be enrolled via Interactive Response Technology (IRT) and will continue 
to receive same dose of secukinumab that they were receiving during the treatment period of 
core study CAIN457F2306. The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will then 
specify a unique medication number for the first package of investigational treatment to be 
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5.4
Treatment blinding
This will be a double-blind, double-dummy treatment trial till Week 156. Subjects and
investigative site staff will remain blinded to the identity of the treatment until Week 156, 
using the following methods:
1. Randomization/treatment assignment data (from the core study) are kept strictly 
confidential until the time of unblinding and will not be accessible by subjects or 
investigative site staff
2. The identity of the treatments will be concealed by the use of investigational treatment s
that are all identical in packaging, schedule of administration and appearance 
A double-dummy design is used because the identity of the study treatments (PFS) (75mg vs. 
150mg) cannot be disguised due to their different volumes (0.5 ml vs. 1.0 ml).
Up to Week 156, unblinding investigative site staff will only occur in the case of subject 
emergencies (see Section 5.5.10).
Starting at Week 156, the treatment arm for individual subjects will be unblinded and the 
study will be conducted open-label.
5.5
Treating the subject
5.5.1
Subject numbering
Each subject is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a subject, the Subject Number will not be reused. This being an extension study, 
the subject numbers will remain same as that of core study CAIN457F2306; new subject 
numbers will not be assigned.
5.5.2
Dispensing the investigational treatment
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance.
The investigational treatment packaging has a 2-part label. A unique medication number 
printed on each part of this label corresponds to one of the two treatment arms. Investigator 
staff will identify the investigational treatment package(s) to dispense to the subject by 
contacting the IRT and obtaining the medication number(s). Immediately before dispensing 
the package to the subject, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that subject’s unique 
subject number.
After Week 132, if subjects opt for domiciliary treatment/home administration (at time points 
specified in Table 6-1, Table 6-2, and Table 6-3) the investigator will dispense, via IRT, an 
appropriate number of investigational treatment packages for domiciliary administrations. 
Detailed instructions on the self-administration of the study treatment will be described in the 
IFU. The IFU will be provided to each subject and should be reviewed in detail by the subject
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5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. The investigator should educate the subject on how to
properly store the study treatment if the subject is self-administering at home.
The investigator must maintain an accurate record of the receipt and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Subjects
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.
5.5.4
Instructions for prescribing and taking study treatment
All study treatments (75 mg secukinumab or 150 mg secukinumab; after implementation of 
Amendment 1 secukinumab 75 mg, 150 mg or 300 mg) will be self-administered 
subcutaneously by subjects every four weeks throughout the study. The caregiver or site staff 
will administer the injection only to those subjects who are not able to self-administer the PFS 
injection.
Each subject will require two PFS per dose (i.e. two uniquely numbered medication packages)
till (and including) Week 152. Starting at Week 156 and implementation of Amendment 1, 
subject will require one or two PFS per dose, depending on the dose they are assigned to as 
per investigator’s judgement. Week 156 is the beginning of the open-label study period. 
Up to Week 128, all doses of study treatment will be self-administered by the subject at the 
study site after the study visit assessments have been completed. Starting at Week 132 the 
subjects will be allowed to self-administer the PFS at home.
All study medication packages assigned to the subject during the study will be in the IRT
database. It shall be recorded on the corresponding eCRF(s) whether the subject self-
administered the PFS, or whether site staff or the caregiver administered the PFS and whether 
it was administered at home or at site.
The PFS will be provided by site staff to the subject, who will self-administer the injections at 
the specified study time point. Detailed instructions for self-administration of study treatment 
will be described in the IFU that are to be provided to each subject.
Initially self-injection will take place under the supervision of a site staff member. At Week 
104E1 visit the subjects will be instructed by the site staff, using the IFU, on how to self-
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self-injection. The first study treatment administration will occur at the Week 104E1 visit 
after inclusion/exclusion criteria have been confirmed, all study scheduled assessments have 
been performed and the scheduled blood samples have been drawn.
At subsequent site visits, subjects will be asked to refer to the IFU and to proceed with se lf-
injection.
At each subsequent study visit at site, all study assessments, including the completion of 
Patient Reported Outcomes (PROs) and pre-dose blood sample collection (wherever required) 
(Table 6-1, Table 6-2 and Table 6-3), should be completed prior to the self-administration of 
the study treatment.
All dosages dispensed to the subject and all dose changes during the study must be recorded 
on the Dosage Administration Record eCRF. Immediately before dispensing the package to 
the subject, investigator staff will detach the outer part of the label from the packaging and 
affix it to the source document (Drug Label Form) for that subject’s unique subject number. 
For those subjects who opt for domiciliary / home administrations (at protocol specified time 
points) site staff will dispense (via IRT), at the prior site visit, an appropriate number of 
investigational treatment packages for the applicable upcoming domiciliary administrations.
The investigator should promote compliance by instructing the subject to attend the study 
visits as scheduled and by stating that compliance is necessary for the subject’s safety and the 
validity of the study. The subject 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.
Administration
Secukinumab solution for s.c. injection will be provided in PFS. Two s.c. injections should be 
self-administered at each visit / time-point (secukinumab 75mg in 0.5mL plus placebo 1mL or 
secukinumab 150mg in 1mL plus placebo 0.5mL) till (and including Week 152). Starting at
Week 156, placebo injections will not be required. Hence, upon implementation of 
Amendment 1, one or two s.c. injections would be dispensed for each dosing time point, 
depending on the secukinumab dose the patient is assigned to by the investigator.
Subjects will be instructed at Week 104E1 by site staff on how to self-inject secukinumab via 
PFS, in accordance with the IFU. The study treatment solution should be injected 
subcutaneously into an appropriate injection site, and each injection should be given at a 
different site.
Each new injection should be given at least one inch from the previously used site. If subject 
chooses the abdomen, 2 inches area around navel should be avoided. Investigational treatment
should not be injected into areas where the skin is tender, bruised, red, or hard, or where the
subject has scars or stretch marks. Injection sites should be rotated to reduce the risk of 
reaction.
Single syringes will be packed in individual boxes. The boxes containing the PFS with study 
treatment solution should be kept at 2 to 8°C (36°F to 46°F, do not freeze) and protected from 
light. Prior to administration, the unopened boxes containing the PFS should be allowed to 
come to room temperature in a place protected from light for approximately 20 minutes. Used 
 


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syringes should be disposed immediately after use in a sharps container OR according to the 
regulatory requirements in the respective country.
The caregiver or site staff will administer the injection only to those subjects who are not able 
to self-administer the PFS injection.
Domiciliary administration
Starting with week 132 (after initial 24 weeks of extension study of self-administered 
treatment under the supervision of site staff), subjects will be allowed to self-administer the 
PFS at home when they are not visiting the site for any other trial related procedures. The trial 
related safety and efficacy procedures will be conducted every 12-16 weeks during Treatment 
Periods 3, 4 and 5.
The subjects will be allowed to self-administer treatment at home (starting from Week 132) 
only if they have exhibited correct use for self-administering the PFS at the site during the 
first 24 weeks of treatment. At such time points, if requested by subjects, a caregiver would 
also be allowed to administer study medication after having received proper training by site
staff and having exhibited ability to perform the injection procedure to the subject at the site.
It should be recorded on the corresponding eCRF(s) whether the subject self-administered the 
PFS and whether it was administered at home or at the site.
Prior to self-administration at home, subjects should contact the investigator / site staff in case 
they are experiencing any AE/SAEs or have any concerns.
If the subject is not able / not confident to self-administer the PFS, and the caregiver is 
unable/unwilling to perform the injection, he/she should visit the site every 4 weeks 
during the treatment period and site staff will administer the PFS.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments are not permitted until Week 156.
After approval and implementation of Amendment 1, patients previously treated with 
secukinumab 75 mg may receive either 75 mg, 150 mg or 300 mg, and patients 
previously treated with secukinumab 150 mg may receive 150 mg or 300 mg, as deemed 
appropriate by the investigators. The decision may be taken at any on-site visit. When 
dose escalation has been performed for one patient, no dose reduction can be performed 
at a later stage.
Study treatment interruption is also not permitted with the following exceptions:

Study treatment interruption is permitted only if, in the opinion of the inv estigator, a 
subject is deemed to be placed at a significant safety risk unless dosing is temporarily 
interrupted. In such cases study treatment should be interrupted only during the time 
that this risk is present and ongoing. Study treatment can be restarted at the next 
scheduled visit after resolution of the safety risk.

The effect of secukinumab on live vaccines is unknown; therefore live vaccines should 
not be administered during participation in the study. In case a live vaccine has been 
 


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administered due to a medical urgency, study treatment should be interrupted for 12 
weeks.
The reason for any study treatment interruption must be recorded on the corresponding eCRF 
page.
5.5.6
Rescue medication
Rescue medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a subject is experiencing either no benefit from participation in 
the trial or worsening / exacerbation of their disease. Serious consideration should be given to 
withdraw subjects who require significant amounts of rescue medication. All medication 
changes must be recorded in the Prior/ Concomitant medications eCRF page.
Subjects will continue to be on background MTX (if they were already taking MTX at the 
start of core study CAIN457F2306) throughout the study. The dose of MTX may be adjusted 
as deemed appropriate and necessary at the investigator’s discretion in this extension study.
Any use of rescue medication must be recorded on the corresponding Concomitant 
Medications eCRF.
5.5.7
Concomitant treatment
The investigator should instruct the subject to notify the study site of any new medications 
he/she takes after enrollment into the study. All medications, procedures and significant non-
drug therapies (including physical therapy and blood transfusions) administered after 
enrollment must be recorded on the Concomitant medications Dose Administration Record in 
the CRF.
Methotrexate
In subjects on MTX , dose of MTX (≤25 mg/week) may be adjusted as deemed appropriate 
and necessary at the investigator’s discretion.
Folic acid
Subjects taking MTX must also be taking folic acid supplementation during the trial to 
minimize the likelihood of MTX associated toxicity. Folic acid supplementation should not be 
taken on the same day of MTX intake.
Systemic corticosteroids
The dose and regimen of systemic corticosteroids (oral or intramuscular) may be modified as 
deemed appropriate and necessary and as per investigator’s judgment and subject need. Any 
change in the dose of systemic corticosteroids during the trial must be recorded on the 
corresponding eCRF page.
Intra-articular corticosteroids
As per investigator’s judgment and subject need, intra-articular corticosteroid injections can 
be performed. The total dose administered must be recorded on the corresponding eCRF page.
 


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Non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-1 or COX-2 
inhibitors) and acetaminophen/paracetamol
Subjects taking NSAIDs, low strength opioids or paracetamol/acetaminophen PRN can 
continue to do so in the study; however, they must refrain from any intake during at least the 
24 hours before a visit with disease activity assessment. Any change of the NSAID / 
paracetamol / acetaminophen treatment during the trial should be recorded on the 
corresponding eCRF page.
5.5.8
Prohibited Treatment
Use of the treatments displayed in Table 5-1 is NOT allowed during this extension study 
unless otherwise stated.
Table 5-1
Prohibited treatment
Prohibited treatments
Action to be taken
Any other biologic agent (e.g. etanercept, infliximab, 
adalimumab)*
Discontinue study treatment
Any other investigational treatment or participation in another 
interventional trial
Consult with Novartis study team
Live vaccines should not be given until 12 weeks after last study 
treatment administration
Interrupt study treatment
*These agents fall under the category of biologic immunomodulators
5.5.9
Discontinuation of study treatment and premature subject withdrawal
Study treatment must be discontinued if the investigator determines that its continuation 
would result in a significant safety risk for a subject. The following circumstances require 
study treatment discontinuation:

Withdrawal of informed consent

Emergence of the following adverse events:

Any severe or serious adverse event that is not compatible with administration of 
study medication, including adverse events that require treatment with an 
unacceptable co-medication

Onset of lymphoproliferative disease or any malignancy except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or non-
invasive malignant colon polyps which are being or have been removed

Life-threatening infection

Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the subject at a safety risk for continuation in the study 
(A general guidance on clinically notable laboratory values is provided in Appendix 1).

Pregnancy

Use of any biologic immunomodulating agent except secukinumab
 


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
Any protocol deviation that results in a significant risk to the subject’s safety
In addition to the requirements mentioned above for study treatment discontinuation, the 
investigator should discontinue study treatment for a given subject if there is a lack of 
improvement or worsening of their symptoms, or if, on balance, he/she believes that 
continuation would be detrimental to the subject’s well-being.
For subjects who discontinue study treatment a Dosage Administration Record eCRF should 
be completed, giving the date and primary reason for stopping study treatment.
The investigator must also interact with the IRT to register the subject’s discontinuation from 
study treatment.
Subjects may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information on the appropriate Study Phase Disposition CRF.
For all subjects who discontinue or withdraw from the study, the investigator should ensure 
that the subject completes an end of treatment visit (corresponding to the last visit for the 
subject’s current period of treatment) 4 weeks after last study treatment, and also returns after 
an additional 8 weeks for a final follow-up visit (12 weeks after last study treatment, see 
Table 6-1, Table 6-2 and Table 6-3). The final visit should be performed before any new 
treatment is initiated.
Lost to follow-up
For subjects who are lost to follow-up (i.e. those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
subject, e.g. dates of telephone calls, registered letters, emails etc.
Replacement
Subjects who are prematurely withdrawn from the study will not be replaced.
5.5.10
Emergency breaking of treatment assignment
During the blinded study period, emergency treatment code breaks should only be undertaken 
when it is essential to treat the subject safely and efficaciously. Most often, study treatment
discontinuation and knowledge of the possible treatment assignments are sufficient to treat a 
study subject who presents with an emergency condition. Emergency treatment code breaks 
are performed using the IRT. When the investigator contacts the system to break a treatment 
code for a subject, he/she must provide the requested subject identifying information and 
confirm the necessity to break the treatment code for the subject. The investigator will then 
receive details of the investigational drug treatment for the specified subject and a fax or 
email confirming this information. The system will automatically inform the Novartis monitor 
for the site and the Global Trial Leader (GTL) that the code has been broken.
 


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It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the subject how to contact 
his/her backup in cases of emergency when he/she is unavailable. The investigator will 
provide the protocol number (CAIN457F2306E1), investigational treatment name if available, 
subject number, and instructions for contacting the local Novartis CPO (or any entity to which 
it has delegated responsibility for emergency code breaks) to the subject in case an emergency 
treatment code break is required at a time when the investigator and backup are unavailable.
5.5.11
Study completion and post-study treatment
A subject will be considered to have completed the study if he/she received treatment for 260 
weeks in the combined core study and extension study (last dose being administered at Week 
256) and upon completion of the scheduled study assessments and procedures up to and 
including Visit F268.
Information on the subject’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the appropriate Study Phase Completion 
eCRF page.
A Study Phase Completion evaluation (associated with the last visit of the subject’s phase of 
the study: e.g. Week 156, Week 208 or Week 260) must also be performed when a subject 
prematurely withdraws from the study for whatever reason. In any case, the investigator or 
site staff must contact the IRT as soon as possible to record the subject’s study completion 
(Visit F268) and/or discontinuation.
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include another treatment outside of the study as deemed appropriate by the investigator. This 
treatment may be any non-biologic DMARD. In case of a biologic treatment, a waiting period 
of 3 months before initiating the treatment is recommended.
5.5.12
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. The 
investigator will be responsible for informing IRBs and/or ECs of the early termination of the 
trial.
6
Visit schedule and assessments
Table 6-1, Table 6-2 and Table 6-3 list all of the assessments and indicate with an “X” when 
the visits are performed.
Subjects should be seen for all visits on the designated day or as close to it as possible. 
Subjects should not receive study medication within less than 2 weeks after the previous 
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During the treatment periods, subjects may be seen at an unscheduled visit, e.g. if they 
experience deterioration of their condition, or AEs that in the opinion of the investigator need 
intervention or repeated laboratory testing. During these unscheduled visits, study treatment 
will not be administered. Subjects who discontinue study treatment will continue to be 
followed for safety assessments. They are not considered withdrawn from the study.
Subjects who discontinue study treatment before completing the study, and those who 
prematurely withdraw from the study for any reason should be scheduled for a study visit 4 
weeks after their last study treatment administration, at which time all the assessments listed 
for EoT for the given treatment period (Week 156 or 208 or 260) will be performed (see
Section 5.5.9). Subjects will then return to the study site 12 weeks after the last study 
treatment administration for further assessments as indicated under the follow-up visits (F268).
If they refuse to return for these assessments or are unable to do so, every effort should be 
made to contact them or a knowledgeable informant by telephone or by sending appropriate 
correspondence (i.e. certified letter) immediately. At this contact, the safety (e.g., potential 
occurrence of AE or SAE) and the primary reason for a subject’s premature withdrawal 
should be determined.
At a minimum, subjects will be contacted for safety evaluations during the 12 weeks 
following the last study visit or following the last administration of study treatment 
(whichever is later), including a final contact at the 12-week point. Documentation of attempts 
to contact the subject should be recorded in the source.
Order of assessments:

Subject to complete PROs prior to any investigator assessments.

