Conditions: Psoriatic Arthritis
Keywords: PsA ACR CASPAR inflammatory arthritis spondylitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 258
Healthy volunteers: no

Brief summary:
To demonstrate that the efficacy of secukinumab 300 mg at Week 16 was superior to placebo in adult patients with active PsA based on the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response.

Detailed description:
Treatment Period 1 was defined as the period from Randomization through Week 16 (prior to the Week 16 dose). At the start of placebo-controlled Treatment Period 1, patients were randomized via Interactive Response Technology (IRT) in a 2:2:1 ratio to 1 of 3 treatment groups.

Group 1- Secukinumab 300 mg: secukinumab 300 mg (2 s.c. injections of the 150-mg dose) once weekly for 5 weeks (at Baseline, Weeks 1, 2, 3, and 4), followed by dosing every 4 weeks.

Group 2- Secukinumab 150 mg: secukinumab 150 mg (1 s.c. injection of the 150-mg dose and 1 s.c. injection of placebo) once weekly for 5 weeks (at Baseline, Weeks 1, 2, 3, and 4), followed by dosing every 4 weeks.

Group 3- Placebo: placebo (2 s.c. injections of 150 mg secukinumab placebo per dose) once per week for 5 weeks (at Baseline, Weeks 1, 2, 3, and 4), followed by dosing every 4 weeks.

At each study treatment visit 2 s.c. injections in the form of prefilled syringes (PFS) were administered. This was necessary to maintain the blind, as secukinumab in PFS is available in either 1.0 mL (150 mg) or 2 x 1.0 mL (300 mg). Placebo to secukinumab was also available in 1.0 mL to match the active drug.

Rescue medication was not allowed before completion of Week 16 assessments.

Treatment Period 2 patients receiving secukinumab 300 mg (Group 1) continued to receive the same dose up to Week 48.

At Weeks 16, 28, and 40 patients on secukinumab 150 mg (Group 2) were classified as responders (≥20% improvement from BL in both tender and swollen joint counts) or nonresponders.

* At Weeks 16, 28, and 40 patients on secukinumab 150 mg (Group 2) who were responders continued to receive secukinumab 150 mg (1.0 mL) plus placebo (1.0 mL) every 4 weeks until next evaluation of responder status at Weeks 28 or 40.
* Patients who did not meet the responder criteria at Week 16, 28, or 40 started receiving secukinumab 300 mg s.c. every 4 weeks and continued this dose up to Week 48.
* Patients on placebo (Group 3) regardless of their responder status started receiving secukinumab 300 mg s.c. every 4 weeks from Week 16 up to Week 48.

Arms:
arm 1: secukinumab 300mg s.c. injection arm 2: secukinumab 150 mg s.c. injection arm 3: Placebo s.c. injection

Interventions: intervention 1: Secukinumab 300 mg intervention 2: Secukinumab 150 mg intervention 3: Placebo
Intervention descriptions: intervention 1: 150 mg x 2 s.c. injection intervention 2: 150 mg s.c. injection intervention 3: Placebo

Protocol document:
Prot_000.pdf: 
US Clinical Development & Medical Affairs - General Medicine 
AIN457/Secukinumab
Clinical Trial Protocol CAIN457FUS01 / NCT02798211
A randomized, double-blind, placebo-controlled, parallel-
group, multicenter study to evaluate the safety and efficacy 
of secukinumab 300 mg and 150 mg in adult patients with 
active psoriatic arthritis after 16 weeks of treatment 
compared to placebo and to assess the safety, tolerability 
and efficacy up to 52 weeks
Authors
Document type:
Amended Protocol Version
Version number:
v02 Clean
Clinical trial phase:
IV 
Release date:
12-Dec-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 03 (August 2015)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment 2 ....................................................................................................................10
Amendment 1 ....................................................................................................................10
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................22
1.1
Background............................................................................................................22
1.2
Purpose ..................................................................................................................23
2
Study objectives.................................................................................................................24
2.1
Primary objective(s)...............................................................................................24
2.2
Secondary objectives .............................................................................................24
25
3
Investigational plan ...........................................................................................................25
3.1
Study design...........................................................................................................25
3.2
Rationale for study design .....................................................................................27
3.3
Rationale for dose/regimen, route of administration and duration of treatment....27
3.4
Rationale for choice of comparator .......................................................................28
3.5
Purpose and timing of interim analyses/design adaptations..................................29
3.6
Risks and benefits..................................................................................................29
4
Population..........................................................................................................................30
4.1
Inclusion criteria ....................................................................................................30
4.2
Exclusion criteria...................................................................................................31
5
Treatment...........................................................................................................................33
5.1
Protocol requested treatment .................................................................................33
5.1.1
Investigational treatment.......................................................................33
5.1.2
Additional study treatment....................................................................34
5.2
Treatment groups...................................................................................................34
5.3
Treatment assignment and randomization.............................................................35
5.4
Treatment blinding.................................................................................................35
5.5
Treating the patient................................................................................................36
5.5.1
Patient numbering .................................................................................36
5.5.2
Dispensing the investigational treatment ..............................................36


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5.5.3
Handling of study treatment..................................................................36
5.5.4
Instructions for prescribing and taking study treatment........................37
5.5.5
Permitted dose adjustments and interruptions of study treatment ........38
5.5.6
Rescue medication ................................................................................38
5.5.7
Concomitant treatment..........................................................................39
5.5.8
Prohibited treatment..............................................................................40
5.5.9
Discontinuation of study treatment .......................................................42
5.5.10
Withdrawal of consent ..........................................................................42
5.5.11
Loss to follow-up ..................................................................................43
5.5.12
Emergency breaking of assigned treatment code..................................43
5.5.13
Study completion and post-study treatment..........................................43
5.5.14
Early study termination.........................................................................44
6
Visit schedule and assessments .........................................................................................44
6.1
Information to be collected on screening failures..................................................50
6.2
Patient demographics/other baseline characteristics .............................................50
6.2.1
Demographics .......................................................................................50
6.2.2
PsA/Psoriasis history/ Prior psoriasis therapies ....................................50
6.2.3
Smoking history ....................................................................................50
6.2.4
Co-morbidities-Cardiovascular history.................................................50
6.2.5
Relevant medical history / Current medical conditions ........................50
6.2.6
Prior and concomitant medications.......................................................51
6.2.7
Chest X-ray ...........................................................................................51
6.2.8
Determination of tuberculosis status.....................................................51
6.3
Treatment exposure and compliance .....................................................................52
6.4
Efficacy..................................................................................................................52
6.4.1
American College of Rheumatology (ACR) response..........................53
6.4.2
Tender 78 joint count and swollen 76 joint count.................................54
6.4.3
Patient Reported Outcomes (PRO)/QoL Assessments .........................54
6.4.4
Physician’s global assessment of disease activity.................................57
6.4.5
High Sensitivity C-reactive protein (hsCRP)........................................57
6.4.6
Erythrocyte sedimentation rate (ESR) ..................................................57
58
6.4.8
DAS28 and EULAR response...............................................................58
6.4.9
Psoriatic Arthritis Disease Activity Score (PASDAS)..........................58
6.4.10
Minimal disease activity .......................................................................59
6.4.11
Dactylitis Assessments..........................................................................59


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6.4.12
Enthesitis Assessments..........................................................................59
60
6.4.14
Psoriasis Area and Severity Index (PASI) ............................................60
6.4.15
Investigator’s Global Assessment (IGA mod 2011) .............................62
62
6.4.17
Physician’s global assessment of fingernail disease severity (VAS)....64
64
6.4.19
Appropriateness of efficacy assessments..............................................64
6.5
Safety.....................................................................................................................65
6.5.1
Physical examination ............................................................................65
6.5.2
Vital signs..............................................................................................65
6.5.3
Height and weight .................................................................................66
6.5.4
Electrocardiogram (ECG) .....................................................................66
6.5.5
Laboratory evaluations..........................................................................66
6.5.6
Pregnancy and assessments of fertility .................................................67
6.5.7
Tolerability of secukinumab .................................................................67
6.5.8
Additional parameters ...........................................................................67
6.5.9
Appropriateness of safety measurements..............................................67
7
Safety monitoring ..............................................................................................................67
7.1
Adverse events.......................................................................................................67
7.2
Serious adverse events...........................................................................................69
7.2.1
Definition of SAE .................................................................................69
7.2.2
SAE reporting........................................................................................70
7.3
Liver safety monitoring .........................................................................................70
7.4
Pregnancy reporting...............................................................................................71
8
Data review and database management.............................................................................71
8.1
Site monitoring ......................................................................................................71
8.2
Data collection.......................................................................................................71
8.3
Database management and quality control............................................................72
8.4
Data Monitoring Committee..................................................................................72
8.5
Adjudication Committee........................................................................................72
9
Data analysis......................................................................................................................72
9.1
Analysis sets ..........................................................................................................73
9.2
Patient demographics and other baseline characteristics.......................................73
9.3
Treatments .............................................................................................................73
9.4
Analysis of the primary variable............................................................................73


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9.4.1
Variable.................................................................................................73
9.4.2
Statistical model, hypothesis, and method of analysis..........................74
9.4.3
Handling of missing values/censoring/discontinuations.......................74
9.4.4
Supportive analyses...............................................................................74
9.5
Analysis of secondary variables ............................................................................74
9.5.1
Efficacy variables..................................................................................74
9.5.2
Safety variables .....................................................................................76
9.6
Interim analyses .....................................................................................................77
9.7
Sample size calculation..........................................................................................77
10 Ethical considerations........................................................................................................77
10.1
Regulatory and ethical compliance........................................................................77
10.2
Informed consent procedures.................................................................................77
10.3
Responsibilities of the investigator and IRB/IEC..................................................78
10.4
Publication of study protocol and results...............................................................78
11 Protocol adherence ............................................................................................................78
11.1
Protocol Amendments ...........................................................................................79
12 References .........................................................................................................................79
12.1
Appendix 1: Clinically notable laboratory values and vital signs .........................81
12.2
Appendix 2: The classification criteria for psoriatic arthritis (CASPAR).............82
83
12.4
Appendix 4: American College of Rheumatology (ACR) Measures and 
Criteria of Response ..............................................................................................83
12.5
Appendix 5: Disease Activity Score (DAS) ..........................................................84
12.6
Appendix 6: The Psoriasis Area and Severity Index (PASI).................................87
87
12.8
Appendix 8: Health Assessment Questionnaire (HAQ) ........................................89
 
91
12.10 Appendix 10: Guidelines for administering the PRO questionnaires....................92
List of tables
Table 5-1
Prohibited medication ...........................................................................41
Table 6-1
Assessment schedule.............................................................................46
Table 6-2
The PASI scoring system ......................................................................61
Table 6-3
The IGA mod 2011 rating scale............................................................62
Table 6-4
Score for percent of nail with onycholysis or oil-drop dyschromia......63


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Table 6-5
Score for number of pits........................................................................63
Table 6-6
Score for percent of nail with crumbling present..................................64
List of figures
Figure 3-1
Study design..........................................................................................27


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List of abbreviations
ACR
American College of Rheumatology
AE
Adverse event
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
ANCOVA
analysis of covariance
Anti-CCP
Anti-cyclic citrullinated peptide
AS
Ankylosing Spondylitis
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
BSA
Body Surface Area
BL
Baseline
CASPAR
Classification criteria for Psoriatic Arthritis
CRF
Case Report/Record Form (paper or electronic)
CRP
C-reactive protein
CTC
Common Toxicity Criteria
DAS
Disease Activity Score
DLQI
Dermatology Life Quality Index
DMARD
Disease Modifying Anti-rheumatic Drug
DS&E
Drug Safety & Epidemiology
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA/EMEA
European Medicines (Evaluation) Agency
ESR
Erythrocyte Sedimentation Rate
EULAR
European League Against Rheumatism
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAQ-DI©
Health Assessment Questionnaire – Disability Index
HRQoL
Health-related Quality of Life
hsCRP
High sensitivity C-Reactive Protein
IEC
Independent Ethics Committee
IGA mod 2011
Investigator’s Global Assessment modified 2011
IL
Interleukin
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra Uterine Device
IUS
Intra Uterine System
i.v.
intravenous(ly)
LFT
Liver function test


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LOCF
last-observation-carried-forward
MCS
Mental Component Summary
MDA
Minimal Disease Activity
MedDRA
Medical dictionary for regulatory activities
mmHg
Millimeter mercury
MTX
Methotrexate
NSAID
Non-steroidal anti-inflammatory drug
PASDAS
Psoriatic Arthritis Disease Activity Score
PASI
Psoriasis Area and Severity Index
PBO
Placebo
PCS
Physical Component Summary
PFS
Prefilled syringe
PK/PD
Pharmacokinetic/Pharmacodynamic
PoC
Proof of Concept
PPD
Purified protein derivative
PRN
Pro re nata (as required)
PRO
Patient Reported Outcome
PsA
Psoriatic arthritis
QoL
Quality of Life
RBC
Red blood cell
RF
Rheumatoid factor
SAE
Serious adverse event
s.c.
Subcutaneous(ly)
SCR
Screening
SF-12
Medical Outcome Short Form (12) Health Survey
SJC
Swollen Joint Count
SpA
Spondyloarthritis
SUSAR
Suspected Unexpected Serious Adverse Reactions
TJC
Tender Joint Count
TNF
Tumor necrosis factor
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
White blood cell
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort 
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the trial
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
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 protocol-
specified concomitant background therapies  when these are 
standard treatments in that indication
Medication number
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system
Protocol
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial.
Premature subject withdrawal
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
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
Subject Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study


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Amendment 2
Rationale for Amendment
The purpose for Amendment 2 is to update Table 6-1 (Assessment Schedule) to include the 
visits at which the Enthesitis Evaluation must be done.
Amendment 1 
Rationale for Amendment
The purpose for Amendment 1 is to update the following Sections and Tables.

Section 4.1: Inclusion criteria number four (4) was updated to justify the need for a 
baseline skin scoring accordingly.  Therefore, it was reworded to: a target psoriatic skin 
lesion and a PASI score of 1 or greater. 

Section 5.2: Patients will receive treatment up to Week 48 and no treatment will be 
administered at the EOT Visit/Week 52. 

Section 5.5.8 and Table 5.1: The table was rearranged to clarify that no biologics are 
allowed in the study. This is to prevent any further confusion that was observed since the 
study launched.

Section 6: Previous version required a 4 week waiting time even for those patients who 
are treatment naïve, and do not need a washout or repeat assessments. The related section 
of FUTURE 5 global protocol is adapted to prevent a 4 week waiting period for those 
patients. Screening will now be more flexible in duration up to 8 weeks prior to 
randomization based on the time required to wash out prior anti-rheumatic medications.  
Patients that do not require a washout can proceed onto the baseline visit once all 
inclusion criteria and none of the exclusion criteria are met.  

Section 6.4.2: Was updated to remove the Independent Joint Assessor requirement.  This 
is the first study evaluating various typical findings for PsA such as TJC, SJC, PASI, IGA, 
enthesitis, dactylitis 
. Therefore, it is unlikely for the site personnel to have 
independent assessors for each evaluation. In order to best reflect the current standard of 
practice, it is per the Investigator’s discretion to decide who will be performing the 
evaluations.


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
Section 6.4.6: Updated to emphasize the importance that the Erythrocyte Sedimentation 
Rate test must be performed locally.

Section 6.5.6: Updated to include that a serum β-hCG test will be performed in all women 
of child bearing potential at Screening Visit 2; and a local urine pregnancy tests will be 
performed at the specified visits as indicated in Table 6-1.

Appendix 12.10: The PROs Guidelines for the SitePad have been updated.


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Protocol summary
Protocol number
CAIN457FUS01
Title
A randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study to evaluate the safety and efficacy of secukinumab 300 
mg and 150 mg in adult patients with active psoriatic arthritis after 16 
weeks of treatment compared to placebo and to assess the safety, 
tolerability and efficacy up to 52 weeks
Brief title
Study to evaluate the safety and efficacy of Cosentyx® (secukinumab) 
300 mg and 150 mg in adult patients with active psoriatic arthritis (PsA) 
after 16 weeks of treatment compared to placebo 
Sponsor and Clinical 
Phase
Novartis / Phase IV
Investigation type
Drug: Biological
Study type
Interventional
Purpose and rationale
The purpose of this study is to provide 16 week safety, efficacy and 
tolerability data in adult biologic naïve PsA patients with target skin 
lesions and evaluate the effect of secukinumab on PsA specific clinical 
findings such as dactylitis, enthesitis and psoriatic lesions. The study will 
also evaluate the early efficacy of the treatment at the first scheduled 
clinical visit after starting a treatment (i.e., at Week 4) and long term 
safety and efficacy up to 52 weeks
Primary Objective(s) 
To demonstrate that the efficacy of secukinumab 300 mg at Week 16 is 
superior to placebo in adult patients with active PsA based on the 
proportion of patients achieving an American College of Rheumatology 
20 (ACR20) response.
Secondary Objectives
To evaluate: 

The efficacy of secukinumab 150 mg compared to placebo at 
Week 16 in patients with active PsA based on the proportion of 
patients achieving an American College of Rheumatology 20 
(ACR20) response.

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the proportion of patients with 
dactylitis in the subset of patients who have dactylitis at baseline.

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the proportion of patients with 
enthesitis in the subset of patients who have enthesitis at 
baseline.

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 in subset of patients with active PsA and 
number of tender and swollen joints less than 10 at baseline 
based on the proportion of patients achieving ACR20, ACR50, 
and ACR70 responses

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the proportion of patients 
achieving ACR50 and ACR70 responses.

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the proportion of patients 
achieving Minimal Disease Activity (5 of the following 7 criteria: 
≤1 tender joint, ≤1 swollen joint, PASI ≤1 or IGA mod 2011 ≤1, 


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patient assessment of pain (0-100 Visual Analog Scale (VAS)) 
≤15, patient global assessment of disease (VAS) ≤20, HAQ-DI 
≤0.5, tender entheseal points ≤1).

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the proportion of patients 
achieving a PASI75, PASI90, and PASI100 responses 

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the change from baseline in 
DAS28-CRP. 

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the change from baseline in 
Psoriatic Arthritis Disease Activity Score (PASDAS). 

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the change from baseline in SF12.

The efficacy of secukinumab 300 mg and 150 mg compared to 
placebo at Week 16 based on the change from baseline in HAQ-
DI. 