Investigator to complete investigator assessments (Physician’s global assessment of 
disease activity)

All remaining study visit procedures (e.g., laboratory sample collection, vital signs 
measurements etc.) must be completed prior to study treatment dosing.

Study treatment administration (administration by site staff or self-administration as per 
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Table 6-1
Assessment schedule (Week 104E1 to Week 156)
Epoch
Treatment Period 3
Week (relative to baseline of core study CAIN457F2306)
104E
1
108
112
E1
116
120
124
128
132
136
140
144
148
152
156 and 
TD and/or 
PSW
Informed consent
X
Inclusion/exclusion criteria
X
Physical examination
*
S
S
S
S
Weight
*
X
X
Vital signs
*
X
X
X
X
ECG
*
X
X
Administration of s.c. study treatment via PFS at study site
X
X
X
X
X
X
X
X
X
Administration of s.c. study treatment via PFS at  home1
X
X
X
X
X
Hematology, blood chemistry, urinalysis
*
X
X
X
X
Urine pregnancy test2
*
X
X
X
X
Concomitant medication/non-drug therapy
Update as necessary throughout the study
AE/SAE (including injection site reaction, occurrence of 
infection)
Update as necessary throughout the study
X-Ray (hands/wrists + feet)
*
X5
ANA
*
X
Anti-dsDNA
*
X
PK assessments (at pre-dose)
*
X
High sensitivity C-Reactive protein (hsCRP)
*
X
X
X
X
Erythrocyte Sedimentation Rate (ESR)2
*
X
X
X
X
Tender and swollen joint counts (TJC78, SJC76)
*
X
X
X
X
Patient’s assessment of PsA pain (VAS)
*
X
X
X
X
Patient’s global assessment of disease activity (VAS)
*
X
X
X
X
Physician’s global assessment of disease activity (VAS)
*
X
X
X
X
Health Assessment Questionnaire (HAQ-DI)
*
X
X
X
X
 


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Epoch
Treatment Period 3
Week (relative to baseline of core study CAIN457F2306)
104E
1
108
112
E1
116
120
124
128
132
136
140
144
148
152
156 and 
TD and/or 
PSW
Lipids4
*
X
X
Cardiovascular panel
*
X
Treatment period 3 completion form
X
TD = Investigational treatment discontinuation; PSW = Premature subject withdrawal. Subjects who prematurely discontinue treatment or are withdrawn prematurely 
during treatment period 3 should return for assessments associated with Week 156 (4 weeks after last study treatment) and the follow-up visit (Week F268) 12 weeks 
after last study treatment.
X = assessment to be recorded in clinical data base
S = assessment to be recorded on source documents
* These assessments shall be conducted as part of the core study CAIN457F2306 and will not be repeated in this extension study
1 Subjects who are unable to self-administer the PFS injection at home will visit the site and site staff will administer PFS injection for them
2 Kits will be provided by central lab and tests are to be performed locally
4 Fasting (more than 12 hours) samples to be obtained 
5 Subjects who discontinue will have their X-rays taken only if more than 6 months have elapsed since their last X-rays 
 


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Table 6-2
Assessment schedule (Week 160 to Week 208)
Epoch
Treatment Period 4
Week (relative to baseline of core study
CAIN457F2306)
160
164
168
172
176
180
184
188
192
196
200
204
208 and 
TD and/or 
PSW
Physical examination
S
S
S
S
Weight
X
X
Vital signs
X
X
X
X
ECG
X
X
Administration of s.c. study treatment via PFS at study site
X
X
X
X
Administration of s.c. study treatment via PFS at  home1
X
X
X
X
X
X
X
X
X
Hematology, blood chemistry, urinalysis
X
X
X
X
Urine pregnancy test2
X
X
X
X
Concomitant medication/non-drug therapy
Update as necessary throughout the study
AE/SAE (including injection site reaction, occurrence of 
infection)
Update as necessary throughout the study
X-Ray (hands/wrists + feet)
X5
ANA
X
Anti-dsDNA
X
PK assessments (at pre-dose)
X
High sensitivity C-Reactive protein (hsCRP)
X
X
Erythrocyte Sedimentation Rate (ESR)2
X
X
Tender and swollen joint counts (TJC78, SJC76)
X
X
Patient’s assessment of PsA pain (VAS)
X
X
Patient’s global assessment of disease activity (VAS)
X
X
Physician’s global assessment of disease activity (VAS)
X
X
Health Assessment Questionnaire (HAQ-DI)
X
X
 


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Epoch
Treatment Period 4
Week (relative to baseline of core study
CAIN457F2306)
160
164
168
172
176
180
184
188
192
196
200
204
208 and 
TD and/or 
PSW
Lipids4
X
X
Cardiovascular panel
X
Treatment period 4 completion form
X
TD = Investigational treatment discontinuation; PSW = Premature subject withdrawal. Subjects who prematurely discontinue treatment or are withdrawn prematurely 
during treatment period 4 should return for assessments associated with Week 208 (4 weeks after last study treatment) and the follow-up visit (Week F268) 12 weeks 
after last study treatment.
X = assessment to be recorded in clinical data base
S = assessment to be recorded on source documents
1 Subjects who are unable to self-administer the PFS injection at home will visit the site and site staff will administer PFS injection for them
2 Kits will be provided by central lab and tests are to be performed locally
4 Fasting (more than 12 hours) samples to be obtained
5 Subjects who discontinue will have their X-rays taken only if more than 6 months have elapsed since their last X-rays
 


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Table 6-3 Assessment Schedule (Week 212 to Week 260 and Follow-up)
Epoch
Treatment Period 5
Post 
Treatment 
FU
Week (relative to baseline of core study
CAIN457F2306)
212
216
220
224
228
232
236
240
244
248
252
256
260
268 and 
TD and/or 
PSW
Physical examination
S
S
S
S
S
Weight
X
X
X
Vital signs
X
X
X
X
X
ECG
X
X
Administration of s.c. study treatment via PFS at study site
X
X
X
Administration of s.c. study treatment via PFS at  home1
X
X
X
X
X
X
X
X
X
Hematology, blood chemistry, urinalysis
X
X
X
X
X
Urine pregnancy test2
X
X
X
X
X
Concomitant medication/non-drug therapy
Update as necessary throughout the study
AE/SAE (including injection site reaction, occurrence of 
infection)
Update as necessary throughout the study
X-Ray (hands/wrists + feet) (until implementation of 
Amendment 2)
X5
ANA
X
Anti-dsDNA
X
PK assessments (at pre-dose)
X
X
High sensitivity C-Reactive protein (hsCRP)
X
X
X
Erythrocyte Sedimentation Rate (ESR)
X
X
X
Tender and swollen joint counts (TJC78, SJC76)
X
X
Patient’s assessment of PsA pain (VAS)
X
X
Patient’s global assessment of disease activity (VAS)
X
X
Physician’s global assessment of disease activity (VAS)
X
X
Health Assessment Questionnaire (HAQ-DI)
X
X
 


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Epoch
Treatment Period 5
Post 
Treatment 
FU
Week (relative to baseline of core study
CAIN457F2306)
212
216
220
224
228
232
236
240
244
248
252
256
260
268 and 
TD and/or 
PSW
Lipids4
X
X
Cardiovascular panel
X
Treatment period 5 completion form
X
Follow-up period completion form
X
TD = Investigational treatment discontinuation; PSW = Premature subject withdrawal. Subjects who prematurely discontinue treatment or are withdrawn prematurely 
during treatment period 5 should return for assessments associated with Week 1260 (4 weeks after last study treatment) and the follow-up visit (Week F268) 12 weeks 
after last study treatment.
X = assessment to be recorded in clinical data base
S = assessment to be recorded on source documents
1 Subjects who are unable to self-administer the PFS injection at home will visit the site and site staff will administer PFS injection for them
2 Kits will be provided by central lab and tests are to be performed locally
4 Fasting (more than 12 hours) samples to be obtained
5 Subjects who discontinue will have their X-rays taken only if more than 6 months have elapsed since their last X-rays. After implementation of Amendment 2, no X-Rays 
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6.1
Information to be collected on screening failures
Not applicable since data on subjects who do not enter extension study after completion of 
the core study (CAIN457F2306) will be collected in the same study database.
6.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data collected on all subjects and 
recorded in the eCRF of the core study (CAIN457F2306) will be carried forward in this 
extension study (CAIN457F2306E1). Both, the core study (CAIN457F2306) and 
extension study (CAIN457F2306E1) data will be entered in the same database.
6.3
Treatment exposure and compliance
All dates and times of study treatment administration will be recorded on the appropriate 
Dosage Administration Record eCRF page.
Drugs administered prior to start of treatment and other drugs continuing or started during 
the study treatment period will be entered in the Prior/Concomitant medications or 
significant non-drug therapies eCRF page. 
Compliance is expected to be 100%, unless temporary interruption is needed for safety 
reasons as described in Section 5.5.5. Compliance will also be assessed by a Novartis 
monitor using information provided by the authorized site personnel.
6.4
Efficacy
The efficacy outcome measures used in this study are the standard measures used across 
all PsA trials and required for filing. 

American College of Rheumatology (ACR) 20, 50 and 70 responses

Swollen Joint Count (SJC)/Tender Joint Count (TJC)

Patient’s assessment of PsA pain intensity (VAS scale)

Patient’s global assessment of disease activity (VAS scale)

Physician’s global assessment of disease activity (VAS scale)

Health Assessment Questionnaire – Disability Index (HAQ-DI©)

Erythrocyte Sedimentation Rate (ESR) and high sensitivity C-Reactive Protein 
(hsCRP)


 

Disease Activity Score (DAS28) 




 


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


Physician global fingernail disease severity assessment (VAS)
All efficacy assessments should be performed prior to administration of study treatment.
Details relating to the administration of all PROs are provided in Appendix 10.
6.4.1
American College of Rheumatology (ACR) response
The primary efficacy variable is the clinical response to treatment according to ACR20, 
ACR50 and ACR 70 improvement in disease activity over time up to Week 260. A subject 
will be considered a responder according to ACR20 criteria if he/she has at least:

20% improvement in tender 78-joint count

and 20% improvement in swollen 76-joint count

and 20% improvement in at least 3 of the following 5 measures:

Patient’s assessment of PsA pain (measured on a VAS 100 mm)

Patient’s global assessment of disease activity (measured on a VAS 100 mm)

Physician’s global assessment of disease activity (measured on a VAS 100 mm)

Patient self-assessed disability (Health Assessment Questionnaire [HAQ-DI©] 
score)

Acute phase reactant (C-reactive protein [hsCRP] or ESR)
Similarly, a subject will be considered a ACR50 (or ACR70) responder if he/she shows at 
least 50% (or 70%) improvement as per the above mentioned criteria.
The ACR response is to be assessed at the visits/time points shown in Table 6-1, Table 6-2
and Table 6-3.
 
6.4.1.1
Tender 78 joint count and swollen 76 joint count
Joint counts will be performed by an assessor(s) who must be well trained and part of the 
site personnel. Whenever possible, the same evaluator should perform these assessments 
at all visits.
The 78 joints assessed for tenderness include the 2 temporomandibular, 2 sternoclavicular,
2 acromioclavicular joints, 2 shoulders, 2 elbows, 2 wrists, 2 first carpometacarpal, 10 
metacarpophalangeal, 10 proximal interphalangeal, 8 distal interphalangeal joints of the
hands, the 2 hip, 2 knee, 2 ankle, 2 tarsus, 10 metatarsophalangeal, 10 proximal 
interphalangeal, and 8 distal interphalangeal joints of the feet. All of these except for the 
hips are assessed for swelling. Joint tenderness and swelling are to be graded present (1) or 
absent (0). Synovial fluid and/or soft tissue swelling but not bony overgrowth represents a 
positive result for swollen joint count. Dactylitis of a digit in the foot or hand counts as 
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Data is to be recorded for tender and swollen joints (right or left side), i.e. a box (no, yes 
or not applicable) needs to be ticked for all joints. The total number of tender and swollen 
joints (right and left) will be automatically calculated in the eCRF.
6.4.1.2
Patient’s assessment of PsA pain intensity
The patient’s assessment of pain will be performed using 100 mm visual analog scale 
(VAS) ranging from “no pain” to “unbearable pain” after the question “Please indicate 
with a vertical mark ( | ) through the horizontal line the most pain you had from your 
psoriatic arthritis today”.
6.4.1.3
Patient’s global assessment of disease activity
The patient’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from ”very good” to ”very poor”, after the question "Considering all the ways 
psoriatic arthritis affects you, please indicate with a vertical mark ( | ) through the 
horizontal line how well you are doing today”. 
6.4.1.4
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.
6.4.1.5
HAQ-DI
The HAQ-DI is a secondary efficacy endpoint for this study. It is also one of the 
components of the ACR response. The HAQ © was developed by Stanford University and 
is one of the most widely used measures to assess the long-term influence of chronic 
disease on a subject's level of functional ability and activity restriction. The disability 
assessment component of the HAQ, the HAQ-DI, assesses a subject's level of functional 
ability and includes questions of fine movements of the upper extremity, locomotor 
activities of the lower extremity, and activities that involve both upper and lower 
extremities. There are 20 questions in eight categories of functioning including dressing, 
rising, eating, walking, hygiene, reach, grip, and usual activities. The stem of each item 
asks over the past week "Are you able to …" perform a particular task. Each item is 
scored on a 4-point scale from 0 to 3, representing normal (normal, no difficulty [0]), 
some difficulty (1), much difficulty (2), and unable to do (3). 
The purpose of the HAQ-DI in this study is to assess the functional ability of subjects with 
PsA.
Details relating to the administration of all PROs are provided in Appendix 10.
6.4.1.6
High Sensitivity C-reactive protein (hsCRP)
Blood for this assessment will be obtained in order to identify the presence of 
inflammation, to determine its severity, and to monitor response to treatment.
 


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Since the results of this test may unblind study personnel, the hsCRP results from samples 
collected during the treatment period till Week 152 will be revealed only during the open 
label part of this study.
6.4.1.7
Erythrocyte sedimentation rate (ESR)
Blood for ESR, which is helpful in diagnosing inflammatory diseases and is used to 
monitor disease activity and response to therapy, will be obtained at scheduled visits (see 
Table 6-1, Table 6-2 and Table 6-3).
6.4.2
Radiographic assessments
Separate radiographs of each hand/wrist (PA) and each foot (AP) will be taken at Week 
156, 208 and 260. 
From time of implementation of Amendment 2, radiographs at Week 260 will not be 
obtained as part of the study.
Bone erosion, joint space narrowing (JSN), and total radiographic scores will be 
determined using a PsA modified van der Heijde-Sharp (vdH-S) scoring method (van der 
Heijde 2005)  that includes the second through fifth distal interphalangeal (DIP) joints of 
each hand. Erosions (0–5 in the hands and 0–10 in the feet) and JSN (0–4) will be graded 
separately in six wrist joints, all metacarpophalangeal, proximal interphalangeal, and DIP 
joints of each hand, and the first interphalangeal joint and all metatarsal phalangeal joints 
for each foot. The total radiographic score (hands and feet combined) ranges from 0 to 528, 
with higher scores indicating more articular damage. The maximum total erosion score is 
360. The maximum total JSN score is 168.  
 
 Radiologists will be trained on the X-ray 
acquisition and further details will be provided in a manual for the radiologists, e.g. joint 
placement and beam positioning. 
In case of analogue X-rays films, the original film will be sent to the central reading CRO 
and will undergo quality control and will be digitized. Standard film and cassettes will be 
provided to all centers that do not produce digital X-rays. In case of digital equipment, 
sites need to confirm minimum requirements with the imaging CROs Digital X-rays will 
be transferred electronically. 
In case of insufficient quality, the center will be advised and trained on any quality issues 
prior to the repeat X-ray and to keep any repeat X-rays to a minimum.
Subjects who discontinue study treatment before the end of the trial, hands/wrists and feet 
X-rays will be taken at the time of study treatment discontinuation. However, if a
radiograph of hands/wrist and feet was performed within last 6 months of early 
discontinuation visit then it does not need to be performed. Likewise, if a scheduled X-ray 
at Week 156, 208 or 260 is scheduled less than 6 months after any prior hands/wrists and 
feet X-rays, it does not need to be performed. All following X-rays will be performed as 
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The readings of the X-rays and the scoring will be performed centrally. Complete X-ray 
procedures will be defined in an Imaging Manual provided to the centers by an Imaging 
CRO designated by Novartis.
6.4.4
DAS28 
The DAS28 is a measure of disease activity based on Swollen and Tender Joint Counts, ESR 
or CRP and the Patient Global Assessment. A DAS28 score > 5.1 implies active disease, ≤ 3.2 
low disease activity, and < 2.6 remission. 
 
 


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6.4.11
Physician’s global assessment of fingernail disease severity (VAS)
The physician’s assessment of nail disease activity will be performed using 100 mm VAS 
ranging from no disease activity to maximal disease activity, after the question “After you 
have viewed all the fingernails of a subject, consider all aspects of the subject’s fingernails 
and place a vertical line on the scale giving a global assessment of their fingernails”.
6.4.12
Appropriateness of efficacy assessments
The efficacy outcome measures used in this study are the standard measures used across many 
psoriatic arthritis trials and they are required for regulatory filing.
6.5
Safety

Evaluation of AE/ SAEs

Physical examination

Vital signs

Weight

Electrocardiogram

Local tolerability (injection site reactions)
 


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
Laboratory evaluations (Hematology, Clinical Chemistry, Lipid Panel, Urinalysis)

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
The physical examination will include the examination of general appearance, skin, neck, 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological system.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present before signing the ICF must be included in the 
relevant medical history eCRF. Significant findings made after signing the ICF which meet 
the definition of an AE must be recorded in the Adverse Event eCRF.
6.5.2
Vital signs
This will include blood pressure and pulse rate measurements after 5 minutes rest in sitting 
position.
If possible, vital signs assessments should be performed by the same study site staff member 
using the same validated device throughout the study.
6.5.3
Height and weight
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing) (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.
Height will not be measured in this study as it is already measured in the core study 
CAIN457F2306.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected listed below (except 
urinalysis, UPT and ESR). Details on the collection, shipment of samples and reporting of 
results by the central laboratory are provided in the laboratory manual. For the identification 
of clinically notable values, see Appendix 1. All subjects with laboratory tests containing 
clinically significant abnormal values are to be followed until the values return to normal 
ranges or until a valid reason, other than treatment related AE, is defined.
 


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6.5.4.1
Hematology
Hemoglobin, platelet, red blood cell (RBC), white blood cell (WBC) and differential white 
blood cell counts will be measured at scheduled visits.
6.5.4.2
Clinical chemistry
Serum chemistries will include glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, 
total protein, albumin, and uric acid.
6.5.4.3
Lipid panel
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
cholesterol and triglycerides will be measured from a fasting blood sample.
6.5.4.4
Cardiovascular panel
A cardiovascular profile including lipoprotein (a), apolipoprotein B-100, apolipoprotein A-1, 
and adiponectin will be measured from a blood sample.
6.5.4.5
Urinalysis
Dipsticks will be provided by the central laboratory to the sites for local urinalysis 
assessments. The urinalysis results for standard parameters such as protein, glucose, blood 
and WBCs will be recorded in the appropriate eCRF page.
6.5.5
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as indicated in Table 6-1, Table 6-2 and Table 6-3. 
All ECGs must be performed on the ECG machines provided for the study.
All ECGs will be independently reviewed. Instructions for the collection and transmission of 
the ECGs to the independent reviewer will be provided in the ECG investigator manual.
Clinically relevant abnormalities should be recorded on the relevant medical history/Current 
medical conditions eCRF page for the baseline ECG. 
Clinically relevant abnormalities noted after the baseline ECG should be reported as AEs (see
Section 7).
6.5.6
Pregnancy and assessments of fertility
Secukinumab must not be given to pregnant women; therefore effective methods of birth 
control must be used for women of child-bearing potential (see exclusion criteria definitions,
Section 4.2).
All women who are not surgically sterile at screening will have local urine pregnancy tests as 
indicated in Table 6-1, Table 6-2 and Table 6-3. A positive urine pregnancy test requires 
immediate interruption of study treatment until serum β-hCG is performed and found to be 
negative. If positive, the subject must be discontinued from the trial.
 


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6.5.7
Tolerability of secukinumab
Tolerability will be assessed by adverse events, laboratory values, injection site reaction 
 
6.5.9
Additional parameters
Blood will be obtained at time points indicated in Table 6-1, Table 6-2 and Table 6-3 for 
assessing ANA and anti-dsDNA antibodies.
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 for this subject population. The specific focus on infection rates in 
addition to the other safety measures ensures the ability to deliver data on a critical safety 
endpoint for this class of therapy. The radiation exposure that results from X-ray 
measurements is not necessary for medical care but is intended for research purposes only. 
The total amount of radiation from all X-ray measurements performed in this study (3 X-rays 
of hands/wrists and feet) is estimated to be around 1 mSv over 3 years, and is approximately 
equivalent to a uniform whole body exposure of 26 weeks of exposure to natural background 
radiation. For effective radiation doses under 3 mSv (300 mrem), the risk is considered to be 
"minimal". Therefore, the radiation exposure in this study involves minimal risk and is 
 


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necessary to obtain the research information desired and ensure reliable safety measures 
before the treatment with a biologic.
6.6
Other assessments

Quality of Life questionnaires/ Patient reported outcomes (PROs)

Pharmacokinetics
6.6.1
Health-related Quality of Life
The impact of PsA on various aspects of subjects’ health-related quality of life (HRQoL) will 
be assessed using the following validated instruments:

HAQ-DI (see Section 6.4.1.5)


All questionnaires will be available, where possible, in the local languages of the participating 
countries and should be completed by subjects before they see the study physician. Only the 
original paper questionnaires provided can be used (i.e. these pages must not be photocopied)
All questionnaires will be completed at the defined visits/ time points listed in Table 6-1, 
Table 6-2 and Table 6-3 and prior to the subject seeing the investigator for any clinical 
assessment or evaluation. The questionnaires will be in the respondent’s local language. The 
subject should be given sufficient instruction, space, time and privacy to complete the 
questionnaires. The study coordinator should check the questionnaires for completeness and 
encourage the subject to complete any missing responses. The original questionnaires will be 
kept with the subject’s file as the source document.
Completed questionnaires should be reviewed and assessed by the investigator, before the 
clinical examination, for responses which may indicate potential AEs or SAEs. The 
investigator should review not only the responses to the questions in the questionnaires but 
also for any unsolicited comments written by the subject. This assessment should be 
documented in the source records. If AEs or SAEs are confirmed the investigator should 
record the events as per instructions given in the relevant section of the protocol (see Section 
7). Investigators should not encourage the subjects to change the responses reported in the 
completed questionnaires.
Guidelines for administering the PRO questionnaires can be found in Appendix 10.
 


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6.6.2
Pharmacokinetics
Pharmacokinetic (PK) samples will be obtained for all subjects, and secukinumab 
concentrations will be assessed in serum. The PK samples will be collected pre-dose at 
scheduled visits as indicated in Table 6-1, Table 6-2 and Table 6-3. The PK Sample Log can 
be found in the Appendix 2.
All blood samples will be drawn by direct venipuncture in a forearm vein.
The actual sample collection date and exact time will be entered on the PK blood collection 
summary eCRF. Sampling problems will be noted in the Comments section of the eCRF.
The bioanalyst will provide the samples’ concentration data to the team under blinded 
conditions. The bioanalyst will keep this information confidential until Week 156
PK sample handling, labeling and shipment instructions
Laboratory manuals will be provided by the central laboratory with detailed information on 
sample collection, sample handling and shipment.
Tubes and labels will be provided by the central laboratory with study/sample type 
information pre-printed on the label.
Analytical methods
An ELISA method will be used for bioanalytical analysis of secukinumab in serum, with an 
anticipated lower limit of quantification (LLOQ) of 80 ng/mL. The detailed method 
description to assess secukinumab concentration will be described in the bioanalytical raw 
data of the study and in the respective Bioanalytical Data Report (BDR).
7
Safety monitoring
7.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
 


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study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the subject
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information.

the severity grade 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment (no/yes)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.

whether it constitutes a serious adverse event (SAE) 

action taken regarding investigational treatment 

whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
An SAE is any adverse event (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria 

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
 


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hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); investigational treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
medication given; non-drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the investigational 
treatment, the interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed.
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse event reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 12 weeks following the last administration of 
investigational treatment or 30 days after the subject has stopped study participation 
(whichever is later) must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment. 
 


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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to 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 to Novartis within 24 hours 
of becoming aware of the event. 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 investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national
regulatory requirements in participating countries.
7.3
Liver safety monitoring
There has been no safety signal for liver toxicity with secukinumab to date in over 6000
patients exposed and from a mechanism of action standpoint there is no effect of blocking IL-
17A on the liver. Liver function tests will be obtained at regular intervals but special measures 
for liver safety monitoring are not planned.
7.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring while the subject is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment of any pregnancy outcome.
Any SAE experienced during pregnancy must be reported on the SAE Report Form.
 


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8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of subject
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that investigational treatment is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock or upon premature site discontinuation, the investigator will receive copies of 
the subject data for archiving at the investigational site. 
8.3
Database management and quality control
Novartis staff or designee will review the data entered into the CRFs by investigational staff 
for completeness and accuracy and instruct the site personnel to make any required 
corrections or additions. Queries will be sent to the investigational site using an electronic 
data query. Designated investigator site staff is required to respond to the query and confirm 
or correct the data. If the electronic query system is not used, a paper Data Query Form will 
be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to 
 


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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 NovDTD 
Reference List, which employs the Anatomical Therapeutic Chemical (ATC) classification 
system. Concomitant procedures, non-drug therapies and adverse events will be coded using 
the Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis.
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. All the data from the vendor 
database will be sent electronically to Novartis.
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.
8.4
Data Monitoring Committee
A data monitoring committee (DMC) reviewed the safety data of this trial at regular intervals. 
Details regarding the DMC process are available in relevant secukinumab DMC charter. As of 
Amendment 1 and based on the safety results of studies CAIN457F2306 and CAIN457F2312, 
the DMC review will no longer be required.
8.5
Adjudication Committee
An independent adjudication committee consisting of external experts may be used to monitor 
specific safety events, including, but potentially not limited to clinically significant cardio-
and cerebro-vascular events. The events will be reviewed and adjudicated as they occur 
during the conduct of the trial. 
Details regarding the adjudication process will be available in the relevant secukinumab 
Adjudication Committee charter.
9
Data analysis
Summary statistics for continuous variables will generally include the number of subjects (N), 
minimum, lower quartile, mean, median, upper quartile, and maximum. For categorical or 
binary variables, the number and percent of subject in each category will be presented. The
95% confidence intervals will be provided as appropriate to evaluate the efficacy of the
treatment regimens.
 


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Data will be presented by a combination of the ‘original’ and ‘switch’ treatment groups. 
These treatment groups represent the treatment combinations the subjects experience over the 
course of the entire trial in case of re-randomization and dose escalation.
Note that the treatment groups for a subject may differ depending on the time period of the 
analysis and whether one assesses the subject for efficacy or safety.
9.1
Analysis sets
The following analysis sets will be used in this study:
Full analysis set (FAS): The FAS will be comprised of all subjects enrolled in the study with 
at least one post baseline assessment of efficacy. Subjects will be analyzed according to the 
treatment assigned to.
Safety set: The safety set includes all subjects enrolled in the study who took at least 1 dose 
of study treatment during the study. Subjects will be analyzed according to the treatment 
received.
9.2
Subject demographics and other baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and for all subjects in the FAS population of the study. The 
number and percentage of subjects in each category will be presented for categorical variables 
for each treatment group and all subjects.
9.3
Treatments
Study treatment
The analysis of study treatment data will be based on the safety set. The number of active 
injections received will be presented by treatment group. The duration of exposure to study 
treatment will also be summarized by treatment group. In addition, the number and percentage 
of subjects with cumulative exposure levels will be presented.
Concomitant medication
Concomitant medications will be summarized by treatment group. Any medication given at 
least once between the start of the first dose in this extension trial and the date of the last 
study visit in the extension study will be a concomitant medication, including those which 
were started before Week 104E1 and continued into the extension study where study 
treatment is administered.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number 
and percentage of subjects receiving at least one treatment of a particular ATC code and at 
least one treatment in a particular anatomical main group.
Significant concomitant non-drug therapies and procedures will be summarized by primary 
system organ class and MedDRA preferred term.
 


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The number and percentage of subjects receiving concomitant psoriatic arthritis therapy will 
be presented by treatment group as well as the reasons for stopping their therapies (primary 
lack of efficacy, secondary lack of efficacy, lack of tolerability, other) and the total duration 
of exposure to psoriatic arthritis therapies previously.
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
The primary efficacy variable(s) is the clinical response to treatment according to ACR20, 
ACR50 and ACR 70 improvement in disease activity over time up to Week 260. ACR 
response criteria denote the response (i.e., improvement) in signs & symptoms of the disease 
of a subject compared to baseline of the core study. The analysis of the primary variables will 
be based on the FAS. Primarily, CRP will be used instead of ESR to calculate ACR response; 
ESR will only be used in the event CRP is missing.
9.4.2
Statistical model, hypothesis, and method of analysis
No formal hypotheses are planned for this study. 
The proportion of subjects meeting the ACR criteria (ACR20, ACR50, and ACR70) will be 
descriptively summarized for each treatment group. Treatment efficacy will be evaluated by
the 95% confidence interval of the proportion of subjects responding to treatment according to 
the ACR criteria. No statistical comparison is expected to be performed between treatment 
doses.
Results will be presented for the FAS, as well as subgroups by TNF-α status (naive or IR).
9.4.3
Handling of missing values/censoring/discontinuations
Efficacy data will be presented using all available data at the given time point of analysis.
Additionally, under the assumption of missing at random, multiple imputation by treatment 
may be performed for all baseline and post-baseline efficacy variables of interest during the 
trial.
Continuous variables will be analyzed using a mixed-effects model repeated measures 
(MMRM) which is valid under the missing at random (MAR) assumption. For analyses of 
these parameters, if all extension post-baseline values are missing then these missing values 
will not be imputed and this subject will be removed from the analysis of the corresponding 
variable, i.e. it might be that the number of subjects providing data to an analysis is smaller 
than the number of subjects in the FAS.
9.4.4
Supportive analyses
Sensitivity analyses may be performed to assess the robustness of missing data handling. This
may include multiple imputation for ACR20/50.
 


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9.5
Analysis of secondary and exploratory variables
9.5.1
Efficacy variables
For binary variables, the proportion of responders will be summarized over analysis visits. For 
continuous variables, the change from baseline (of core), when available, will be presented. 
The 95% confidence intervals will be provided to evaluate the long-term efficacy of the 
treatments for the secondary variables of interest.
No statistical comparisons between treatments will be provided for the analysis of secondary 
and exploratory variables.
Secondary and exploratory variables include: 

The change from baseline in HAQ-DI

The proportion of subjects with  improvements from baseline in HAQ-DI ≥ minimal 
clinically important difference (MCID)



 

 

 

The change from baseline in DAS28

The proportion of subjects achieving low disease activity (DAS28 ≤ 3.2) and disease 
remission as defined by DAS28 (DAS28 < 2.6)

 


 

 
9.5.2
Safety variables
Adverse events
Treatment emergent adverse events (i.e. events started after the first dose of secukinumab in 
core study or events present prior to the first dose of secukinumab but increased in severity 
based on preferred term and within 84 days after last dose of secukinumab) will be 
summarized. 
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects having any AE, having an AE in each primary system organ class and having each 
individual AE (preferred term). Summaries will also be presented for AEs by severity and for 
study treatment related AEs. If a subject reported more than one adverse event with the same 
preferred term, the adverse event with the greatest severity will be presented. If a subject 
 


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reported more than one adverse event within the same primary system organ class, the subject 
will be counted only once with the greatest severity at the system organ class level, where 
applicable. Serious adverse events will also be summarized. 
The incidence of AEs will be presented per 100 subject years of exposure. 
Separate summaries will be provided for death, serious adverse event, other significant 
adverse events leading to discontinuation and adverse events leading to dose adjustment 
(including study treatment discontinuation).
A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, will be presented.
When adjudication is required of major cardiovascular events, a summary of those types of 
events as reported by the investigator and confirmed by adjudication will be provided.
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from baseline will only 
be summarized for subjects with both baseline (of core study) and post baseline values. 
For each parameter, the maximum change from baseline within each study period will be 
evaluated analogously. 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was 
normal, low, or high for each visit value relative to whether or not the baseline value was 
normal, low, or high. These summaries will be presented by laboratory test and treatment 
group. Shifts will be presented by visit as well as for most extreme values post-baseline.
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values.
ECG
Summary statistics will be presented for ECG variables by visit and treatment group. 
Qualitative changes will be summarized.
 