The overall safety and tolerability of secukinumab 300 mg and 
150 mg  compared with placebo as assessed by vital signs, 
clinical laboratory values, and adverse events (AE) monitoring.
Study design
This study uses a multicenter, randomized, double-blind, placebo-
controlled, parallel-group design. Approximately 250 adult patients (in 
2:2:1 ratio; 100 secukinumab 300 mg, 100 secukinumab 150 mg and  50 
placebo) with active PsA and a target skin lesion and a PASI score of 1 
or greater will be randomized from approximately 65 investigative sites in 
the United States. 
Screening will be flexible in duration based on the time required to wash 
out prior anti-rheumatic medications and have a duration of up to 8 weeks 
before randomization, followed by a treatment period up to Week 52.
Patients that do not require a washout can proceed onto the 
baseline visit once all inclusion criteria and none of the exclusion 
criteria are met.
At baseline (BL), patients whose eligibility is confirmed will be 
randomized to one of three treatment groups and will enter the Placebo 
Controlled Treatment Period.
Treatment Period 1
Treatment Period 1 is defined as the period from Randomization
through Week 16 (prior to the Week 16 dose). At the start of Treatment 
Period 1, patients will be randomized via IRT in a 2:2:1 ratio to one of
three treatment groups.

Group 1- Secukinumab 300 mg: secukinumab 300 mg (two s.c.
injections of the 150 mg dose) once weekly for five weeks (at
Baseline, Weeks 1, 2, 3, and 4), followed by dosing every four
weeks.

Group 2- Secukinumab 150 mg: secukinumab 150 mg (one s.c.
injection of the 150 mg dose and one s.c. injection of placebo)
once weekly for five weeks (at Baseline, Weeks 1, 2, 3, and 


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4), followed by dosing every four weeks.

Group 3- Placebo: placebo (t w o  s.c. injection of 150 mg 
secukinumab placebo per dose) once per week for five
weeks (at Baseline, Weeks 1, 2, 3, and 4), followed by dosing
every four weeks.
At each study treatment visit two s.c. injections in the form of PFS will be 
administered. This is necessary to maintain the blind, as secukinumab in 
PFS is available in either 1.0 mL (150 mg) or 2 x 1.0 mL (300mg). 
Placebo to secukinumab is also available in 1.0 mL to match the active 
drug.
Rescue medication is not allowed until Week 16.
Treatment Period 2

Patients receiving secukinumab 300 mg (Group 1) will continue 
to receive the same dose up to Week 48.

At Weeks 16, 28 and 40 patients on secukinumab 150 mg 
(Group 2) will be classified as responders (≥ 20% improvement 
from BL in both tender and swollen joint counts) or non-
responders.

At Weeks 16, 28 and 40 patients on secukinumab 150 
mg (Group 2) who are responders will continue to 
receive secukinumab 150 mg (1.0 mL) plus placebo (1.0 
mL) every 4 weeks until next evaluation of responder 
status at weeks 28 or 40. 

Patients who did not meet the responder criteria at Week 
16, 28 or 40 will start receiving secukinumab 300 mg s.c. 
every 4 weeks and will continue this dose up to Week 48.

Patients on placebo (Group 3) regardless of their responder 
status will start receiving secukinumab 300 mg s.c. every 4 
weeks from Week 16 up to Week 48.
Population
The study population will be comprised of approximately 250 patients 
who have passed screening assessments, comply with eligibility criteria 
and have provided written consent.

Male and female patients aged at minimum 18 at time of consent, 
with active PsA fulfilling the CASPAR criteria. 

Patients must have symptoms for at least 6 months with 
moderate to severe PsA and must have ≥3 tender joints out of 78 
and ≥3 swollen joints out of 76 at BL (dactylitis of a digit counts 
as one joint each).

Patients must have a target skin lesion and a PASI score of 1 or 
greater.

Patients must report active disease despite current or previous 
NSAIDs and / or DMARDs. Concomitant therapy with MTX (≤25 
mg/week) will be acceptable, if dose and route of administration 
have been stable for at least four weeks prior to the 


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randomization visit.

Patients can be re-screened only once and re-screening study
related procedures should not be performed prior to written re-
consent by the subject. Mis-randomized Patients or discontinued 
patients cannot be re-screened.

Enrollment will stop as soon as the target number of randomized 
patients is reached.
Inclusion criteria
1.
Patient 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.
Male or non-pregnant, non-lactating female patients at least 18 
years of age
3.
Diagnosis of PsA classified by CASPAR criteria and with 
symptoms for at least 6 months with moderate to severe PsA 
who must have had at Baseline ≥3 tender joints out of 78 and 
≥3 swollen joints out of 76 (dactylitis of a digit counts as one joint 
each)
4.
A target skin psoriatic lesion and a PASI score of 1 or greater
5.
RF and/or Anti-cyclic citrullinated peptide (antiCCP) antibodies
            negative at screening
6.
Patients who are regularly taking NSAIDs as part of their PsA 
therapy are required to be on a stable dose for at least 2 weeks 
before study randomization and should remain on a stable dose 
up to Week 16
7.
Patients taking corticosteroids should be on a stable dose of ≤10 
mg/day prednisone or equivalent for at least 2 weeks before 
randomization and must remain on a stable dose up to Week 16
8.
Patients taking MTX (≤ 25 mg/week) are allowed to continue their 
medication if the dose is stable for at least 4 weeks before 
randomization and must remain on a stable dose up to study 
completion 
9.
Patients on MTX must be on folic acid supplementation at 
randomization
10. Patients who are on a DMARD other than MTX must discontinue 
the DMARD 4 weeks prior to randomization visit except for 
leflunomide, which should be discontinued for 8 weeks prior to 
randomization unless a cholestyramine washout has been 
performed 
Exclusion criteria
1.
Chest X-ray or chest MRI with evidence of ongoing infectious or 
malignant process, obtained within 3 months prior to screening 
and evaluated by a qualified physician 
2.
Previous exposure to secukinumab or other biologic drug directly 
targeting IL-17 or IL-17 receptor
3.
Use of any investigational drug and/or devices within 4 weeks 
before randomization or a period of 5 half-lives of the 
investigational drug, whichever was longer
4.
Ongoing use of prohibited psoriasis treatments / medications 
(e.g., topical corticosteroids, ultraviolet therapy) at randomization. 
The following wash out periods need to be observed:


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
Oral or topical retinoids 4 weeks

Photochemotherapy (e.g. Psoralen Plus Ultraviolet Light 
Therapy (PUVA)) 4 weeks

Phototherapy (UVA or UVB) 2 weeks 

Topical skin treatments (except on face, eyes, scalp and 
genital area during screening, only corticosteroids with 
mild to moderate potency) 2 weeks
5.
History of hypersensitivity to the study drug or its excipient or to 
drugs of similar chemical classes
6.
Any intramuscular or intravenous corticosteroid treatment within 
4 weeks before randomization
7.
Any therapy by intra-articular injections (e.g. corticosteroid) within 
4 weeks before randomization
8.
Patients who ever received biologic immunomodulating agents 
including those targeting TNFα,  IL-6 and IL-12/23 investigational 
or approved
9.
Previous treatment with any cell-depleting therapies including but 
not limited to anti-CD20, investigational agents (e.g., 
alemtuzumab, anti-CD4, anti-CD5, anti-CD3, anti-CD19)
10. Pregnant or nursing (lactating) women, where pregnancy is 
defined as the state of a female after conception and until the 
termination of gestation, confirmed by a positive human chorionic 
gonadotropin (hCG) laboratory test 
11. Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are 
using effective methods of contraception during the entire study 
or longer if required by locally approved prescribing information. 
Effective contraception is defined in the Exclusion Criteria in 
Section 4.2. 
12. Active ongoing inflammatory diseases other than PsA that might 
confound the evaluation of the benefit of secukinumab therapy
13. Underlying metabolic, hematologic, renal, hepatic, pulmonary, 
neurologic, endocrine, cardiac, infectious or gastrointestinal 
conditions which in the opinion of the investigator 
immunocompromises the patient and/or places
the patient at unacceptable risk for participation in an 
immunomodulatory therapy
14. Significant medical problems or diseases, including but not 
limited to the following: uncontrolled hypertension (≥160/95 
mmHg), congestive heart failure [New York Heart Association 
status of class III or IV], uncontrolled diabetes
15. History of clinically significant liver disease or liver injury as 
indicated by abnormal liver function tests such as SGOT (AST), 
SGPT (ALT), alkaline phosphatase, or serum bilirubin. The 
investigator should be guided by the following criteria:
Any single parameter should not exceed 2 × upper limit of normal 
(ULN). 
a.
A single parameter elevated up to and including 2 × ULN should 
be re-checked once more as soon as possible, and in all cases, 
at least prior to enrollment/randomization, to rule out lab error
b.
If the total bilirubin concentration is increased above 2 × ULN, 