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9.5.4
Pharmacokinetics
All subjects with concentration data will be included in the pharmacokinetic data analysis.
Pharmacokinetic variables
The following pharmacokinetic parameter will be determined: Cmin,ss. Cmin,ss will be 
determined using Phoenix software. Individual serum concentrations in g/ml will be listed. 
All concentrations below the limit of quantification or missing data will be labeled as such in 
the concentration data listings. Concentrations below the Limit of Quantification will be 
treated as zero in summary statistics for concentration data only.
 


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During modeling of the pharmacokinetics of secukinumab, the broad principles outlined in the 
FDA Guidance for Industry: Population Pharmacokinetics will be followed.
Statistical methods for pharmacokinetic analyses
Summary statistics by visit/time will be provided for the above mentioned parameter and will 
include arithmetic and geometric means, SD, median, minimum and maximum. Individual 
concentrations will be listed by subject.
9.6
Interim analyses
Interim analyses are planned in order to support regulatory filing and for purposes of 
publication after subjects complete year 1 (Treatment period 3), and year 2 (Treatment period 
4) of treatment in this extension study. Additional analyses may be performed to support 
health authority interactions, as necessary.
9.7
Sample size calculation
It is estimated that 80~90% of subjects originally randomized to secukinumab will complete 
the entire treatment period and be eligible for entry into the extension (320~360 subjects). 
Likewise, 70~80% of the subjects originally randomized to placebo (140~160 subjects) will 
be eligible. In total, it is estimated that 460~520 subjects will be eligible for enrollment in this 
extension study.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the subject. 
In cases where the subject’s representative gives consent, the subject should be informed 
about the study to the extent possible given his/her understanding. If the subject is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
 


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conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the subject source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted.
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Under no circumstances should an investigator collect additional data 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs. 
 


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If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
11.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for subject safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any subject
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations.
12
References
References are available upon request
Barrett JC, Hansoul S, Nicolae DL et al. (2008) Genome-wide association defines more than 
30 distinct susceptibility loci for Crohn's disease. Nat Genet; 40(8):955-62
Cassel SE, Bieber JD, Rich P, et al. (2007) The Modified Nail Psoriasis Severity Index: 
Validation of an Instrument to Assess Psoriatic Nail Involvement in Patients with Psoriatic 
Arthritis. J Rheumatol; 34:123-9
Cella DF, Tulsky DS, Gray G, et al. (1993) The Functional Assessment of Cancer Therapy 
(FACT) scale: Development and validation of the general measure. Journal of Clinical 
Oncology; 11(3):570-9.
Chilton F, Collett RA. (2008) Treatment choices, preferences and decision-making by patients 
with rheumatoid arthritis. Musculoskeletal Care; 6:1–14.
Coates LC, Fransen J, Helliwell PS. (2010) Defining minimal disease activity in psoriatic 
arthritis: a proposed objective target for treatment. Ann Rheum Dis; 69(1):48-53.
Curran SA, FitzGerald OM, Costello PJ, et al. (2004) Nucleotide sequencing of psoriatic 
arthritis tissue before and during methotrexate administration reveals a complex inflammatory 
T cell infiltrate with very few clones exhibiting features that suggest they drive the 
inflammatory process by recognizing antigens. J Immunol; 172:1935-44
Feldmann SR and Krueger GG. (2005) Psoriasis assessment tools in clinical trials. Ann 
Rheum Dis;64 Suppl 2:ii65-8; discussion ii69-73.
Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. (1995) 
American College of Rheumatology. Preliminary definition of improvement in rheumatoid 
arthritis. Arthritis Rheum; 38(6):727-35.
Fredriksson T and Pettersson U (1978) Severe psoriasis-oral therapy with a new retinoid. 
Dermatologica; 157:238-44.
 


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Fries JF, Spitz P, Kraines G, Holman H. (1980) Measurement of Patient Outcome in 
Arthritis.Arthritis Rheum; 23:137-145.
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 
Gladman DD. (2007) Axial disease in psoriatic arthritis. Curr Rheumatol Rep; 9(6):455-60
Gottlieb A, Griffiths CEM, Ho VC, et al. (2005) Efficacy and tolerability of oral 
pimecrolimus in the treatment of moderate to severe chronic plaque type psoriasis: a double-
blind, multicentre, randomized dose-finding trial. Br J Dermatol; 152:1219-27
Hamm R, Patel B, Whittlestone T, Persad R. (2000) Patient self-injection: a new approach to 
administering luteinizing hormone-releasing hormone analogues. BJU Int; 86:840-842. 
Helliwell PS, Fitzgerald O, Fransen J et al. (2012) The development of candidate composite 
disease activity and responder indices for psoriatic arthritis (GRACE project). Ann Rheum 
Dis; 0:1–6. doi:10.1136/annrheumdis-2012-201341
Kivitz A, Cohen S, Dowd JE, et al. (2006) Clinical assessment of pain, tolerability, and 
preference of an autoinjection pen versus a prefilled syringe for patient self-administration of 
the fully human, monoclonal antibody adalimumab: the TOUCH trial. Clin Ther; 28:1619–
1629.
Koenders MI, Lubberts E, Oppers_Walgreen B, et al. (2005) Blocking of interleukin-17 
during reactivation of experimental arthritis prevents joint inflammation and bone erosion by 
decreasing RANKL and interleukin-1. Am J Pathol; 167:141-9
Kushner I. (1991) C-reactive protein in rheumatology. Arthritis Rheum; 34(8):1065-68.
Mallya RK, De Beer FC, Berry H, et al. (1982) Correlation of clinical parameters of disease 
activity in rheumatoid arthritis with serum concentration of C-reactive protein and erythrocyte
sedimentation rate. J Rheumatol; 9(2):224-8.
Mease PJ (2008) Psoriatic Arthritis. In: Klippel JH, Stone JH, Crofford LJ et al, eds. Primer 
on Rheumatic Diseases. 13th ed. New York: Springer Science, p. 170-192 
Mease PJ, Goffe BS, Metz, J, et al. (2000) Etanercept in the treatment of psoriatic arthritis and 
psoriasis:a randomized trial. Lancet; 356:385-90 
Moll JM and Wright V (1973) Psoriatic arthritis. Semin Arthritis Rheum; 3:55-78 
Moseley TA, Haudenschild DR, Rose L et al. (2003) Interleukin-17 family and IL-17 
receptors. Cytokine Growth Factor Rev;14(2):155-74 
Nash P, Mease PJ, Braun J, et al. (2005) Seronegative spondylarthropathies: to lump or to 
split? Ann Rheum Dis; 64:9-13
Stamp LK, James LJ, Cleland LG (2004) Interleukin-17: the missing link between T-cell 
accumulation and effector cell actions in rheumatoid arthritis? Immunol Cell Biol;82(1):1-9 
Tassiulas I, Duncan SR, Centola M, et al (1999) Clonal characteristics of T cell infiltrates in 
skin and synovium of patients with psoriatic arthritis. Hum Immunol; 60:479-491
 


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Protocol No. CAIN457F2306E1
Taylor W, Gladman D, Helliwell, et al (2006) Classification criteria for psoriatic arthritis. 
Arthritis Rheum; 54:2665-73 
Turkiewicz AM, Moreland LW (2007) Psoriatic arthritis: current concepts on pathogenesis-
oriented therapeutic options. Arthritis Rheum; 56(4):1051-66
van der Heijde D, Sharp J, Wassenberg S, Gladman D (2005) Imaging: a review of scoring 
methods in psoriatic arthritis. Ann Rheum Dis; 64(Suppl. II):ii61–ii64.
Van Leeuwen MA, Van Rijswijk MH, Van der Heijde DM, et al (1993) The acute phase 
response in relation to radiographic progression in early rheumatoid arthritis: a prospective 
study during the first three years of the disease. Br J Rheumatol; 32(suppl 3):9-13.
Ware J, Kosinki M, Gandeck B. (1993) SF-36 Health Survey manual and interpretation guide. 
Boston: The Health Institute, New England Medical Center.
Ware J, Kosinki M, Gandeck B (1994) SF-36 Health Survey manual and interpretation guide. 
Update. Boston: The Health Institute, New England Medical Center.
Weisman S, Pollack CR, Gottschalk RW. (2003) Psoriasis disease severity measures: 
comparing efficacy of treatments for severe psoriasis. J Dermatolog Treat; 14:158-165.
Witowski J, Ksiazek K, Jörres A. (2004) Interleukin-17: a mediator of inflammatory 
responses. Cell Mol Life Sci;61(5):567-79.
Wolfe F. (1997) Comparative usefulness of C-reactive protein and erythrocyte sedimentation 
rate in patients with rheumatoid arthritis. J Rheumatol; 24:1477-85.
Yellen SY et al. (1997) Measuring Fatigue and Other Anemia-Related Symptoms with the 
Functional Assessment of Cancer Therapy (FACT) Measurement System. Journal of Pain and 
Symptom Management; 13:63-74.
 


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13
Appendices
13.1
Appendix 1: Clinically notable laboratory values and vital signs
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests.
Clinically notable values will be forwarded to Novartis at the same time that they are sent to 
investigators. Any action based on these laboratory values should be discussed with Novartis 
personnel.
Table 13-1
Safety Analyses: Expanded Limits and Notable Criteria
Notable criteria
Laboratory variable
Standard units
SI units
Liver function and related variables
SGOT (AST)
>3 x ULN
>3 x ULN
SGPT (ALT)
>3 x ULN
>3 x ULN
Total Bilirubin
>2 x ULN
>2 x ULN
Alkaline phosphatase
>2.5 x ULN
>2.5 x ULN
Renal function, metabolic and electrolyte variables
Creatinine (serum)
>2 x ULN
>2 x ULN
Hematology variables
Hemoglobin:
≥20 g/L decrease from baseline
Platelet count:
<100x10E9/L
White blood cell count:
<0.8 x LLN
Neutrophils:
<0.9 x LLN
 


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13.2
Appendix 2: Blood collection logs
Table 13-3
Blood collection log for pharmacokinetics
Week
Timepoint
Volume
PK sample 
number
Dose Reference 
ID
Week 156
26208 h (pre-dose)
2 ml
8
1
Week 208
34944 h (pre-dose)
2 ml
9
1
Week 260
43680 h (anytime)
2 ml
10
1
Week 268
45024 h (anytime)
2 ml
11
1
 


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13.4
Appendix 4: American College of Rheumatology (ACR) Measures 
and Criteria of Response
Number of tender joints:
Joint counts will be performed by a well trained assessor who must be part of the site 
personnel. Whenever possible, the same evaluator should perform these assessments at all 
visits.
The 78 joints assessed for tenderness include the 2 temporomandibular, 2 sternoclavicular, 2 
acromioclavicular joints, 2 shoulders, 2 elbows, 2 wrists, 2 first carpometacarpal, 10 
metacarpophalangeal, 10 proximal interphalangeal, 8 distal interphalangeal joints of the hands, 
the 2 hip, 2 knee, 2 ankle, 2 tarsus, 10 metatarsophalangeal, 10 proximal interphalangeal, and 
8 distal interphalangeal joints of the feet. 
Joint tenderness is to be scored as present (1) or absent (0).
Number of swollen joints:
Joints are to be scored as either swollen (1) or not swollen (0). The 76 joints to be examined 
for swelling are the same as those examined for tenderness, however excluding both hip joints.
Patient's assessment of PsA pain
On a 100 mm non- anchored visual analog scale, from no pain to unbearable pain.
Patient's global assessment of disease activity
On a 100 mm non-anchored visual analog scale, from no arthritis activity to maximal arthritis 
activity, after the question "Considering all the ways your arthritis affects you, draw a line on 
the scale for how well you are doing".
Physician's global assessment of disease activity
On a 100 mm non-anchored visual analog scale, from no arthritis activity to maximal arthritis 
activity
Patient's assessment of physical function
Health Assessment Questionnaire – HAQ-DI©
ACR20/50/70*
A patient will be considered as improved according the ACR20 criteria* if she/he has at least 
20 % improvement

in the two following measures:
o Tender joint count
o Swollen joint count
 


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
and at least 3 of the following 5 measures:
a. Patient's assessment of pain,
b. Patient's global assessment of disease activity,
c. Physician's global assessment of disease activity,
d. Health Assessment Questionnaire (HAQ©) score,
e. C-reactive protein (CRP)/Erythrocyte Sedimentation Rate (ESR).
ACR50 = 50 % improvement in at least 3 of the 5 measures and 50 % improvement in the 
swollen and tender joint count.
ACR70 = 70 % improvement in at least 3 of the 5 measures and 70 % improvement in the 
swollen and tender joint count.
Reference: (Felson 1995)
 


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13.5
Appendix 5: Disease Activity Score 28(DAS28)
The Disease Activity Score 28 (DAS28) is a combined index to measure the disease activity 
in patients with RA. 
 
Evaluation of response to a treatment can be made much easier and more objective using the 
DAS28. Just assess the number of swollen and tender joints and measure the ESR. The DAS 
will provide you with a number between 0 and 10, indicating how active the disease is at this 
moment. Recently the DAS28-CRP has been developed. The C-reactive protein (CRP) or 
hsCRP may be used as an alternative to ESR in the calculation of the DAS28.
Using the DAS, several thresholds have been developed for high disease activity, low disease 
activity or remission. Also response criteria have been developed based on the DAS28, so 
when the DAS28 of a patient is measured at two time-points (e.g. before the start of a 
treatment and after 3 months), the patients clinical response can be assessed.
The DAS28 in clinical trials
Comparing the DAS28 from one patient on two different time-points, it is possible to define 
improvement or response. 
 
Tender and swollen 28-joint count:
The 28-joints assessed for DAS28 include the 2 shoulders, 2 elbows, 2 wrists, 2 knees, 10 
metacarpophalangeal (MCP) and 10 proximal interphalangeal (PIP) joints.
In order to calculate the DAS28, information about the following disease variables is needed:

The number of swollen joints and tender joints should be assessed using 28-joint count 
(tender28 and swollen28).

The erythrocyte sedimentation rate (ESR) should be measured in mm/hour.

The patient’s general health (GH) or global disease activity measured on a Visual 
Analogue Scale (VAS) of 100 mm (both are useable for this purpose) must be obtained.
Using this data, the DAS28 can be calculated using the following formula:
DAS28 = 0.56 * sqrt(TJC28 + 0.28 * sqrt(SJC28) + 0.70 * ln(ESR) + 0.014 * GH
 


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The DAS28 provides you with a number on a scale from 0 to 10 indicating the current activity 
of the psoriatic arthritis of your patient. A DAS28 above 5.1 means high disease activity 
whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a 
DAS28 lower than 2.6 (comparable to the PsA remission criteria).
Disease Activity Scores using C-reactive protein
C-reactive protein (CRP) or hsCRP may be used as an alternative to ESR in the calculation of 
the DAS28, using the formulas below. CRP is a more direct measure of inflammation than 
ESR, and it is more sensitive to short-term changes (Kushner 1991). CRP production is 
associated with radiological progression in RA (Van Leeuwen 1993)), and is considered at 
least as valid as ESR to measure RA disease activity (Mallya 1982, Wolfe 1997). Another 
advantage of determination of CRP is that waiting time for the laboratory result is shorter and 
that in case of multicenter studies a central laboratory can be used.
The following formulas to calculate the DAS28 using CRP (mg/L) give good estimations of 
the original DAS28 values on a group level. DAS28-4(CRP = 0.56*sqrt(TJC28) + 
0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96
TJC28: 28 Tender joint count; SJC28: 28 Swollen joint count; CRP: C-reactive protein; GH: 
General Health on a 100mm. Visual Analogue Scale.
It is strongly advised to adhere either to ESR or to CRP determinations.
 


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13.9
Appendix 9: Health Assessment Questionnaire (HAQ) ©
The HAQ(Fries JF et al. 1980) is a validated measure of physical disability and functional 
status. It has four dimensions: disability, pain, drug side effects and dollar costs, although, the 
latter three are rarely used in clinical trials. In this trial only the disability dimension will be 
used. The disability dimension consists of 20 multiple choice items concerning difficulty in 
performing eight common activities of daily living; dressing and grooming, arising, eating, 
walking, reaching, personal hygiene, gripping and activities. Patients choose from four 
response categories, ranging from ‘without any difficulty' to 'unable to do'. The ACR 
Rheumatology Committee on Outcome Measures in RA recommends the use of this 
questionnaire in clinical trials.
Scoring of the HAQ©
The HAQ© will be scored in accordance with the recommendation from the developers 
outlined in the “HAQ PACK” from Stanford University, California.
The following coding is to be used for the 8 categories of the disability outcome dimension:
Without ANY Difficulty
0
With SOME Difficulty
1
With MUCH Difficulty
2
UNABLE to do
3
Within each of the 8 categories only the item indicating the most severe impairment 
contributes to the category score. If the patient requires the use of aids, devices, or help from 
another to accomplish any of the activities in an associated category, then the score for that 
category will be assigned the value 2, unless the score is already 3 (i.e. scores of 0 or 1 are 
increased to 2). Associated categories are defined in the “HAQ PACK”. From the scores for 
each category a Standard Disability Index (SDI) is computed by summing the computed 
scores for each category and dividing by the number of categories answered. The SDI is not 
computed if the patient does not have scores for at least 6 categories. This SDI is the HAQ©
score, which will be used in the statistical analyses of this instrument. The range for this score 
is (0, 3).
HAQ© Data Collection
The HAQ© is to be completed by the patients in their local languages. 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 per question, then this should be brought 
 


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to the attention of the 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 questionnaire and ensure 
that the site number, subject number and initials (if applicable) are identical to the Case 
Record Form. As there are no source data for this questionnaire, the data queries will be 
restricted to patient/visit information.
 


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13.10
Appendix 10: Guidelines for administering the PRO 
questionnaires
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 
 
 If a patient responds ‘most or all of the time’, then the study 
coordinator should inform the study investigator.
Before completion
1. Subjects should be provided with the correct questionnaire

At the appropriate visits, and

In the appropriate language
2. Subjects should have adequate space and time to complete the forms
3. Patients should be provided with a firm writing surface (such as a table or a clip board) 
and a pencil
4. 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. Subjects should initial and date the last page of the questionnaires
4. 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
3. Data should be transcribed from the completed questionnaire to the appropriate screen on 
the e-CRF / electronic device.
4. File completed questionnaire in the patient study files**
*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).
**If for some reason paper questioner is utilized for completion.
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.
 


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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 this 
information is as important as any of the 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.
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 possibly 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. 
 


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A General Information about all questionnaire(s): 
All questionnaires need to be completed by the patients in their local languages. 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 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 questionnaire 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 
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13.11
Appendix 11: Study design of core study CAIN457F2306
The AIN457F2306 core study used a double-blind, randomized, parallel-group, placebo
controlled design. A screening period running 4 weeks before randomization was used to
assess eligibility followed by a treatment period of 2 years (Week 0 through Week 104).
At baseline (BSL), eligible subject were randomized to one of three treatment groups: 

Group 1: Secukinumab i.v. (10mg/kg) at BSL, Weeks 2 and 4, then secukinumab 75 mg 
s.c. starting at Week 8 and injected every 4 weeks 

Group 2: Secukinumab i.v. (10mg/kg) at BSL, Weeks 2 and 4, then secukinumab 150 mg 
s.c. starting at Week 8 and injected every 4 weeks

Group 3: Placebo i.v. at BSL, Weeks 2 and 4, then placebo s.c. starting at Week 8 and 
Week 12
The subjects were stratified as either TNFα inhibitor incomplete responders (TNF-IR) or 
TNFα inhibitor naïve subjects. Approximately 30% of subjects were TNF-IR to ensure a 
representative population for the assessment of efficacy and safety.
At Week 16 (Visit 8), subjects were classified as responders ( ≥20% improvement from 
baseline in both tender and swollen joint counts) or non-responders. Subjects who were 
randomized to placebo at baseline were re-randomized by IRT to receive double blind 
treatment up to 2 years, as follows

Subjects on secukinumab placebo (Group 3) who were responders remained on placebo 
until week 24. At Week 24, these subjects were re-randomized (1:1) to receive either 
secukinumab 75 or 150 mg every 4 weeks

Subjects on secukinumab placebo (Group 3) who were non-responders at Week 16 were 
re-randomized (1:1) to receive either secukinumab 75 mg or 150 mg s.c. every 4 weeks
 


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Figure 13-1
Core Study (CAIN457 F2306) Design
8
16
24
48
Week
-4 to BSL
32
40
56
100 104
52
4
N
R
75mg  or 150mg AIN457 (1:1)
Escape treatment: 75mg  or 150mg AIN457 (1:1)
Group 1
AIN457 i.v. loading 
followed by 75 mg s.c.
n = 200
Group 2
AIN457 i.v. loading 
followed by 150 mg s.c.
n = 200
Group 3
Placebo i.v. 
followed by placebo s.c.
n = 200
F112
NR
Randomization 
AIN457 administration (s.c.)
Placebo to AIN457 administration (s.c.)
Non-responder (<20% reduction in TJC and/or SJC)
AIN457 10 mg/kg administration (i.v.)
Placebo to AIN457 administration (i.v.)
 

SAP_001.pdf: 
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AIN457F2306E1/Secukinumab
Clinical Development
Secukinumab (AIN457)
Clinical Trial Protocol [CAIN457F2306E1] / NCT01892436
A three-year extension study to evaluate the long term efficacy, safety 
and tolerability of secukinumab in patients with active psoriatic arthritis
RAP Module 3 Week 260 Detailed Statistical Methodology 
Amendment 1
Authors:
, Trial Statistician
Document type:
RAP Documentation
Document status:
Final
Release date:
12 March 2018
Number of pages:
50
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of RAP module 3 week
260.
Amendment
Date
Change
Amendment 1
12 March 
2018
Section 2.
 
 
Paragraph 14.1 Adverse Events
The population required for the two tables on the Adverse 
events based on the legal requirements of ClinicalTrials.gov 
and EudraCT (<on-treatment/treatment emergent> adverse 
events which are not serious adverse events with an frequency 
greater than 5% and on <on-treatment/treatment emergent> 
serious adverse events and SAE suspected to be related to 
study treatment) has changed to safety population.
“The tables will include data only from the extension part of 
the trial.”, changed to “The tables will include data from the 
core and the extension part of the trial.”
Paragraph 12.5.
The following text is added:
“Shift tables will be provided comparing the subject’s ACR 
evaluation at the pre up-titration visit relative to the observed 
data of the following week intervals after up-titration: (12-32 
weeks), (36-56 weeks) and (60-80 weeks).” 
Paragraph 12.5.
The following text is added:
 
 
 


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
1
Introduction .........................................................................................................................9
2
Changes to statistical methods planned in the protocol.......................................................9
3
Study objectives...................................................................................................................9
3.1
Primary objectives ...................................................................................................9
3.2
Secondary objectives ...............................................................................................9
10
4
Data presentation...............................................................................................................10
5
Subjects and treatments .....................................................................................................11
5.1
Treatment groups...................................................................................................11
6
Subgroup definitions .........................................................................................................13
7
Assessment windows, baseline and post baseline definitions, missing data handling......13
8
Subject disposition, background and demographic characteristics ...................................14
8.1
Subject disposition.................................................................................................14
8.2
Background and demographic characteristics .......................................................14
9
Medical history..................................................................................................................15
10 Study medication...............................................................................................................15
11 Concomitant medication....................................................................................................15
Concomitant medication in extension ......................................................................................15
Concomitant medication in core or extension..........................................................................16
12 Efficacy evaluation............................................................................................................16
12.1
Description of efficacy variables...........................................................................16
27
12.3
Handling of missing data.......................................................................................28
12.4
Analysis of Primary Variable(s) ............................................................................28
Statistical model, hypothesis, and method of analysis ......................................................28
Supportive analyses...........................................................................................................29
12.5
Analysis of secondary and exploratory variables ..................................................29
32
13 Pharmacokinetic evaluations (change / add PD, PK/PD, Biomarkers, as needed) ...........33
13.1
Pharmacokinetics...................................................................................................33
14 Safety evaluation ...............................................................................................................33
14.1
Adverse events.......................................................................................................34
14.2
Laboratory data......................................................................................................36


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14.3
Vital signs..............................................................................................................38
14.4
Electrocardiogram (ECG)......................................................................................39
14.5
Immunogenicity.....................................................................................................40
14.6
Compound specific safety evaluation....................................................................40
15 Interim analyses.................................................................................................................40
16 Sample size calculation .....................................................................................................40
17 Appendix ...........................................................................................................................41
17.1
Visit Windows .......................................................................................................41
17.2
Interim Locks dates................................................................................................45
17.3
Statistical methodology and assumptions..............................................................46
17.3.1
Analysis of continuous data ..................................................................46
17.3.2
Analysis of binary (and categorical) data..............................................46
17.3.3
Crude incidence and related risk estimates...........................................47
17.3.4
Exposure adjusted incidence rate and related risk estimates ................47
18 References .........................................................................................................................49
List of tables
Table 12-1
Segmental distribution ..........................................................................20
Table 12-2
EULAR response criteria ......................................................................22
25
26
Table 14-1
Overview of analyses on some safety endpoints...................................35
Table 14-2
CTCAE grades for laboratory parameters to be analyzed ....................37
Table 14-3
Liver-related events...............................................................................38
Table 13-4
Criteria for notable vital sign abnormalities..........................................39
Table 17-2
Rules for flagging variables ..................................................................45
Table 17-3
Examples for calculating exposure time for incidence rates (IR).........48


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List of abbreviations
ACR
American College of Rheumatology 
ADA
Anti-Drug Antibodies
AE
Adverse event
ALT
Alanine aminotransferase/Serum Glutamic Pyruvate Transaminase (SGPT)
ANA
Anti-nuclear antibodies
ANCOVA
Analysis of covariance
Anti-CCP
Anti-cyclic citrullinated peptide antibodies
AS
Ankylosing Spondylitis
AST (SGOT)
Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase 
ATC
Anatomical Therapeutic Classification
BMI
Body Mass Index
BSL
Baseline
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CRO
Contract Research Organization
CRP (hsCRP)
(high sensitivity) C-Reactive Protein
DAS
Disease Activity Score
DMARD
Disease Modifying Anti-rheumatic Drug
DMC
Data Monitoring Committee 
DNA
Desoxyribonucleic acid
DS&E
Drug Safety & Epidemiology
dsDNA Ab
Anti-double stranded DNA antibodies
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked Immunosorbent Assay
EMA/EMEA
European Medicnices (Evaluation) Agency
EoS
End of Study
ESR 
Erthrocyte Sedimentation Rate 


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FAS
Full Analysis Set
FDA
Food and Drug Administration
FSH
Follicle-stimulating Hormone
GCP
Good Clinical Practice
GGT 
Gamma Glutamyl Transferase
GTL
Global Trial Leader
HAQ-DI©
Health Assessment Questionnaire – Disability Index
hCG
Human Chorionic Gonadotropin
HDL
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
IA
Interim Analysis
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC/EC
Independent Ethics Committee
IFU
Instructions for Use
IL
Interleukin
IN
Investigator Notification
IR
Incidence Rate
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra Uterine Device
IUS
Intra Uterine System
i.v.
intravenous
LDL
Low Density Lipoprotein
LLN
Lower limit of normal


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LLOQ
Lower Limit of Quantification
MAR
Missing At Random
MedDRA 
Medical Dictionary for Regulatory Activities
mmHG
Millimeter mercury 
MTX
Methotrexate
NSAID
Non-Steroidal Anti-Inflammatory Drug
NovDTD
Novartis Drug/Therapy Dictionary
PDS
Programming and Dataset Specifications
PFS
Pre-filled Syringe
PK
Pharmacokinetic
PoC
Proof of Concept
PRO
Patient Reported Outcome
PsA
Psoriatic Arthritis
QoL
Quality of Life
RA
Rheumatoid Arthritis
RBC
Red blood cells
RDC
Remote Data Capture
RF
Rheumatoid Factor
SAE
serious adverse event
s.c.
Subcutaneous
 
SJC
Swollen joint count
SpA
Spondyloarthritides
SUSAR
Suspected Unexpected Serious Adverse Reaction
TJC
Tender joint count
TNF
Tumor Necrosis Factor 
TNFα-IR
TNFα Inhibitor Incomplete/Inadequate Responders 
ULN
Upper Limit of Normal
UPT
Urine Pregnancy Test
VAS
Visual Analog Scale 


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WBC
White blood cells


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1
Introduction
Data will be analyzed by Novartis according to the data analysis section 9 of the 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.
2
Changes to statistical methods planned in the protocol
No multiple imputation techniques and no MMRM estimation will be performed due to the 
presence of up-titrators. 
 
3
Study objectives
3.1
Primary objectives
To evaluate the long-term efficacy of secukinumab with respect to ACR20, ACR50 and 
ACR70 response over time up to Week 260 in subjects with active PsA and who complete the 
phase III study CAIN457F2306.
3.2
Secondary objectives
1. To evaluate the long-term efficacy of secukinumab with respect to:
a.
Changes in HAQ-DI relative to baseline over time up to Week 260
b. The proportion of subjects with improvements from baseline in HAQ-DI meeting or 
exceeding minimal clinically important difference (MCID) over time up to Week 260
c.
The changes in DAS28 (utilizing hsCRP) relative to baseline over time up to Week 
260
d. The proportion of subjects achieving low disease activity (DAS28 ≤ 3.2) and disease 
remission as defined by DAS28 (DAS28 < 2.6) over time up to Week 260
2. To evaluate the long term safety and tolerability of secukinumab 75 mg and 150 mg as 
assessed by vital signs, clinical laboratory variables, and adverse events monitoring over 
time up to Week 260.


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4
Data presentation
Data analyses will be presented by treatment groups or treatment sequence as appropriate
Unless otherwise stated, summary tables/figures/listings will be on all subjects included in the 
population under consideration. 
Summary statistics for continuous variables will include N, mean, standard deviation, 
minimum, lower quartile, median, upper quartile, maximum. Summary statistics for discrete 
variables will be presented in contingency tables and will include absolute and relative 
frequencies.
For categorical or binary variables, the number and percent of subject in each category will be 
presented. The p-values if presented will be two-sided unless otherwise specified, and 95% 
confidence intervals will be provided as appropriate.


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In general, efficacy data from the extension study period will be reported for clinical study 
report (CSR) and publication(s). Baseline from core and Week 104 visit data will be presented 
appropriately. No formal hypotheses testing will be done. Hence, the p-values and confidence 
intervals provided should be considered as exploratory only. 
Safety data from core and extension studies will be reported cumulatively for CSR and 
publication(s). Placebo safety data from core will not be reported in post text tables. 
All listings will be presented by treatment groups. Safety listings will also include the placebo 
data.
5
Subjects and treatments 
The following analysis sets will be used for the data analysis: 
Extension Full analysis set (extension FAS): The extension FAS will be comprised of all 
subjects enrolled in the extension study and have at least one post baseline assessment of 
efficacy during the extension period. Subjects will be analyzed according to the treatment 
assigned to.
(In this document extension FAS is referred as to FAS).
Of note, FAS will comprise only the subjects from extension whereas safety set will include 
from core or extension, safety set will be larger than FAS.
Up-titration Subset: The up-titration subset will be comprised of subjects from the extension 
FAS set who received at least one dose of the up-titration dose.
 