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total bilirubin should be differentiated into the direct and indirect 
reacting bilirubin. In any case, serum bilirubin should not exceed 
the value of 1.6 mg/dL (27 µmol/L)
16. History of renal trauma, glomerulonephritis, or patients with one 
kidney only, or a serum creatinine level exceeding 1.5 mg/dL 
(132.6µmol/L)
17. Screening total White Blood Cells (WBC) count <3,000/µL, or 
platelets <100,000/µL or neutrophils 1,500/µL or hemoglobin 
<8.5 g/dL (85g/L)
18. Active systemic infections during the last two weeks (exception: 
common cold) prior to randomization
19. History of ongoing, chronic or recurrent infectious disease or 
evidence of tuberculosis infection as defined by either a positive 
Purified protein derivative (PPD) skin test (the size of induration 
will be measured after 48-72 hours, and a positive result is 
defined as an induration of ≥5mm or according to local 
practice/guidelines) or a positive QuantiFERON tuberculosis 
(TB)-Gold test as indicated in the assessment schedule. Patients 
with a positive test may participate in the study if further work-up 
(according to local practice/guidelines) established conclusively 
that the subject had no evidence of active tuberculosis. If 
presence of latent tuberculosis is established then treatment 
according to local country guidelines must have been initiated
20. Known infection with human immunodeficiency virus, hepatitis B 
or hepatitis C at screening or randomization
21. History of lymphoproliferative disease or any known malignancy 
or history of malignancy of any organ system within the past 5 
years (except for basal cell carcinoma or actinic keratoses that 
have been treated with no evidence of recurrence in the past 3 
months, carcinoma in situ of the cervix or non-invasive malignant 
colon polyps that have been removed)
22. Current severe progressive or uncontrolled disease which in the 
judgment of the clinical investigator renders the patient 
unsuitable for the trial
23. Inability or unwillingness to undergo repeated venipuncture (e.g., 
because of poor tolerability or lack of access to veins) 
24. Any medical or psychiatric condition which, in the investigator’s 
opinion, precludes the participant from adhering to the protocol or 
completing the study per protocol
25. Donation or loss of 400 mL or more of blood within 8 weeks 
before randomization
26. History or evidence of ongoing alcohol or drug abuse, within the 
last six months before randomization
27. Plans for administration of live vaccines during the study period 
or within 6 weeks preceding randomization
Investigational and 
reference therapy
Treatment Period 1

Group 1- Secukinumab 300 mg: secukinumab 300 mg (two s.c.
injections of the 150 mg dose) once weekly for five weeks (at
Baseline, Weeks 1, 2, 3, and 4), followed by dosing every four
weeks. 


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
Group 2- Secukinumab 150 mg: secukinumab 150 mg (one s.c.
injection of the 150 mg dose and one s.c. injection of placebo)
once weekly for five weeks (at Baseline, Weeks 1, 2, 3, and 
4), followed by dosing every four weeks. 

Group 3- Placebo: placebo (t w o  s.c. injection of 150 mg 
secukinumab placebo per dose) once per week for five
weeks (at Baseline, Weeks 1, 2, 3, and 4), followed by dosing
every four weeks. 
Treatment Period 2

Patients receiving secukinumab 300 mg (Group 1) will continue 
to receive the same dose up to Week 48.

At Weeks 16, 28 and 40 patients on secukinumab 150 mg 
(Group 2) will be classified as responders (≥ 20% improvement 
from BL in both tender and swollen joint counts) or non-
responders.

At Weeks 16, 28 and 40 patients on secukinumab 150 
mg (Group 2) who are responders will continue to 
receive secukinumab 150 mg (1.0 mL) plus placebo (1.0 
mL) every 4 weeks until next evaluation of responder 
status at Weeks 28 or 40. 

Patients who did not meet the responder criteria at Week 
16, 28 or 40 will start receiving secukinumab 300 mg s.c. 
every 4 weeks and will continue this dose up to Week 48.

Patients on placebo (Group 3) regardless of their responder 
status will start receiving secukinumab 300 mg s.c. every 4 
weeks from Week 16 up to Week 48.
Efficacy assessments

ACR20, ACR50, ACR70 responses 

Tender 78  joint count and swollen 76 joint count

 

Patient’s Assessment of PsA pain intensity

Patient’s global assessment of disease activity (VAS)

Health Assessment Questionnaire (HAQ-DI)

SF-12 
 
 
 

Physician’s global assessment of disease activity (VAS)

High Sensitivity C-reactive protein (hsCRP)

Erythrocyte sedimentation rate (ESR) 

PASI 

DAS28 and EULAR

PASDAS

Minimal Disease Activity


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
IGA mod 2011 

Physician’s assessment of nail disease (VAS)
Safety assessments

Evaluation of AE/SAE’s

Physical examination

Vital signs

Height and weight

QuantiFERON TB-Gold test or PPD skin test

Electrocardiogram

Local tolerability (Injection site reactions)

Laboratory evaluations (Hematology, Clinical Chemistry, Lipid 
Panel, Urinalysis)

Pregnancy and assessment of fertility

Tolerability of secukinumab
Other assessments
Quality of Life questionnaires/ Patient reported outcomes (PROs)
Data analysis
A designated Contract Research Organization will perform the statistical 
analysis.
Unless otherwise specified, all statistical tests will be conducted against a 
two-sided alternative hypothesis, employing a significance level of 0.05.
The following analysis sets will be used for the statistical reporting and 
analyses:
Randomized Set: The Randomized Set includes all randomized patients.  
Safety Set: The Safety Set includes all patients who received at least one 
dose of study medication.  Patients will be included in the analysis 
according to treatment received.
Full Analysis Set:  The Full Analysis Set comprises all patients to whom 
study medication has been assigned.  Patients inappropriately 
randomized (e.g., IRT was called in error for randomization of a screen 
failed subject) will be excluded from this analysis set. 
Data will be summarized with respect to demographic and baseline 
characteristics of all patients, the subgroup of patients with dactylitis at 
baseline, and the subgroup of patients with enthesitis at baseline, for the 
Randomized Set and the Full Analysis Set.
Efficacy, safety, and other data will be summarized.
The primary efficacy variable is ACR20 response (yes, no). The primary 
analysis time point will be at Week 16.
The primary efficacy variable will be analyzed at each time point using a 
logistic regression model with treatment (3 treatment groups), 
methotrexate usage at baseline (yes, no), and body weight as 
explanatory variables (Stokes, Davis, and Koch, 2012).  The odds ratios 
for each dose of secukinumab versus placebo, 95% confidence intervals 
for the odds ratios, and p-values based on the fitted model will be 
reported.  
  
The primary analysis of the primary efficacy variable will be based on the 


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Full Analysis Set. 
Patients who discontinued prematurely for any reason will be considered 
non-responders from the time they discontinued.  Patients who do not 
have the required data to compute ACR response (i.e., tender and 
swollen joint counts and at least three of the five ACR domains) at 
baseline and at the specific time point will be classified as non-
responders.
The primary efficacy variable will also be analyzed at each time point for 
the Full Analysis Set using the Cochran-Mantel-Haenszel (CMH) test to 
compare each dose of secukinumab against placebo, adjusting for 
methotrexate usage at baseline (yes, no) (Stokes, Davis, and Koch, 
2012).  Two 95% confidence intervals for the difference between each 
dose of secukinumab versus placebo in the proportion of patients who 
are ACR20 responders will be calculated using the normal approximation 
to the binomial distribution.  
The secondary efficacy variables are the following:
1.
Dactylitis (yes, no)
2.
Enthesitis (yes, no)
3.
ACR50 response (yes, no)
4.
ACR70 response (yes, no)
5.
Minimal Disease Activity (yes, no)
6.
PASI75 response (yes, no)
7.
PASI90 response (yes, no)
8.
PASI100 (yes, no)
9.
Change from baseline in DAS28-CRP
10. Change from baseline in PASDAS
11. Change from baseline in SF12
12. Change from baseline in HAQ-DI
Two analyses of dactylitis and enthesitis (secondary efficacy variables 1 
and 2) will be performed at each time point.  For the first analysis, the 
data for the subgroup of patients who have dactylitis at baseline will be 
used (similarly for enthesitis) and the analysis of the binary response 
variable (yes, no) will be similar to the analysis of secondary efficacy 
variables 3-8 below.  In the supporting analysis, the data for all patients 
will be used and an ordinal variable will be created based on presence 
(yes) or absence (no) of dactylitis at baseline and a post-baseline visit 
(similarly for enthesitis).  The three categories for the ordinal variable will 
be no/no (category 1), no/yes and yes/no (category 2), and yes/yes 
(category 3).  This ordinal response variable will be analyzed using a 
proportional odds regression model with treatment (3 treatment groups), 
methotrexate usage at baseline (yes, no), and body weight as 
explanatory variables (Stokes, Davis, and Koch, 2012).  
Secondary efficacy variables 3-8 will be analyzed at each time point 
using a logistic regression model with treatment (3 treatment groups), 
methotrexate usage at baseline (yes, no), and body weight as 
explanatory variables (Stokes, Davis, and Koch, 2012).  
Secondary efficacy variables 9-12 will be analyzed at each time point by 


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an analysis of covariance (ANCOVA) model with treatment (3 treatment 
groups), baseline, methotrexate usage at baseline (yes, no), and body 
weight as explanatory variables.    Missing data will be imputed using the 
last-observation-carried-forward (LOCF) method.
  
Analyses of the secondary efficacy variables will be based on the Full 
Analysis Set.
The assessment of safety will be based mainly on the frequency of 
adverse events and laboratory data. Other safety data (e.g., vital signs 
and special tests) will be considered, as appropriate.
Analysis of safety data will be based on the Safety Set.
The sample size was calculated based on the primary efficacy variable 
(i.e., ACR20 response) for the primary comparison (i.e., secukinumab 
300 mg versus placebo).  ACR20 response rates of 50% for 
secukinumab 300 mg and 20% for placebo (corresponding to an odds 
ratio of 4) at Week 16 were assumed, based on results from 
AIN457F2312 (FUTURE 2) study.  Using a continuity-corrected chi-
squared test, an allocation ratio of 2:1, a two-sided significance level of 
0.05, and a power of 0.90, approximately 88 patients in secukinumab 300 
mg group and 44 patients in placebo group will be needed (nQuery 
Advisor 7.0).  Assuming a loss to follow-up rate of 10% and a 2:2:1 
allocation ratio (secukinumab 300 mg: secukinumab 150 mg: placebo), 
the total number of randomized patients will be approximately 250 (100 
on secukinumab 300 mg, 100 on secukinumab 150 mg, and 50 on 
placebo).
Key words
Active Psoriatic Arthritis, Subcutaneous secukinumab in prefilled syringes 
(PFS) , CASPAR


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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 spondyloarthritidies (SpA). While the 
various SpA may be diverse in their clinical presentations, common environmental as well as 
genetic factors associated with susceptibility to SpA are suspected (Turkiewicz and Moreland 
2007). This latter notion was corroborated by findings in a large-scale single nucleotide 
polymorphism scan study, where interleukin (IL)-23R variants that were previously linked to 
Crohn’s disease and psoriasis (diseases that may both co-exist with SpA) conferred risk to 
developing ankylosing spondylitis (AS) (Barrett et al 2008). Together, a common pathway,
including the IL-23/IL-17 axis, may play a role in seronegative SpAs, including PsA.
PsA is a frequent and chronic immune-mediated disease encompassing a spectrum of 
overlapping clinical entities (Moll and Wright 1973). Up to 40% of patients with psoriasis 
will develop PsA, which is both more common and more severe than previously believed
(Taylor et al 2006). PsA is also associated with significant morbidity and disability, and 
constitutes a major socioeconomic burden. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) may improve symptoms in patients with 
mild PsA, but can worsen skin disease and be associated with an increased risk of 
cardiovascular side effects. Similarly, intra-articular injections of corticosteroids and low 
doses of systemic corticosteroids have been used with variable efficacy and significant side 
effects with chronic use.  Disease-modifying anti-rheumatic drugs (DMARDs) are more 
typically used for PsA, and include methotrexate (MTX), sulfasalazine, cyclosporine, and 
leflunomide; however, these therapies may only partially control established disease (Mease 
2008; Mease and Armstrong 2014). Biologic agents such as the tumor necrosis factor (TNF) 
inhibitors adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab are 
approved in patients with PsA to reduce joint disease activity, prevent structural damage, and
improve function (Mease et al 2000, Mease et al 2005). However, TNF-inhibitor therapy may 
result in significant dose-limiting adverse effects, including the development of 
autoantibodies and the induction of a lupus-like syndrome.
Additional approved therapies for patients with PsA 
 
 Several lines of 
evidence support additional therapeutic pathways in PsA. Prominent T cell involvement 
occurs in the pathogenesis of PsA (Tassiulas et al 1999; Curran et al 2004; Mease and 
Armstrong 2014) and clinical trials have shown efficacy of T cell-targeted treatment that has 
included cyclosporine A, CTLA4-Ig, and alefacept. Despite available therapies for PsA, an 
unmet clinical need remains for agents that can be used singly or in combination with other 
therapies and provide effective short and long-term disease control especially on those PsA 
specific clinical findings such as dactylitis and enthesitis with favorable risk/benefit profiles.
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 helper T17 cell subset. Additional effects of anti-IL-17 on bone homoeostasis 


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via receptor activator of nuclear factor kappa-B ligand (RANKL) and IL-1, upstream of 
TNFα,, can be inferred from animal studies (Koenders et al 2005). Assuming a potential role 
of IL-17 cells in the inflammatory infiltrate in PsA, it can be speculated that locally dist urbed 
homeostasis of osteoclastogenic and osteoblastogenic mechanisms characteristic of PsA might 
be affected by IL-17 blockade, thus potentially providing a therapeutic advancement to 
effectively treat dactylitis and enthesitis 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 that is believed to be an important mediator of autoimmunity. Neutralization of IL-
17A has strong preclinical and clinical target validation. 
A proof-of-concept study conducted in patients with PsA (CAIN457A2206) suggesting a
clinically meaningful response for signs and symptoms up to Week 16. The efficacy of
secukinumab in PsA patients is further supported by positive results for signs and symptoms
(i.e. ACR20/50, PASI75/90), resolution of dactylitis, enthesitis and inhibition of radiologic
damage at Week 24 obtained in a phase III study (CAIN457F2306; N=606) employing an
intravenous (i.v.) loading regimen (3x10 mg/kg) of secukinumab Q2W followed by
secukinumab s.c. 75 mg or 150 mg administered Q4W. In another phase III study
(CAIN457F2312; N=397) secukinumab also demonstrated positive efficacy results superior to
placebo in patients with PsA through most components of the arthritic and skin measures of
signs and symptoms and physical function in a population comprised of 65% naïve to TNF -α
inhibitors and 35% patients who were inadequate responders to a TNF-α inhibitor. Based on 
the results of these phase 3 trials, secukinumab received FDA approval in January 2016 for 
the treatment of active PsA and AS in adult patients. Therefore, treatment with secukinumab 
may result in improvement of symptoms and functional joint manifestations in afflicted
patients.
The completed studies of secukinumab recruited both biologic exposed or naïve PsA patients 
with or without psoriatic skin lesions at baseline. Therefore a need for predefined prospective 
data exist for these different subgroups of patients which the precise effects of targeting IL-
17A can be observed more clearly.  The present study will evaluate the safety and efficacy of 
treatment with two doses of secukinumab compared with placebo in patients with active 
psoriatic arthritis and concomitant psoriasis who are naïve to biologic medications including 
tumor necrosis factor alpha (TNFα), IL-6 and IL-12/23 inhibitors. Also in the blinded long 
term extension period of this study, the effect of increasing the dose in non-responders after 
each evaluation every 12 weeks visit will provide valuable information regarding the 
correlation between the level of disease activity and IL-17A inhibition.
1.2
Purpose 
The purpose of this study is to provide 16 week safety, efficacy and tolerability data in 
biologic naïve PsA patients with concomitant psoriatic skin lesions and evaluate the effect of 
secukinumab on PsA specific clinical findings such as dactylitis, enthesitis and psoriatic 
lesions. The study will also evaluate the early efficacy of the treatment at the first scheduled 
clinical visit after starting a treatment (i.e., at week 4) and investigate the remission status of 
all patients at each time points by evaluating the MDA, PASDAS and DAS28-CRP. This will 
be done in the blinded long term extension by increasing the dose to 300 mg in nonresponding 


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patients in 150 mg groups to confirm or support the role of higher IL-17A activity in PsA by 
evaluating the clinical response at every 12 weeks.
2
Study objectives 
2.1
Primary objective(s)
To demonstrate that the efficacy of secukinumab 300 mg at Week 16 is superior to placebo in 
patients with active PsA based on the proportion of patients achieving an American College of 
Rheumatology 20 (ACR20) response.
2.2
Secondary objectives
To evaluate:

The efficacy of secukinumab 150 mg compared to placebo at Week 16 in patients with 
active PsA based on the proportion of patients achieving an American College of 
Rheumatology 20 (ACR20) response.

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the proportion of patients with dactylitis in the subset of patients who have dactylitis at 
baseline.

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the proportion of patients with enthesitis in the subset of patients who have enthesitis at 
baseline.

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 in 
subset of patients with active PsA and number of tender and swollen joints less than 10 at 
baseline based on the proportion of patients achieving ACR20, ACR50, and ACR70 
responses

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the proportion of patients achieving ACR50 and ACR70 responses.

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the proportion of patients achieving Minimal Disease Activity (5 of the following 7 
criteria: ≤1 tender joint, ≤1 swollen joint, PASI ≤1 or IGA mod 2011 ≤1, patient 
assessment of pain (0-100 Visual Analog Scale (VAS)) ≤15, patient global assessment of 
disease (VAS) ≤20, HAQ-DI ≤0.5, tender entheseal points ≤1).

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the proportion of patients achieving a PASI75, PASI90, and PASI100 responses 

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the change from baseline in DAS28-CRP. 

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the change from baseline in Psoriatic Arthritis Disease Activity Score (PASDAS). 

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the change from baseline in SF12.

The efficacy of secukinumab 300 mg and 150 mg compared to placebo at Week 16 based 
on the change from baseline in HAQ-DI. 


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
The overall safety and tolerability of secukinumab 300 mg and 150 mg  compared with 
placebo as assessed by vital signs, clinical laboratory values, and adverse events (AE) 
monitoring.
3
Investigational plan
3.1
Study design
This study uses a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
design. Approximately 250 adult patients (in 2:2:1 ratio; 100 secukinumab 300 mg, 100 
secukinumab 150 mg and  50 placebo) with active PsA and a target skin lesion with PASI 
score of 1 or greater will be randomized from approximately 65 investigative sites in the 
United States. 
Screening will be flexible in duration based on the time required to wash out prior anti -
rheumatic medications and have a duration of up to 8 weeks before randomization, followed 
by a treatment period up to Week 52.
Patients that do not require a washout can proceed onto the baseline visit once all 
inclusion criteria and none of the exclusion criteria are met.
At baseline (BL), patients whose eligibility is confirmed will be randomized to one of 
three treatment groups and will enter the Placebo Controlled Treatment Period
Treatment Period 1
The Treatment Period 1 is defined as starting from Randomization through Week 16 (prior
to the Week 16 dose). At the start of the Placebo-Controlled Treatment Period, patients will
be randomized via IRT in a 2:2:1 ratio to one of three treatment groups (secukinumab 300 mg 
s.c., secukinumab 150 mg s.c. or placebo s.c.).