 
Psoriasis subset: The psoriasis subset will include all FAS subject who have ≥3% of the 
body surface area (BSA) affected by psoriatic skin involvement at baseline.
Nail subset: The nail subset will include all FAS subject who have psoriasis currently in nails 
at baseline.
Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during the treatment period in core or extension study. Subjects will be evaluated according to 
treatment received.
5.1
Treatment groups
The arms included in efficacy tables are based on the treatment sequence (picturing also the 
up-titration) for the periods up to the final lock at week 260. Two separate columns will 
display the assigned and actual treatment resulting in the following treatment sequences:


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Efficacy:

AIN457 10 mg/kg - 75 mg 

AIN457 10 mg/kg - 75 mg - 150 mg 

AIN457 10 mg/kg - 75 mg - 300 mg 

AIN457 10 mg/kg - 150 mg 

Placebo - AIN457 75 mg

Placebo - AIN457 75 mg - 150 mg 

Placebo - AIN457 75 mg - 300 mg 

Placebo - AIN457 150 mg
After week 52 the combination of assigned treatment will also be shown.

AIN457 75 mg & Placebo - AIN457 75 mg

AIN457 150 mg & Placebo - AIN457 150 mg
The treatment sequence following up-titration for the combined groups will be:

AIN457 75 mg & Placebo - AIN457 75 mg - 150 mg

AIN457 75 mg & Placebo - AIN457 75 mg - 300 mg

AIN457 150 mg & Placebo - AIN457 150 mg – 300 mg
Cases might up-titrate twice; for these cases the treatment prior to each up-titration will be 
displayed (that is not the assigned treatment for the 2nd observed up-titration). Therefore, at 
the graphical representation of up-titration the actual treatment dose prior to the switch will be 
displayed.
Regarding safety, the arms included in the entire treatment period are as follows.

Any AIN457 75 mg 

Any AIN457 150 mg 

Any AIN457 300 mg 

Any AIN457 (if appropriate)
Placebo group will be included at the in-text tables and listings of the CSR.


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In the safety listings the groups will be the following:

AIN457 10 mg/kg - 75 mg 

AIN457 10 mg/kg - 150 mg 

Placebo AIN457 75 mg 

Placebo AIN457 150 mg 

Placebo not re-randomized.
6
Subgroup definitions
The primary endpoint and secondary endpoints will be evaluated for TNF-alpha inhibitor 
status and by concomitant MTX use (ACR20/50, 
).
7
Assessment windows, baseline and post baseline 
definitions, missing data handling
Baseline and post-baseline definitions
In general, a baseline value refers to the core study and is the last measurement made prior to 
administration of the first dose of study treatment in core. Baseline information will be 
presented appropriately in the “by visit” summaries in both safety and efficacy tables.
A post-baseline value refers to a measurement taken after the first dose of study treatment in 
core study. 
Analysis visit windows
For visits that occur on or before week 104, analysis visit windows will be used for the data that 
is summarized by visit; they are based on the study evaluation schedule and comprise a set of 
days around the nominal visit day. For any assessment, there are protocol defined scheduled 
visits around which analysis visit windows were created to cover the complete range of days 
within the study. The analysis visit windows and rules for dealing with multiple 
measurements within the windows are described in the Appendix (17.1 Visit Windows).
For visits that occur after week 104, the recorded nominal visit data will be considered.


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8
Subject disposition, background and demographic 
characteristics
8.1
Subject disposition
The number of subjects enrolled in the extension will be presented. The number and 
percentage of subjects in the FAS who completed the period up to week 260 and/or the follow 
up visit and who discontinued the study prematurely (including the reason for discontinuation) 
will be presented for each treatment group (including the up-titrated groups).
For each protocol deviation (PD), the number and percentage of subjects for whom the PD
applies will be tabulated.
8.2
Background and demographic characteristics
Demographics and baseline characteristics will be presented for FAS. Data already collected 
for core study will be presented for the extension analysis subjects as well.  
The following common background and demographic variables will be analyzed according to 
the treatment sequence.
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 years and older, 75 years and older)

Gender

Race

Ethnicity

Weight (<90 kg or ≥90 kg)

Smoking status at baseline
The following disease specific baseline characteristics and history of disease will be 
summarized as well:
CASPAR, TNF-α history (naive or inadequate responder), ACR components, number of prior 
biologic PsA therapies, MTX use (yes or no) and dose at baseline, time since first diagnosis of 
PsA in years, and psoriasis involvement (proportion of patients with psoriasis of hands and 
feet, psoriasis of the nail, and target lesion diameter, psoriasis >= 3% of BSA), DAS28 CRP 
and DAS28 ESR scores, HAQ-DI, 
and systemic use of 
glucocorticoids.
Unless otherwise specified, summary statistics for continuous variables will be presented for 
each treatment group, for each placebo-AIN457 group, for the combination of AIN457 and 


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placebo switchers and finally for all subjects (total) in the FAS. The number and percentage of 
subjects in each category will be presented for categorical variables for each treatment group 
and all subjects (total) in the FAS. 
9
Medical history
Any condition entered on the Relevant medical history / current medical conditions CRF will 
be coded using the MedDRA dictionary. Data collected for core study will be used for the 
extension as well. Data will be summarized by system organ class (SOC) and preferred term 
(PT) of the MedDRA dictionary. Summaries for cardiovascular medical history and psoriasis
history will be provided as well. Disease history and baseline characteristics will be presented 
by treatment group.
Smoking history will be summarized by treatment sequence.
Disease history will be displayed by treatment sequence. Unless otherwise specified, analyses 
will be based on the extension FAS.
10
Study medication
The analysis of study treatment data will be based on the safety set. The number of active 
injections will be summarized by treatment received. The duration of exposure to study 
treatment will also be summarized by treatment received. In addition, the number and 
percentage of subjects with cumulative exposure levels (e.g. any exposure, ≥ 1 week, ≥ 2 
weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented.
Duration of exposure will be calculated as time from first dose of secukinumab in core to the
minimum of (last dose of the treatment + 84 days) and (last visit date). For subjects 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 the entire study 
treatment period.
11
Concomitant medication 
Concomitant medication in extension
Concomitant medications in extension will be summarized by treatment received. Any 
medication given at least once between the start of the first dose in this extension trial and the 
date of the last study visit + 84 days in the extension study, will be a concomitant medication, 


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including those which were started before Week 104E1 and continued into the extension 
study where study treatment is administered.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification
(ATC) codes and grouped by anatomical main group. Tables will show the overall number 
and percentage of subjects receiving at least one treatment of a particular ATC code and at 
least one treatment in a particular anatomical main group.
Significant concomitant non-drug therapies and procedures will be summarized by primary 
system organ class and MedDRA preferred term.
Prior surgeries and procedures are defined as surgeries and procedures executed prior to the
first study dose. Any surgeries and procedures started between the day of the first dos of study 
treatment and within 84 days after the last dose will be concomitant surgeries and procedures, 
including those which were stared pre-baseline and continued into the period where study 
treatment is administered.
The number and percentage of subjects receiving prior and concomitant psoriatic arthritis 
therapy will be presented by treatment group as well as the reasons for stopping their
therapies (primary lack of efficacy, secondary lack of efficacy, lack of tolerability, other) and 
the total duration of exposure to psoriatic arthritis therapies previously.
Concomitant medication in core or extension
Concomitant medications data collected in core and extension will be combined together. 
Data for concomitant medications for core are collected in core study and the same will be 
used. 
Any medication given at least once between the start of the first dose in core trial and the date 
of the last study visit in the extension trial will be summarized. Data will be analyzed on 
safety set.
Prior or concomitant medication will be identified by comparing recorded or imputed start 
and end dates of medication taken to the reference start date. 
Further rules will be given in PDS.
12
Efficacy evaluation
12.1
Description of efficacy variables
ACR 20/50/70
ACR20 is a binary response variable defined for each subject. A subject will be considered a 
responder according to ACR20 criteria if he/she has at least (i.e., ≥):
• 20% improvement from baseline in tender 78-joint count
• 20% improvement from baseline in swollen 76-joint count


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• 20% improvement from baseline in at least 3 of the following 5 measures:
o Patient’s assessment of PsA pain (VAS 100 mm)
o Patient’s global assessment of disease activity (VAS 100 mm)
o Physician’s global assessment of disease activity (VAS 100 mm)
o Patient self-assessed disability (Health Assessment Questionnaire [HAQ-DI©] score)
o Acute phase reactant (C-reactive protein [hsCRP]) or Erythrocyte sedimentation rate 
(ESR).
In the definition above, the baseline value refers to the last measurement made prior to 
administration of the first dose of study treatment in core study. 
The primary objective of this long term efficacy and safety study is to evaluate the proportion 
of subjects achieving ACR20, ACR50 and ACR70 by visit. Primarily, CRP will be used to 
calculate ACR response; ESR will only be used in the event CRP is missing.
ACR50 and ACR70 are defined in the same way as ACR20 by replacing the 20% with 50%
and 70% improvement from baseline, respectively. 
ACRn represents the percent improvement on the continuous scale and from ACRn one can 
directly calculate ACR20, ACR50, and ACR70 using the appropriate cutoffs. This variable is 
defined as:
ACRn = min (x1, x2, x3), where 
x1 = % improvement from baseline in tender 78-joint count
x2 = % improvement from baseline in swollen 76-joint count
and x3 = 3rd largest value of x4, x5, x6, x7, x8 where,
x4 = % improvement from baseline in Patient’s assessment of PsA pain (VAS 100 mm)
x5 = % improvement from baseline in Patient’s global assessment of disease activity 
(VAS 100 mm)
x6 = % improvement from baseline in Physician’s global assessment of disease activity 
(VAS 100 mm)
x7 = % improvement from baseline in Patient self-assessed disability (Health 
Assessment Questionnaire [HAQ©] score)
x8 = % improvement from baseline in Acute phase reactant (C-reactive protein [hsCRP]) 
or Erythrocyte sedimentation rate (ESR)
ACRn can be computed even if up to two values of x4, x5, x6, x7, x8 are missing. ACRn, 
theoretically, cannot be computed, if one or both of x1, x2 is/are missing OR more than three 
values of x4, x5, x6, x7, x8 are missing. 


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


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HAQ-DI response 
The HAQ-DI response is defined by an improvement of at least 0.3 score points compared to 
baseline.
Joint/bone structural damage
The primary score for analyses will be van der Heijde modified Total Sharpe score (vdH-
mTSS) (van der Heijde 1999), The erosion score and joint space narrowing score will be 
analyzed in similar fashion.
Erosions will be assessed each hand (20 locations per hand) and each foot (6 locations per 
foot). The maximum erosion score is 200 for all 40 hand locations, and 120 for all 12 feet 
locations. Thus, the total possible erosion score is 320. 
Joint space narrowing (JSN) will be assessed in each hand (20 locations per hand) and foot (6 
locations per foot). The maximum score is 160 for all 40 hand joints, and 48 for all 12 feet 
joints. Thus, the total possible JSN score is 208. 
Pencil-in-cup: Osteolysis of the proximal phalanx and the base of the distal phalanx resulting 
in a pencil like proximal phalanx covered by cup like base of the distal phalanx. Pencil-in-cup 
will be scored as “P” where applicable. 
Gross Osteolysis: Osteolysis of the phalanx resulting in a loss of the normal joint structure, 
usually accompanied by shortening of the length of the phalanx. Gross osteolysis will be 
scored as “G” where applicable. 
If a joint or bone is not visible (e.g. poor film quality, missing imaging, severe misalignment, 
flexion deformity, dislocation) at the timepoint, the individual joint or bone will be coded as 
Not Visible (N). 
If radiographs at the timepoint show a joint or bone with surgical fusion, replacement 
(prosthesis), or amputation, then the joint or bone will be scored Surgically Modified (S). 
To obtain the total vdH-S score, scores for erosions and JSN in both the hands and feet will be 
added together. Any “P” or “G” will be considered the maximal score for the feature (erosions 
and JSN) per location in the calculation of the total vdH-S score. Any “N” or “S” will be 
considered null in the calculation of the total vdH-S score. The range of scores is 0 ~ 528. 
The joints are divided into 10 segments according to Table 12-1. In each segment an adequacy 
threshold is defined. For each segment, when the change from baseline values are available 
for at least the threshold number of joints, the change from baseline will be calculated for the 
segment, with missing joints imputed by the within-segment mean change over individual 
joints. Otherwise (i.e. if less than threshold number of joints have available change from 
baseline values), the segment change from baseline will be missing. When ≥ 6 segments have 


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evaluable change from baseline values, the overall change from baseline value will be 
calculated, with missing segments imputed by the mean change over segments. Otherwise (i.e. 
if ≤ 5 segments have evaluable change from baseline values), the overall change from baseline 
value will be missing.
Table 12-1
Segmental distribution
Segment
Total number 
of joints
Adequacy 
threshold
Joints at one side
PIP erosions
8 
5
PIP2, PIP3, PIP4, PIP5
DIP erosions
8
5
DIP2, DIP3, DIP4, DIP5
MCP +
thumb erosions
12
7
MCP1, MCP2, MCP3, MCP4, MCP5, INTERPHALANGEAL 
JOINT OF THE HAND
Wrist erosions
12
7
FIRST METACARPAL BONE, DISTAL RADIUS, DISTAL 
ULNA, TRAPEZOID-TRAPEZIUM, NAVICULAR BONE, 
LUNATE BONE
Foot erosions
12
7
MTP1, MTP2, MTP3, MTP4, MTP5, INTERPHALANGEAL 
JOINT 1
PIP JSN
8 
5
PIP2, PIP3, PIP4, PIP5
DIP JSN
8
5
DIP2, DIP3, DIP4, DIP5
MCP +
thumb JSN
12
7
MCP1, MCP2, MCP3, MCP4, MCP5, INTERPHALANGEAL 
JOINT OF THE HAND 
Wrist JSN
12
7
CMC3, CMC4, CMC5, RADIOCARPAL, SCAPHOID-
TRAPEZIUM, CAPITATE-NAVICULAR-LUNATE
Foot JSN
12
7
MTP1, MTP2, MTP3, MTP4, MTP5, INTERPHALANGEAL 
JOINT 1
The readings of the x-rays and the scoring will be performed centrally. Two central 
independent radiograph readers, both blinded to treatment arm and radiograph sequence, will 
analyze the digitized images. In the case that adjudication is needed, a third consensus read 
will be performed. The statistical analysis will use the adjudicated score, if available, or the 
average score from the two readers otherwise.
In the situation that a consensus is made, but not all joints are scored, the missing consensus 
score at an individual joint, both at baseline and post baseline, will be imputed with the 
average of the two individual readers’ scores at the joint for the respective time point, then the 
consensus change from baseline (at patient level) is calculated based upon all individual joints 
with imputation at joint level. 


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DAS28, low disease activity and remission 
The Disease Activity Score (DAS) is a combined index to measure the disease activity in 
patients with RA. 
 
The DAS28 is a measure of disease activity based on Swollen and Tender Joint Counts, CRP 
or ESR, and the Patient Global Assessment. A DAS28 score > 5.1 implies active disease, ≤ 
3.2 low disease activity, and < 2.6 remission.
The following 28 joints will be assessed for tenderness and swelling: metacarpophalangeal IV
(10), thumb interphalangeal (2), hand proximal interphalangeal II-V (8), wrist (2), elbow(2), 
shoulders (2), and knees (2).
The following formulas can be used to calculate the DAS28 with CRP (mg/L) or ESR 
(mm/hour). 
DAS28-CRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*PGA + 0.96
DAS28-ESR = 0.56*sqrt(tender28) + 0.28*sqrt(swollen28) + 0.70*ln(ESR) + 0.014*PGA


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TJC28: 28 Tender joint count; SJC28: 28 Swollen joint count; CRP: C-reactive protein; PGA: 
Patient Global Assessment
If any component measurement is missing, DAS28 will be missing.
DAS28-CRP will be primary for analysis; DAS-ESR will be secondary.
DAS28-CRP (or ESR) remission is defined as a DAS28-CRP (or ESR) index score less than 
2.6. Low disease activity is defined as DAS28-CRP (or ESR) index less than or equal to 3.2. 
ACR Components
Tender 78 joint count and swollen 76 joint count 
The 78 joints assessed for tenderness include the 2 temporomandibular, 2 sternoclavicular, 2 
acromioclavicular joints, 2 shoulders, 2 elbows, 2 wrists, 2 first carpometacarpal, 10 
metacarpophalangeal, 10 proximal interphalangeal, 8 distal interphalangeal joints of the hands, 
the 2 hip, 2 knee, 2 talo-tibial, 2 mid-tarsal, 10 metatarsophalangeal, 10 proximal 
interphalangeal, and 8 distal interphalangeal joints of the feet. All of these except for the hips 
are assessed for swelling. Joint tenderness and swelling are to be graded present (1) or absent 
(0). Synovial fluid and/or soft tissue swelling but not bony overgrowth represents a positive 
result for swollen joint count. Dactylitis of a digit in the foot or hand counts as one tender and 
swollen joint.