Group 1- Secukinumab 300 mg: secukinumab 300 mg (two s.c. injections of the 150
mg dose) once weekly for five weeks (at Baseline, Weeks 1, 2, 3, and 4), followed
by dosing every four weeks. 


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
Group 2- Secukinumab 150 mg: secukinumab 150 mg (one s.c. injection of the 150
mg dose and one s.c. secukinumab injection of placebo) once weekly for five weeks
(at Baseline, Weeks 1, 2, 3, and 4), followed by dosing every four weeks.

Group 3- Placebo: placebo (two s.c. injection of 150 mg secukinumab 
placebo per dose) once per week for five weeks (at Baseline, Weeks 1, 2, 3, 
and 4), followed by dosing every four weeks. 
Treatment Period 2

Patients receiving secukinumab 300 mg (Group 1) will continue to receive the same dose 
up to Week 48.

At Weeks 16, 28 and 40 patients on secukinumab 150 mg (Group 2) will be classified as 
responders (≥ 20% improvement from BL in both tender and swollen joint counts) or non-
responders.

At Weeks 16, 28 and 40 patients on secukinumab 150 mg (Group 2) who are 
responders will continue to receive secukinumab 150 mg (1.0 mL) plus placebo (1.0 
mL) every 4 weeks until next evaluation of responder status at weeks 28 or 40. 

Patients who did not meet the responder criteria at Week 16, 28 or 40 will start 
receiving secukinumab 300 mg s.c. every 4 weeks and will continue this dose up to 
Week 48.

Patients on placebo (Group 3) regardless of their responder status will start receiving 
secukinumab 300 mg s.c. every 4 weeks from Week 16 up to Week 48.
Rescue medication will not be allowed during the day of the clinical visit and before 
completion of Week 16 assessments (Section 5.5.6). Although no subject will be restricted 
from receiving necessary rescue medications for lack of benefit or worsening of disease, 
patients will be discontinued from the study if rescued with prohibited biologics (as described 
in (Section 5.5.8) and should obtain end of study assessments at the earliest possible date, 
provided consent to do so has not been withdrawn.   


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Figure 3-1
Study design 
3.2
Rationale for study design
The double-blind, randomized, parallel-group placebo controlled design used in this study is 
aligned with Phase III trials of other biologics in this disease area and is in accordance with 
existing international guidelines. The treatment duration of the placebo group is kept to a 
minimum and the placebo group will be re-assigned to active treatment after Week 16 
(primary analysis time point). The blinding is maintained beyond Week 16 so as to ensure 
reliable efficacy and safety assessments. The regular assessments of disease activity ensures 
that patients 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. 
Long-term treatment data up to 52 weeks are being generated to explore secukinumab’s long-
term efficacy and safety in this population.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The dosing regimens in this study rely upon dose-efficacy relationships observed in a proof of 
concept (PoC) trial (CAIN457A2206) and two phase 3
trials (CAIN457F2306,
CAIN457F2312) in PsA, as described below. The PoC trial in PsA (CAIN457A2206)
suggested that after two i.v. secukinumab doses of 10 mg/kg given 3 weeks apart,
secukinumab demonstrated high efficacy, achieving an ACR20 response at Week 6 in 62% of
the TNF-naïve patients on secukinumab vs. 20% on placebo, and was well-tolerated (McInnes 
et al 2013). The phase 3 trials in PsA, CAIN457F2306 assessed the efficacy of both 75 mg 
and 150 mg s.c. maintenance doses (every 4 weeks) after loading regimens consisting of 3 i.v. 
doses of 10 mg/kg given at BL, Weeks 2 and 4, and CAIN457F2312 assessed the efficacy of 
75 mg, 150 mg and 300 mg s.c. maintenance doses (every 4 weeks) after loading regimens 
consisting of s.c. doses of 75 mg, 150 mg or 300 mg given at BL, Weeks 1, 2, and 3. Given
the similarity of the ACR20 response seen at the Week 24 primary analysis time point for the


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150 mg dose in each of these studies, regardless of whether the loading dosing was i.v.
(CAIN457F2306: 50.0% for 150 mg vs 17.3% for placebo) or s.c. (CAIN457F2312: 51.0%
for 150 mg vs 15.3% for placebo), 150 mg is a sufficient dose to provide clinically an d
statistically significant efficacy, whereas higher loading doses of secukinumab do not appear
to confer a greater response on the primary efficacy variable of ACR20 at Week 24. In Study
CAIN457F2312, PASI75 and PASI90 response was assessed in the subgroup of patients who
had ≥ 3% skin involvement with psoriasis at baseline. For both PASI75 and PASI90 response
rates, the difference to placebo at Week 24 was statistically significant for the secukinumab
150 mg and 300 mg doses (PASI75: 48.3%, p = 0.0006 and 63.4%, p < 0.0001; PASI90:
32.8%, p = 0.0029 and 48.8%, p = 0.0002, respectively). The percentage of responders
increased as secukinumab dose increased, with the secukinumab 300 mg dose demonstrating a
meaningful improvement over the secukinumab 150 mg dose (treatment differences between
secukinumab 300 mg and 150 mg for PASI75 and PASI90 were 15.1% and 16.0%,
respectively). Of note, the 75 mg s.c. loading (once weekly) followed by maintenance (once 
monthly) tested in CAIN457F2312 achieved a statistically significant but clinically lower 
effect size in ACR20 response of 29.3% and did not achieve statistically significant 
improvements in any of the efficacy variables tested in a pre-defined testing hierarchy, 
including PASI75, PASI90 DAS28 CRP, SF36 PCS, HAQ-DI©, ACR50, dactylitis and 
enthesitis.
This study is evaluating secukinumab 300 mg and 150 mg s.c. doses for the treatment of 
adults with active PsA and a baseline psoriatic skin lesions of PASI 1 and higher . As the 
phase 3 program suggested that patients with concomitant skin lesions may have more 
pronounced clinical benefits with 300 mg, all the placebo patients will receive secukinumab 
300 mg after the completion of placebo controlled period (Week 16). The non-responders in 
Group 2 (150 mg patients) will receive secukinumab 300 mg after the completion of Week 16 
as well as at every clinical visit until the completion of the study (Weeks 20, 24, 28, 32, 36, 40, 
44 and 48) based on their responder status.
Also in order to minimize the patient’s exposure to placebo, this study will utilize a 2:2:1 
randomization that only 1 out 5 patients will receive placebo for a duration of 16 weeks where 
the meaningful clinical differentiation is observed in the phase 3 FUTURE studies.
In summary, the secukinumab regimen in this study is based on data suggesting optimal 
efficacy in PsA and optimal safety and efficacy in the treatment of skin disease in patients 
with psoriasis.
3.4
Rationale for choice of comparator
A placebo arm is included in this study up to the primary analysis time point at Week 16. Due 
to the nature of the disease and the outcome measures used (ACR criteria) a placebo arm is 
necessary to obtain reliable efficacy measurements. The continuation of the placebo group up 
to the primary analysis time point at Week 16 can be supported from an ethical standpoint. 
Moreover the inclusion of a placebo group is in accordance with health authority guidelines, 
including (FDA 1999/EMA 2009). The parallel-group placebo controlled design used in this 
study is aligned with Phase III trials of other biologics in this disease area and is in 
accordance with international guidelines. The treatment duration of the placebo group is kept 
to a minimum and the placebo group will be re-assigned to active treatment at the end of 


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Week 16. The regular assessment of disease activity ensures that patients 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. 
3.5
Purpose and timing of interim analyses/design adaptations
The database of this study will be locked twice, first after the end of Treatment Period 1
(Week 16) and again after the end of Treatment Period 2 (Week 52).  Data analyses will 
follow each database lock. The main analysis (or test) for the primary objective will be done 
at Week 16.  As Week 16 is the primary analysis time point, no adjustment to the significance 
level of 0.05 will be made.
3.6
Risks and benefits 
Secukinumab has shown confirmed efficacy in several inflammatory diseases and approved 
by the EMA and FDA for the treatment of active PsA and AS in adult patients. 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 (AE) 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 generally 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 individual risks as outlined above, the expected risk profile of 
secukinumab from a mechanism of action perspective is anticipated to be similar or
improved compared to the approved inflammatory cytokine-targeting therapies. The risk to
patients in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring and extensive guidance to the investigators, provided in the current
version of the IB. The completed FUTURE 1 and 2 trials confirmed the significant clinical 
benefits to secukinumab treatment in PsA patients observed as early as 1-3 weeks in all PsA 
related joint, skin and other symptoms such as dactylitis and enthesitis.
From the standpoint of the overall risk-benefit assessment, current trial with secukinumab is 
justified.