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If the number of joints for which data were available (e.g., T) is less than 78/76 for the 
tender/swollen joint assessment, the number of tender/swollen joints (e.g., t) will be scaled up 
proportionately (i.e., 78*t/T or 76*t/T for tender or swollen joint count).  
Patient’s assessment of PsA Pain
The patient’s assessment of pain will be performed using 100 mm visual analog scale (VAS) 
ranging from “no pain” to “unbearable pain” after the question “Please indicate with a 
vertical mark ( | ) through the horizontal line the most pain you had from your psoriatic 
arthritis today”.
Patient’s global assessment of PsA disease activity
The patient’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from ”very good” to ”very poor”, after the question "Considering all the ways 
psoriatic arthritis affects you, please indicate with a vertical mark ( | ) through the horizontal 
line how well you are doing today”. 
Physician’s global assessment of PsA 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.
Erythrocyte sedimentation rate (ESR)
Blood for ESR, which is helpful in diagnosing inflammatory diseases and is used to monitor 
disease activity and response to therapy, will be obtained at scheduled visits.
High-sensitivity C-reactive protein (hsCRP)
Blood for this assessment will be obtained in order to identify the presence of inflammation, 
to determine its severity, and to monitor response to treatment. Since the results of this test 
may unblind study personnel, results from the central lab will be provided for screening and 
baseline only. The hsCRP results from samples collected during the treatment period will be 
revealed following database lock only.


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12.3
Handling of missing data
For primary analysis, data will be presented using all observed data at the given time point of 
analysis.
No multiple imputation or Mixed Models for Repeated Measures (MMRMS) will be 
considered since the influence of up-titrators in each group population violates the MAR 
assumption.
12.4
Analysis of Primary Variable(s)
The primary efficacy variable(s) is the clinical response to treatment according to ACR20, 
ACR50 and ACR 70 improvement in disease activity over time up to Week 260.
ACR response criteria denote the response (i.e., improvement) in signs & symptoms of the 
disease of a subject compared to baseline of the core study. 
The analysis of the primary variables will be based on the FAS. Primarily, CRP will be used 
instead of ESR to calculate ACR response; ESR will only be used in the event CRP is missing.
Shift tables will be provided comparing the subject’s ACR evaluation at the pre up-titration 
visit relative to the observed data of the following week intervals after up-titration: (12-32 
weeks), (36-56 weeks) and (60-80 weeks). The ACR grouping presented in the table will be: 
ACR < 20, 20 <ACR < 50, 50 < ACR < 70, ACR > 70.
Graphical representation (line plots) of ACR20, ACR50 and ACR70 response over time and 
Sankey-style bar chart for the ACR response within the subjects that up-titrated from 150 mg 
to 300 mg (provided that up-titration has been occurred for more than 8 weeks) will be drawn 
from the observed data. 
Additionally, observed data tables will summarize the ACR20, ACR50 and ACR70 response 
following up-titration when assessed. Results will be illustrated in line plots.
Also individual subject listings of the ACR components as well as for the ACR20/50/70 
response will be given.
Statistical model, hypothesis, and method of analysis
No formal hypotheses are planned for this study. The proportion of subjects meeting the ACR 
criteria (ACR20, ACR50, and ACR70) will be descriptively summarized for each treatment 
by absolute and relative frequencies followed by 95% confidence intervals for the proportion 
of patients responding to treatment according to the ACR criteria from Week 1 onwards based
on the pooled data from core and extension study. Results regarding ACR20/50/70, will be 
presented overall in the FAS population as well as in subgroups by TNFα status (naive or IR)
and by concomitant use of MTX as appropriately.
Placebo group (core study) in efficacy analysis will not be considered. 


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Supportive analyses
Sensitivity analyses using multiple imputations for missing assessments for ACR 20, ACR 50 
and ACR 70 will not be performed.
12.5
Analysis of secondary and exploratory variables
Secondary and exploratory variables for the final analysis of the extension study include:

The change from baseline in HAQ-DI

The proportion of subjects with improvements from baseline in HAQ-DI ≥ minimal 
clinically important difference (MCID=0.3)

The change from baseline in DAS28-CRP

The proportion of subjects achieving low disease activity (DAS28 ≤ 3.2) and disease 
remission as defined by DAS28 (DAS28 < 2.6) 

 

 

 

 


 

 

 



 



 


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All the above efficacy variables will be analyzed on the FAS (unless otherwise specified) for 
all applicable analysis visits based on the observed data.
For binary variables, the proportion of responders along with the 95% CI will be presented by 
treatment groups over analysis visits. 
For continuous variables, the change from baseline (of core) when available, will be 
summarized. 
 
 
 
Figures will be provided for the following parameters:


DAS28-CRP and SF-36 PCS change from baseline.

HAQ-DI score (change from baseline) overall and following the up-titration 

HAQ-DI response overall and following the up-titration 

HAQ-DI response by TNF-α inhibitor status. 

Remission response and low disease activity response according to DAS28-CRP 

.

 
Individual listings will be considered for all efficacy variables of the study.
Joint/bone structural damage at Week 156, 208
The changes in joint/bone structural damage (total sharp score, and its components, erosion 
score and joint spacing narrowing score) will be summarized by the same treatment groups as 
follows using evaluable data of each x-ray reading session:

Baseline to:
o
Week 24
o
Week 52
o
Week 104
o
Week 156
o
Week 208

Week 24 to:
o
Week 52
o
Week 104
o
Week 156


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o
Week 208

Week 52 to:
o
Week 104 
o
Week 156
o
Week 208

Week 104 to:
o
Week 156
o
Week 208
The above analyses will be done on both FAS and X-ray completers where X-ray completers 
are those subjects that had X-ray measures at baseline, Week 16/24, Week 52, Week 104, 
Week 156 and Week 208. Subgroup analyses by TNF-alpha inhibitor status will be provided.
Analyses will be performed for each reading campaign, as appropriate depending on the 
available data.
For the purpose of the campaign 3 the readings of baseline, week 156 and week 208 will be 
used for the analysis. Any data on week 260 will be shown only in listings.
Individual listings will be provided for Joint structural damage components.


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13
Pharmacokinetic evaluations (change / add PD, PK/PD, 
Biomarkers, as needed)
13.1
Pharmacokinetics
All completed subjects with quantifiable pharmacokinetic (PK) measurements of 
secukinumab will be included in the pharmacokinetic data analysis. Serum concentrations will 
be expressed in mass per volume units. All concentrations below the limit of quantification as 
well as missing data will be labeled as such in the concentration data listings. PK 
concentrations will be summarized by visit and treatment group. In addition to mean, standard 
deviation (SD), coefficient of variation (CV), median and quartiles, the geometric mean and 
geometric coefficient of variation (CV) and n(log) will be presented. The formula for deriving 
the geometric mean and CV (%) is as following: 

CV (%) = (SD/mean)*100,

geometric mean=exp( (sum of log transformed data) / number of non-missing data points 
after log transformation),

geometric CV = sqrt( exp( variance of log-transformed data)-1)*100.
In addition, sample number, concentration, sample date, sample time at pre-dose and minutes 
pre-dose will be listed by treatment sequence.
Values below lower limit of quantification/below detection limit will be imputed by 0.
Pharmacokinetic data of the study treatment will be analyzed with a population-
pharmacokinetic mixed effects model. The analysis will be based on a pooled data set, 
including pharmacokinetic samples from previous studies. The modeling approach will be 
further detailed in a modeling plan. Results will be reported separately.
14
Safety evaluation
Safety analyses will be done on the safety set.
Summaries will be presented cumulatively from core and extension. For subjects who 
switched from placebo to secukinumab in core, their data prior to switch will only be reported
in in-text tables and listings. 
Safety analyses will be performed on treatment received or actual treatment as described 
below:
The actual treatment or treatment received for summaries of safety data will differ to the 
treatment assigned at randomization if a subject received the wrong treatment during the core 
and extension study or if the subject up-titrated to a higher dose.


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Subjects who switch treatment during the study (e.g. from placebo to active treatment, or had 
dose escalation) will be counted to both groups using the appropriate start and stop exposure 
date.
14.1
Adverse events
The crude incidence of treatment emergent adverse events on secukinumab (i.e. events started 
after the first dose of secukinumab in core study or events present prior to the first dose of 
secukinumab but increased in severity based on preferred term and within 84 days after last
dose of secukinumab) will be summarized by primary system organ class and preferred term
for the entire treatment period. Confidence intervals for the crude rate will be derived as 
described in Section 17.2.3.1 In addition, exposure time-adjusted rates (incidence rate) 
including 95% confidence intervals will be provided for selected terms for the entire treatment 
period, (see Section 17.2.4.1) to adjust for differences in exposure.
Adverse events reported will be presented in descending frequency according to its incidence 
in total secukinumab group (combining all secukinumab treatment groups) starting from the 
most common event. 
Summary statistics will be provided by primary system organ class and preferred term for the 
entire treatment period for all TEAEs, for serious TEAEs, for possibly related TEAEs, for
deaths, for TEAEs causing treatment discontinuation, other serious or clinically significant 
treatment emergent adverse events or related discontinuations, for TEAEs leading to 
temporary dose interruptions, for SPP risks and for adjudicated major adverse cardiovascular 
events (MACE). Separate summaries for adverse events suspected to be related to study drug, 
will also not be displayed in the current analysis.
TEAEs will also be summarized by primary system organ class and preferred term for the 
entire treatment period in time segments of 52 and 26 weeks.
Summaries (crude incidence only) will be presented for TEAEs by maximum severity as well. 
If a particular AE ‘severity’ is missing, this variable will be listed as missing and treated as 
missing in summaries. 
If a subject reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a subject reported more than one adverse 
event within the same primary system organ class, the subject will be counted only once with 
the greatest severity at the system organ class level, where applicable.  
When adjudication is required of major cardiovascular events, a summary of those types of 
events as reported by the investigator and confirmed by adjudication will be provided.
Exposure adjusted incidence rates for TEAEs, selected lower lever risk terms based on 
TEAEs, serious adverse events, adverse events leading to discontinuation, common AEs 
(frequency >2% in the Any AIN457 group during the first 24 weeks of treatment or IR> 5/100 
subject years during the entire treatment period), SPP risks and MACE will be summarized by 
primary system organ class and/or by preferred term for the entire period. 
The incidence of AEs will be presented per 100 subject years of exposure.


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Exposure adjusted incidence rates for TEAEs will also be provided for specific common or 
very common TEAEs (very common TEAEs are described in the Core Data Sheet).
Adverse events will be reported separately by SMQ according to MedDRA. The MedDRA 
version used for reporting will be described in a footnote.
Algorithms for date imputations will be provided in the PDS.
The safety analyses that will be performed for treatment emergent AEs, labs, ECG and vital 
signs for each analysis period is described in table below.
Listings will be provided for all adverse events, all non-fatal serious adverse events, deaths, 
adverse events leading to discontinuation from study treatment or temporary dose interruption, 
adverse events by SPP risks and adjudicated MACE events (myocardial infarctions, strokes, 
and cardiovascular deaths). 
For SAEs that occurred during screening a listing will be prepared for all subjects screened 
including screening failures.
No graphical displays of the crude incidence rates and exposure-adjusted rates will be 
presented for any AEs and serious AEs by system organ class in the current interim analysis.
An overview of the safety analyses and which will be performed for each analysis period is 
described in Table 14-1.
Table 14-1
Overview of analyses on some safety endpoints
Analysis 
period
AEs & SAEs
AEs by 
severity
Study drug 
related AEs
AEs-SMQ
Risk
Notables for
(vitals/
ECG), lab 
criteria
Entire 
Treatment 
crude 
incidence
exposure time 
adjusted 
incidence*
crude 
incidence
crude 
incidence
exposure 
time 
adjusted 
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
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
frequency greater than 5% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class 
and preferred term on the safety set population.
The tables will include data from the core and the extension part of the trial.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:


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
a single occurrence will be counted if there is ≤ 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end 
date of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective will be included.
14.2
Laboratory data
The summary of lab data will only include on treatment data, which are defined as those lab 
assessments after the first dose of secukinumab in core and on or before last dose + 84 days.
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, chemistry and urinalysis). In addition to the individual laboratory parameters the 
ratios “total cholesterol / HDL” and “apolipoprotein B / apolipoprotein A1” will be derived 
and summarized.
For urinalysis, frequency tables across visits will be presented.
Descriptive summary statistics for the absolute value at study visits as well as the change from 
baseline to extension study visits will be presented in tabular fashion. These descriptive 
summaries will be presented by laboratory test and treatment dose. Change from baseline will 
only be summarized for subjects with both baseline and post baseline values and will be 
calculated as:
change from baseline = post baseline value – baseline value
The maximum change (maximum decrease and maximum increase) from baseline for each lab 
parameter, will also be analyzed. Shift tables will be provided comparing the subject’s 
baseline laboratory evaluation relative to the visit’s observed data. 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 dose.
Reported laboratory assessments with either a less than or greater than sign (“<” or “>”) will 
be used for analysis after removal of the sign and conversion to standard unit. These
laboratory data will be displayed in listings using the standard unit with the reported sign (“<” 
or “>”).”
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 14-2: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 


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gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG).
These summaries will be split into hematology and chemistry for study level reports and the 
pooled summary of clinical safety.
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 the initial 
treatment phase of the core study. Subjects with abnormal laboratory values will be listed and 
values outside the normal ranges will be flagged.
Table 14-2
CTCAE grades for laboratory parameters to be analyzed
CTCAE v4.0 Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
HGB decreased (Anemia)
<LLN – 100 g/L
<100 – 80 g/L
<80 g/L
Life-threatening
consequences; 
urgent intervention 
indicated
Platelet count decreased
<LLN – 75.0 x10e9 /L
<75.0 - 50.0 x10e9 /L
<50.0 – 25.0 x10e9 /L
<25.0 x 10e9 /L
White blood cell decreased
<LLN - 3.0 x 10e9 /L
<3.0 - 2.0 x 10e9 /L
<2.0 - 1.0 x 10e9 /L
<1.0 x 10e9 /L
Neutrophil count decreased
<LLN - 1.5 x 10e9 /L
<1.5 - 1.0 x 10e9 /L
<1.0 - 0.5 x 10e9 /L
<0.5 x 10e9 /L
Lymphocyte count 
decreased
<LLN - 0.8 x 10e9/L
<0.8 - 0.5 x 10e9 /L
<0.5 - 0.2 x 10e9 /L
<0.2 x 10e9 /L
Creatinine increased*
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN
>1.5 - 3.0 x baseline; 
>1.5 - 3.0 x ULN
>3.0 baseline; 
>3.0 - 6.0 x ULN
>6.0 x ULN
TBL increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALP increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Glucose increased 
(Hyperglycemia )
>ULN - 8.9 mmol/L
>8.9 - 13.9 mmol/L
>13.9 - 27.8 mmol/L
>27.8 mmol/L
Glucose decreased 
(Hypoglycemia)
<LLN - 3.0 mmol/L
<3.0 - 2.2 mmol/L
<2.2 - 1.7 mmol/L
<1.7 mmol/L
Cholesterol high
>ULN - 7.75 mmol/L
>7.75 - 10.34 mmol/L
>10.34 - 12.92 mmol/L
>12.92 mmol/L
Hypertriglyceridemia
1.71 - 3.42 mmol/L
>3.42 - 5.7mmol/L
>5.7 - 11.4 mmol/L
>11.4 mmol/L
*Note: for “creatinine increased” the baseline criteria do not apply
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 14-3:


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Table 14-3
Liver-related events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
AST
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
ALT or AST
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
TBL
>1.5xULN, >2xULN, >3xULN,
ALP
>2xULN, >3xULN. >5xULN
ALT or AST & 
TBL
ALT or AST>3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >8xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN
ALP & TBL
ALP >3xULN & TBL >2xULN
ALP >5xULN & TBL >2xULN
ALT or AST & 
TBL & ALP
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law)
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or 
bile duct disease; ALP may also be increased in malignancy. FDA therefore terms 
Hy’s Law cases as indicators of pure hepatocellular injury. This does not mean 
that cases of ALT or AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result 
in severe DILI.
Notes:1) In studies which enroll subjects with pre-existing liver disease, baseline LFT may 
be increased above ULN; in such a case it is meaningful to add the condition “and worse 
than baseline” to the abnormality criteria
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. 
The criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN.
Individual subject laboratory data listings will be provided for all subjects as well as for
subjects with newly occurring or worsening CTCAE grades, or with newly occurring or 
worsening after baseline abnormalities in lipid parameters, or with newly occurring or 
worsening after baseline abnormalities in liver enzymes. 
No box plots over time or other graphs will be presented for any of the laboratory parameters.
14.3
Vital signs
The summary of vital signs will only include on treatment data, which are defined as those 
vital sign measurements after the first dose of study treatment and on or before last dose + 84 
days.
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit in extension only be presented for subjects with both a 
baseline (of core study) and post baseline values. These descriptive summaries will be 
presented by vital sign and treatment dose. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value


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Analysis in vital sign measurements using descriptive summary statistics for the change from 
baseline until each post-baseline visit will be performed.
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 13-4 below.
Table 14-4
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg)
>= 140 mmHg or < 90 mmHg
Diastolic blood pressure (mmHg)
>=90 mmHg or <60 mmHg
Pulse (bpm)
> 100 bpm or <60 bpm
Individual subject listing of vital signs and a listing for the newly occurring notably 
abnormalities will be provided.
14.4
Electrocardiogram (ECG)
The summary of ECG will only include on treatment data, which are defined as those ECG 
measurements after the first dose of study treatment and on or before last dose + 84 days.
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 only be summarized by computing the number and percentage of subjects (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
Subjects with notable abnormal ECG parameters as described above, after baseline will be 
summarized.
Summary statistics will be presented for ECG variables by visit and treatment dose in safety 
population.
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.