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4
Population
The study population will be comprised of the following patients who have passed screening 
assessments, comply with eligibility criteria and have provided written consent:
Male and female patients aged at minimum 18 at time of consent, with active PsA fulfilling 
the CASPAR criteria (described in Appendix 2). Patients must have symptoms for at least 6 
months with moderate to severe PsA and must have ≥3 tender joints out of 78 and ≥3 swollen 
joints out of 76 at baseline (dactylitis of a digit counts as one joint each).
Patients must have a target psoriatic skin lesion with a PASI score of 1 or greater at the time 
of screening.
A total of approximately 250
patients will be randomized in approximately 65 
rheumatology/dermatology centers in the United States. A screening failure rate of 
approximately 30% and post-randomization loss to follow-up rate of 10% is anticipated. 
Patients who drop out after they have been randomized will not be replaced. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Patient must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must give a written, signed and dated informed 
consent before any study assessment is performed
2. Male or non-pregnant, non-lactating female patients at least 18 years of age
3. Diagnosis of PsA classified by CASPAR criteria and with symptoms for at least 6 months 
with moderate to severe PsA who must have had at Baseline ≥3 tender joints out of 78 
and ≥3 swollen joints out of 76 (dactylitis of a digit counts as one joint each)
4. A target psoriatic skin lesion and a PASI score of 1 or greater
5. RF and/or Anti-cyclic citrullinated peptide (anti-CCP) antibodies negative at screening.
6. Patients who are regularly taking NSAIDs as part of their PsA therapy are required to be 
on a stable dose for at least 2 weeks before study randomization and should remain on a 
stable dose up to Week 16
7. Patients taking corticosteroids should be on a stable dose of ≤10 mg/day prednisone or 
equivalent for at least 2 weeks before randomization and must remain on a stable dose up 
to Week 16
8. Patients taking MTX (≤ 25 mg/week) are allowed to continue their medication if the dose 
is stable for at least 4 weeks before randomization and must remain on a stable dose up to 
study completion
9. Patients on MTX must be on folic acid supplementation at randomization
10. Patients who are on a DMARD other than MTX must discontinue the DMARD 4 weeks 
prior to randomization visit except for leflunomide, which should be discontinued for 
8 weeks prior to randomization unless a cholestyramine washout has been performed.


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4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process, 
obtained within 3 months prior to screening and evaluated by a qualified physician 
2. Previous exposure to secukinumab or other biologic drug directly targeting IL-17 or IL-17 
receptor
3. Use of any investigational drug and/or devices within 4 weeks before randomization or a 
period of 5 half-lives of the investigational drug, whichever was longer
4. Ongoing use of prohibited psoriasis treatments / medications (e.g., topical corticosteroids, 
ultraviolet therapy) at randomization. The following wash out periods need to be observed:
a.
Oral or topical retinoids 4 weeks
b. Photochemotherapy (e.g. Psoralen Plus Ultraviolet Light Therapy (PUVA)) 4 weeks
c.
Phototherapy (UVA or UVB) 2 weeks 
d. Topical skin treatments (except in face, eyes, scalp and genital area during screening, 
only corticosteroids with mild to moderate potency) 2 weeks
5. History of hypersensitivity to the study drug or its excipient or to drugs of similar 
chemical classes.
6. Any intramuscular or intravenous corticosteroid treatment within 4 weeks before 
randomization
7. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
randomization
8. Patients who ever received biologic immunomodulating agents including those targeting 
TNFα, IL-6 and IL-12/23 investigational or approved
9. Previous treatment with any cell-depleting therapies including but not limited to anti-
CD20, investigational agents (e.g., alemtuzumab, anti-CD4, anti-CD5, anti-CD3, anti-
CD19)
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test 
11. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective contraception during the entire study or 
longer if required by locally approved prescribing information. 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


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
Male sterilization (at least 6 months prior to screening). For female patients on 
the study, the vasectomized male partner should be the sole partner for that 
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)

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 six months 
of spontaneous amenorrhea as defined by Central Lab FSH and/or estradiol levels
12. Active ongoing inflammatory diseases other than PsA that might confound the evaluation 
of the benefit of secukinumab therapy 
13. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, 
cardiac, infectious or gastrointestinal conditions which in the opinion of the investigator 
immunocompromises the patient and/or places the patient at unacceptable risk for 
participation in an immunomodulatory therapy
14. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥160/95 mmHg), congestive heart failure [New York Heart 
Association status of class III or IV], uncontrolled diabetes
15. History of clinically significant liver disease or liver injury as indicated by abnormal liver 
function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, or serum 
bilirubin. The investigator should be guided by the following criteria:
a.
Any single parameter should not exceed 2 × upper limit of normal (ULN). A single 
parameter elevated up to and including 2 × ULN should be re-checked once more as 
soon as possible, and in all cases, at least prior to enrollment/randomization, to rule 
out lab error
b. If the total bilirubin concentration is increased above 2 × ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. In any case, serum 
bilirubin should not exceed the value of 1.6 mg/dL (27 µmol/L)
16. History of renal trauma, glomerulonephritis, or patients with one kidney only, or a serum 
creatinine level exceeding 1.5 mg/dL (132.6µmol/L)
17. Screening total White Blood Cells (WBC) count <3,000/µL, or platelets <100,000/µL or 
neutrophils 1,500/µL or hemoglobin <8.5 g/dL (85g/L)
18. Active systemic infections during the last two weeks (exception: common cold) prior to 
randomization
19. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis 
infection as defined by either a positive Purified protein derivative (PPD) skin test (the 
size of induration will be measured after 48-72 hours, and a positive result is defined as an 


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induration of ≥5mm or according to local practice/guidelines) or a positive 
QuantiFERON tuberculosis (TB)-Gold test as indicated in the assessment schedule. 
Patients with a positive test may participate in the study if further work-up (according to 
local practice/guidelines) established conclusively that the subject had no evidence of 
active tuberculosis. If presence of latent tuberculosis is established then treatment 
according to local country guidelines must have been initiated
20. Known infection with human immunodeficiency virus, hepatitis B or hepatitis C at 
screening or randomization
21. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for basal cell carcinoma or actinic 
keratoses that have been treated with no evidence of recurrence in the past 3 months, 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been 
removed)
22. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
investigator renders the patient unsuitable for the trial
23. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins) 
24. Any medical or psychiatric condition which, in the investigator’s opinion, precludes the 
participant from adhering to the protocol or completing the study per protocol
25. Donation or loss of 400 mL or more of blood within 8 weeks before randomization
26. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
randomization
27. Plans for administration of live vaccines during the study period or within 6 weeks 
preceding randomization.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
Novartis will supply the following study treatments:

Investigational Treatment: 
Secukinumab 150 mg provided in 1.0 mL in PFS for s.c. injection. 

Reference Therapies: 
Secukinumab placebo provided in 1.0 mL PFS for s.c. injection.
NOTE: The PFS are packed in double blinded fashion for the entire duration of the study. The 
study medication will be labeled as follows:

All double blind secukinumab and placebo PFS will be labeled as AIN457 
150mg/1.0ml/Placebo. Patients will be provided with detailed instructions and 
guidance on how to self-administer the s.c. injection using the PFS and following the 
Instructions for Use (IFU). The investigational drug will be administered by the 


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subject into the appropriate injection site of the body under the supervision of the site 
staff at each visit.
For detailed instructions for storage of the study treatments, please refer to Section 5.5.3.1 and 
the pharmacist manual.
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial.
5.2
Treatment groups
At the Baseline Visit, patients will be assigned via Interactive Response Technology (IRT) in
a 2:2:1 ratio to one of the three treatment groups (secukinumab 300 mg s.c., secukinumab 150 mg 
s.c. or placebo s.c.).
Treatment Period 1

Group 1- Secukinumab 300 mg: secukinumab 300 mg (two s.c. injections of the 150 mg
dose) once weekly for five weeks (at Baseline, Weeks 1, 2, 3, and 4), followed by
dosing every four weeks. 

Group 2- Secukinumab 150 mg: secukinumab 150 mg (one s.c. injection of the 150 mg
dose and one s.c. injection of placebo) once weekly for five weeks (at Baseline, Weeks
1, 2, 3, and 4), followed by dosing every four weeks. 

Group 3- Placebo: placebo (two s.c. injection of 150 mg secukinumab 
placebo per dose) once per week for five weeks (at Baseline, Weeks 1, 2, 3, and 4),
followed by dosing every four weeks. 
Treatment Period 2

Patients receiving secukinumab 300 mg (Group 1) will continue to receive the same dose 
up to Week 48.

At Weeks 16, 28 and 40 patients on secukinumab 150 mg (Group 2) will be classified as 
responders (≥ 20% improvement from BL in both tender and swollen joint counts) or non-
responders.

At Weeks 16, 28 and 40 patients on secukinumab 150 mg (Group 2) who are 
responders will continue to receive secukinumab 150 mg (1.0 mL) plus placebo (1.0 
mL) every 4 weeks until next evaluation of responder status at Weeks 28 or 40. 

Patients who did not meet the responder criteria at Week 16, 28 or 40 will start 
receiving secukinumab 300 mg s.c. every 4 weeks and will continue this dose up to 
Week 48.

Patients on placebo (Group 3) regardless of their responder status will start receiving
secukinumab 300 mg s.c. every 4 weeks from Week 16 up to Week 48.
Patients will self-administer all secukinumab and placebo doses at the study site up to Week 
48. After they have received training by the site on how to self-administer their secukinumab 
and placebo doses.