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14.5
Immunogenicity
A listing of immunogenicity (anti-AIN457 antibodies) and a table with an overview of 
patients with anti-drug antibodies for patients with baseline or treatment emergent ADA will 
be provided.
14.6
Compound specific safety evaluation
Safety topics of interest, such as risks defined in the Safety Profiling Plan, 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 potential compound and class-
related risks and routine 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.
15
Interim analyses
Interim analyses are planned in order to support regulatory filing and for purposes of 
publication after subjects complete year 1 (Treatment period 3), and year 2 (Treatment period 
4) of treatment in this extension study. Additional analyses may be performed to support 
health authority interactions, as necessary.
16
Sample size calculation
It is estimated that 80~90% of subjects originally randomized to secukinumab will complete 
the entire treatment period and be eligible for entry into the extension (320~360 subjects). 
Likewise, 70~80% of the subjects originally randomized to placebo (140~160 subjects) will 
be eligible. In total, it is estimated that 460~520 subjects will be eligible for enrollment in this 
extension study.


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17
Appendix
17.1
Visit Windows
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one 
of the visit windows. E.g., if the Week 112 visit of a subject is delayed and occurs on Day 810 
instead of on Day 785, say, it will be re-aligned to visit window Week 116. In the case of 
major deviations from the visit schedule, or due to unscheduled visits, several assessments of 
a subject may fall in a particular visit window (either scheduled or unscheduled or optional 
site visits). Statistical approaches to handle multiple assessments in a given visit window are 
specified below. 
For lab/ECG/vital signs, follow-up (F/U) visit is excluded from analysis visit mapping 
window. Only assessments that come as F/U nominal visit will be directly assigned as 
analysis F/U visit. Other assessments that are beyond the last on-treatment visit window 
(W264) or after nominal F/U visit date won't be mapped to any analysis visit. F/U visit will 
not be included in the summary tables by visit.
For visits that occur after week 104 only the recorded nominal visit should be used.
Of note, subjects are allowed to have gaps in visits. Optional site visits will not be presented 
in summaries but will be used for mapping to planned visits. All data collected will be 
displayed in listings. 


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Table 17-1
Analysis visit windows
Analysis 
Visit
Target 
Day
Analysis 
Visit 
Window 
Group
1
Group
2
Group
3
Group
4
Group5
Group6
Group7
Group8
Group9
Group1
0
Group1
1
Group1
2
Group1
3
Group1
4
Group1
5
Baseline
1
Up to 1*
Up to 
1*
Up to 
1*
Up to 
7
Up to 
1*
Up to 
1*
Up to 
1*
Up to 
1*
Up to 
1*
Up to 
1*
Up to 
1*
Up to 
30
Up to 
1*
Up to 
1*
Up to 
1*
Up to 1*
Week 1
8
2-11
2-11
2-11
2-11
2-11
Week 2
15
12-22
12-22
12-22
2-22
12-22
12-22
Week 4
29
23-43
23-43
23-43
2-71
23-43
23-43
2-43
2-57
23-43
Week 8
57
44-71
44-71
44-71
44-71
44-71
44-71
2-85
44-71
Week 12
85
72-99
72-99
72-99
8-127
72-99
72-99
72-99
58-99
72-99
Week 16
113
100-127
100-
127
100-
127
2-141
72-141
100-
141
100-
141
100-
141
86-141
2-239
31-141
100-
141
100-127
Week 20
141
128-155
128-
155
128-
155
128-155
Week 24
169
156-183
156-
183
156-
183
128-
449
142-
267
142-
267
142-
197
142-
197
142-
267
142-
267
142-
267
2-267
2-267
142-
197
156-183
Week 28
197
184-211
184-
211
184-
211
184-211
Week 32
225
212-239
212-
239
212-
253
198-
253
198-
253
198-
253
212-239
Week 36
253
240-267
240-
267
240-267
Week 40
281
268-295
268-
295
254-
323
254-
323
254-
323
254-
323
268-295
Week 44
309
296-323
296-
323
296-323
Week 48
337
324-351
324-
351
324-351
Week 52
365
352-379
352-
393
324-
393
268-
547
268-
547
324-
393
324-
393
268-
547
268-
449
240-
547
268-
547
268-
547
268-
477
324-
393
352-393
Week 56
393
380-407


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Analysis 
Visit
Target 
Day
Analysis 
Visit 
Window 
Group
1
Group
2
Group
3
Group
4
Group5
Group6
Group7
Group8
Group9
Group1
0
Group1
1
Group1
2
Group1
3
Group1
4
Group1
5
Week 60
421
408-435
394-
449
394-
449
394-
449
394-
449
394-
449
394-449
Week 64
449
436-463
Week 68
477
464-491
450-
505
450-
505
450-
505
450-
505
450-
505
450-505
Week 72
505
492-519
Week 76
533
520-547
506-
561
506-
561
506-
561
506-
561
450-
631
506-
561
506-561
Week 80
561
548-575
Week 84
589
576-603
562-
617
562-
617
562-
617
562-
617
478-
659
562-
617
562-617
Week 88
617
604-631
Week 92
645
632-659
618-
687
618-
687
618-
687
618-
687
618-
687
618-673
Week 96
673
660-687
Week 100
701
688-715
674-715
Week 104
729
716-743
688-
743
688-
743
450-
743
548-
743
548-
743
688-
743
688-
743
548-
743
632-
743
548-
743
548-
743
548-
743
660-
743
688-
743
716-743
Group1: ACR components,  HAQ-DI, Tender and Swollen Joints
Group2: Hematology, blood chemistry, urinalysis, skin test
Group4: WPAI-GH, cardiovascular panel 
Group5: PK
Group6:
Group7: 
 
Group8: 
Group9: Lipids
Group10: ECG
Group11: X-ray


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Analysis 
Visit
Target 
Day
Analysis 
Visit 
Window 
Group
1
Group
2
Group
3
Group
4
Group5
Group6
Group7
Group8
Group9
Group1
0
Group1
1
Group1
2
Group1
3
Group1
4
Group1
5
Group12: Immunology, 
Group13: Weight
Group14: Pregnancy test, hormones
Group15: Vital signs
* The first administration of randomized study treatment (first dose) is defined as 1.


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The following rules are used to determine the window for an applicable visit post baseline: 
“Lower limit” = “upper limit of prior applicable visit” + 1. “Upper limit” = “target day of 
current visit” + integer part of (“target day of next applicable visit” – “target day of current 
visit”)/2. Lower limit of the first applicable visit is always Day 2.
The mapping described above applies to all visits including optional site visits (not just 
scheduled visits). Optional site visits, repeat and/or unscheduled visits (which will be 
numbered in the database according to new NCDS standards) will be mapped for analysis 
purposes in the same way as scheduled visits.  This leaves the possibility, then, for multiple 
measurements within an analysis window. The following conventions will be used to 
determine the appropriate measurement to be summarized in the event of multiple 
measurements within a visit window.
Table 17-2
Rules for flagging variables
Timing of 
measurement
Type of data
Rule
Baseline of core
All data
The last measurement made prior to administration of the first dose of study 
treatment in core– note this may include measurements taken on the day of 
randomization (e.g. lab). If a patient did not receive any dose of study treatment 
then the randomization date will be used.
Post-baseline efficacy
All data
The measurement closest to the target will be used. In the event two 
measurements are taken equally apart (e.g. 1 before target date and 1 after) the 
first one will be used. 
Post-baseline safety
Summary visit 
information (e.g. 
lab, ECG, etc.)
The measurement closest to the target will be used. In the event two 
measurements are taken equally apart (e.g. 1 before target date and 1 after) the 
first one will be used.
Post-baseline safety 
Notable 
abnormalities 
(e.g. lab)
The most extreme measurement in the window will be used.  Note this means a 
patient can have a notably high and notably low measurement within a window. 
No visit windows were used in case of up-titrations. The before up-titration measurement is
considered as the last visit measurement, performed on or before the date that patient took the 
up-titration dose. The up-titration data analysis will be based on week intervals; it is 
accounting for the time period between the actual date of exposure to the up-titrated dose and 
the last visit date of the subject:

4 – 8 weeks after up-titration

12 – 32 weeks after up-titration

36 – 56 weeks after up-titration

60 – 80 weeks after up-titration

84 – 104 weeks after up-titration
17.2
Interim Locks dates
Annual locks for analysis purposes were performed.
This the final lock of the study at week 260. It includes all subjects who have completed week 
260 assessment and/or the follow up treatment visit.


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17.3
Statistical methodology and assumptions
17.3.1
Analysis of continuous data
17.3.1.1 Summary statistics for continuous data
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, maximum) will be provided for continuous data by visit and treatment group. 
17.3.2
Analysis of binary (and categorical) data
17.3.2.1 Summary statistics for binary and categorical data
Summary statistics for discrete variables will be presented in contingency tables and will 
include count and frequency in each category. If applicable, confidence intervals will be 
derived as well based on the score method including continuity correction [Newcombe 
(1998)]:
With z as (1-alpha/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-
alpha/2), n as total number of subjects (i.e. number of subjects in the denominator), and p as 
estimated crude incidence (number of subjects with event / n ) it is 
p
q

1
Then the lower limit is
























2
2
2
2
1
4
1
2
1
2
,0
max
100
z
n
nq
p
n
z
z
z
np
L
and the upper limit is
























2
2
2
2
1
4
1
2
1
2
,1
min
100
z
n
nq
p
n
z
z
z
np
U
.
SAS code for risk difference:
Proc freq data=acr order=formatted; 
Tables response*trt/ riskdiff;
Run;
(Note the response value should be sorted with ‘1’ ahead of ‘0’.)


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17.3.3
Crude incidence and related risk estimates 
17.3.3.1 Crude incidence and 100*(1-α)% confidence interval
For n subjects, each at risk to experience a certain event with probability π, the crude 
incidence is estimated as p=x/n, where x is the number of subjects with the event.
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the 
relative frequency based on the score method including continuity correction (Newcombe 
1998). 
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/2), 
n as total number of subjects (i.e. number of subjects in the denominator), and p as estimated 
crude incidence (number of subjects with event / n ) it is 
p
q

1
.
Then the lower limit is:























2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
and the upper limit is























2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
.
Note: if L > (100 x p) then L = (100 x p) and if U < (100 x p) then U = (100 x p).
If appropriate, an exact 100*(1-α)% confidence interval (Clopper-Pearson 1934) will be 
obtained by using the SAS procedure PROC FREQ with the EXACT BINOMIAL statement. 
However, the confidence interval derived via the score method including continuity correction 
will be the default in safety analyses.
17.3.4
Exposure adjusted incidence rate and related risk estimates
17.3.4.1 Exposure adjusted incidence rate and 100*(1-α)% confidence interval
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will 
be modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 



n
j
jt
T
1
and D is the number of subjects with 
at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson 
variable with parameter θT and observed value D can be obtained based on (Garwood, 1936), 


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from which an exact 100*(1-α)% confidence interval for D/T will be derived as follows 
(Sahai, 1993; Ulm, 1990):
Lower confidence limit   
T
c
L
D
2,2
/
5.0


for D>0, 0 otherwise,
Upper confidence limit 
T
c
U
D 2
2,2
/
1
5.0




where
k
c ,

is the αth quantile of the Chi-square distribution with k degrees of freedom.
The example below shows how this should be handled for cases where subjects switch 
treatment. In particular for summarizing ‘Any AIN’ as a group, one should take into 
consideration the sequence of treatments while calculating exposure time for subjects.  
Table 17-3
Examples for calculating exposure time for incidence rates (IR)
1st 
treatment
1st exposure
2nd 
treatment
2nd 
exposure
Event days (in 
terms of study day)
Exposure for IR
Placebo
100 days
150 mg 
200 days
50 (1st trt)
110 (10 days into 
2nd trt)
Placebo: 50 days 
(event)
150 mg: 10 days 
(event)
Any AIN: 10 days 
(event)


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18
References
 
 
 
 
 
AIN457A efficacy MAP M3, available in Cabinets//CREDI Projects/A/AIN457A 
/Administrative files/CIS (Clinical Information Sciences)/Biostatistics
AIN457 safety MAP M3, available in Cabinets//CREDI Projects/A/AIN457A/Administrative 
files/CIS (Clinical Information Sciences)/Biostatistics
Biostatistical Guidance on Analysis Sets in Clinical Trials, available in Cabinets/CREDI 
TABULU/B&SR/CIS Process Documentation/Guidances (outside of ESOPS)/Others
Chandran V, Bhella S, Schentag C, Gladman DD (2007).Functional assessment of chronic 
illness therapy-fatigue scale is valid in patients with psoriatic arthritis.  Ann Rheum Dis. 
66(7):936-9.
‘CIS liver safety’ guidance, available in Cabinets/CREDI TABULU/B&SR/CIS Process 
Documentation/Guidances (outside of ESOPS)/Others
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika, 26; 404–413.
Coates LC, Fransen J, Helliwell PS (2010) Defining minimal disease activity in psoriatic 
arthritis: a proposed objective target for treatment. Ann Rheum Dis.69(1):48-53.
Committee for medicinal products for human use (CHMP), European Medicines Agency for 
the Evaluation of Medicines for Human Use. (2004) Guideline on clinical investigation of 
medicinal products indicated for the treatment of psoriasis. CHMP/EWP/2454/02 corr 
document. London, UK.
CSR template available in the CREDI template area: Cabinets/CREDI Templates /CTD
Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453.
‘Japan Specific Requirements from PMDA’ guidance, available in Cabinets/CREDI 
TABULU/B&SR/CIS Process Documentation/Guidances (outside of ESOPS)/Working with 
Japan.


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Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Statistics in Medicine; 17: 857-872.
Program Case Retrieval Sheet available in Cabinets/CREDI Projects/A/AIN457A/Integrated 
Medical Safety
Safety Profiling Plan stored in CREDI (Cabinets/CREDI Projects/A/AIN457A/Integrated 
Medical Safety)
Sahai H, Khurshid Anwer (1993). Confidence intervals for the mean of a poisson distribution: 
a review. Biom J, 35 (7); 857-867
Ulm K (1990). A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology, 131(2); 373-375
van der Heijde DM (1999). How to Read Radiographs According to Sharp/van der Heijde 
Method. J Rheumatol. 26(3):743-745.
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E (1997). Measuring fatigue and 
other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) 
measurement system. J Pain Symptom Manage;13:63–74.