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5.3
Treatment assignment and randomization 
At Visit 2/Baseline, all eligible patients will be randomized via Interactive Response 
Technology (IRT) to one of the treatment groups in a ratio of 2:2:1 (secukinumab 300mg: 
secukinumab 150mg: placebo). The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment 
group in the system and will specify a unique medication number for the first package of 
investigational treatment to be dispensed to the subject. The randomization number will not be 
communicated to any of the site staff.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).
The randomization scheme for patients will be reviewed and approved by a member of the 
Biostatistics group.
5.4
Treatment blinding
Patients, investigators/site staff, persons performing assessments, and Novartis study 
personnel will remain blinded to individual treatment assignment from the time of
randomization until the final database lock using the following methods:
1. Randomization data will be kept strictly confidential until the time of unblinding, and will 
not be accessible by anyone else involved in the study with the following exceptions:

Specific vendors whose role in trial conduct requires their unblinding (e.g., IRT)

Drug Supply Management (DSM);
2. The identity of secukinumab and placebo prefilled syringes (PFS) will be concealed by
identical packaging, labeling, schedule of administration, and appearance.
As the primary analysis time point is Week 16, there will be a database lock after all patients 
have completed the Week 16 visit and data are clean and complete. At that time, only the 
statistician and programmer(s) from the designated CRO will be unblinded in order to 
perform the analysis. Results from the analyses of all data through Week 16, will be reported. 
For publication purposes, summary results from the Week 16 primary analysis time point may 
be shared with the health care community, however individual subject-level data will remain 
blinded until the end of the trial.
Unblinding will only occur in the case of subject emergencies (see Section 5.5.12), at the time 
of the primary analysis (Week 16) for designated CRO personnel only, and at the conclusion 
of the study.


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A full analysis of all data will be performed when all patients have completed the study.
5.5
Treating the patient
5.5.1
Patient numbering
Each subject is uniquely identified in the study by a combination of his/her center number and
subject number. The center number is assigned by Novartis to the investigative site. After the
subject has signed the ICF, the investigator or his/her staff will contact the IRT and provide
the requested identifying information for the subject. At each site, the first subject is assigned
subject number 1, and subsequent patients are assigned consecutive numbers (e.g. the second
subject is assigned subject number 2; the third subject is assigned subject number 3). Once
assigned to a subject, a subject number will not be reused. If the subject fails to be
randomized for any reason, the IRT must be notified within 2 days and the reason for not
being randomized will be entered on the Screening Phase Disposition Form within the eCRF. 
The appropriate eCRF(s) pages should also be completed.
Patients can only be re-screened once and will receive a new subject number after they have
been re-consented. Patients who are mis-randomized cannot be re-screened.
5.5.2
Dispensing the investigational treatment
Each study site will be supplied by Novartis with investigational treatment (active treatment 
or placebo) in packaging of identical appearance.
The investigational treatment packaging has a 2-part label. A unique medication number is 
printed on each part of this label, which corresponds to placebo or active treatment. 
Investigator staff will identify the investigational treatment packages to dispense to the subject 
by contacting the IRT and obtaining the medication numbers. Immediately before dispensing 
the package to the subject, the 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.
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. 
Medication labels will be in English and comply with legal requirements in the U.S. They will 
include storage conditions for the investigational treatment but no information about the 
patient except for the medication number.
The PFS (150 mg active/placebo) sealed in their outer box must be stored in a locked 
refrigerator between 2°C and 8°C (36°F and 46°F) and protected from light. They must be 


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carefully controlled in accordance with regulations governing investigational medicinal 
products and local regulations.
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by monitors during site visits or remotely and at the completion of the trial. 
Patients 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.
Destruction of the unused drug should be done according to local requirements and after 
approval by Novartis clinical team.
5.5.4
Instructions for prescribing and taking study treatment
All study treatment (150 mg secukinumab, or placebo) will be self-administered 
subcutaneously throughout the study after the study assessments for the visit have been 
completed. Site staff will administer the injection only to those patients who are not able to 
self-administer the PFS injection. Detailed instructions on the self-administration of the study 
treatment will be described in the Instructions For Use (IFU) and provided to each subject.
The first study treatment administration will occur at the randomization visit (BL) after
inclusion/exclusion criteria have been confirmed, all study scheduled assessments have been 
performed and the scheduled blood samples have been drawn. 
The subject will be instructed by the site staff, utilizing the IFU, on how to self-inject via PFS. 
Patients will be asked to raise any questions, if they have any, and then to proceed with self -
injection. Self-injection will take place under the supervision of a site staff member. At the 
Week 1 and subsequent visits, patients will be asked to refer to the IFU and to proceed with 
self-injection of the study drug.
Study treatment will be administered weekly following the BL dose (Weeks 1, 2, 3, & 4) and 
every 4 weeks thereafter (Week 8 until Week 48)
All dates and times of injections self-administered by the subject during the study must be 
recorded on the Dosage Administration Record eCRF. Immediately before dispensing the 
drug package to the subject, the investigator staff will detach the outer part of the label from 
the packaging and affix it to the source document (Drug Label Form) for that subject’s unique 
subject number. 
The investigator should promote compliance by instructing the subject to 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.


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5.5.4.1
Administration
Secukinumab Solution for Subcutaneous Injection (active or placebo, respectively) will be 
provided in prefilled syringes (PFS). 

Secukinumab (active) 150 mg/mL solution in a single-use Sensoready® pen or placebo 
Single syringes will be packed in individual boxes. The boxes containing the safety prefilled 
syringes with study treatment solution should be kept at 2 to 8°C (36°F and 46°F) and 
protected from light. Prior to administration the boxes containing the safety prefilled syringes 
with study treatment solution should be allowed to come to room temperature unopened for 
about 20 minutes before administration. Used safety syringe should be disposed immediately 
after use in a sharps container.
Patients will be instructed at BL by the site staff on how to self-inject either secukinumab or 
placebo (blinded) via PFS following the IFU. After the BL visit, the injections will be self-
administered into the appropriate site of the body (thighs, arms, abdomen), and each injection 
should be given at a different injection site. 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 drug should not be injected into areas where the skin is 
tender, bruised, red, or hard, or where subject has scars or stretch marks. Injection sites should 
be changed to reduce the risk of reaction.
At study visits when pre-dose blood samples have to be drawn, the study medication will be 
self-injected only after the blood samples have been taken.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments are not permitted. Study treatment interruption is also not 
permitted with the following exceptions:
Study treatment interruption is only permitted if, in the opinion of the investigator, a subject is 
deemed to be placed at a significant safety risk unless dosing is temporarily interrupted. In 
such cases study treatment should be interrupted only during the time that this risk is present 
and ongoing. Study treatment can be restarted at the next scheduled visit after resolution of 
the safety risk. 
The effect of secukinumab on live vaccines is unknown; therefore live vaccines should not be 
administered during participation in the study. In case a live vaccine has been administered 
due to a medical urgency, study treatment should be interrupted for 12 weeks. Any study 
treatment interruption must be recorded on the corresponding Dose Administration Record 
eCRF page and all assessments should be completed as scheduled.
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.
Rescue medication must not be used before completion of Week 16 assessments.


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Changes in NSAIDs concomitant therapy is permitted after Week 16 assessments per 
investigator’s clinical judgment.  Any use of rescue medication must be recorded on the 
corresponding Concomitant Medications eCRF.
Please see Section 5.5.7 for additional details.
5.5.7
Concomitant treatment
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded.
Guidelines for the use of specific medications are provided below:
Methotrexate (MTX)
Patients taking MTX (up to 25 mg/week) must be on a stable dose for at least 4 weeks before 
randomization and maintained stable throughout the duration of the study. 
Folic acid
Patients on MTX must be taking folic acid supplementation before randomization and during 
the study to minimize the likelihood of MTX associated toxicity.
Leflunomide wash-out with cholestyramine
In case of leflunomide treatment, a wash-out of 8 weeks has to be performed. 
However, another wash-out procedure might be considered. Cholestyramine could be given 
orally to wash-out the leflunomide at a dose of 8 g t.i.d. Cholestyramine reduced plasma 
levels of the active leflunomide metabolite by approximately 40 % in 24 hours and by 49% to 
65% in 48 hours in three healthy volunteers. The administration of cholestyramine is 
recommended in patients who require a drug elimination procedure. If a subject receives 8 g 
t.i.d. for 11 days, the subject could be safely randomized 4 weeks after the beginning of the 
11-day treatment period.
Systemic corticosteroids
Treatment with systemic corticosteroids is permitted up to a maximum daily dosage of 10 mg 
prednisone equivalent and the dose is stable within the 2 weeks preceding randomization. The 
subject should remain on a stable dose until Week 16. 
Corticosteroid dose reductions below 10 mg prednisone equivalent are permitted after 
Week 16, although the corticosteroid dose should not be reduced more than 1 mg prednisone 
equivalent every 4 weeks. Any change in the dose of systemic corticosteroids during the trial 
must be recorded on the corresponding eCRF page.
Intra-articular corticosteroids are not permitted within the 4 weeks preceding randomization 
and up to Week 16. After Week 16, no more than one joint per 24-week period may be 
injected. No single injection should exceed 40 mg of triamcinolone (or equivalent) and the 


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total dose of intra-articular corticosteroid may not exceed 80 mg of triamcinolone (or 
equivalent) during the study.
Non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-1 or COX-2 
inhibitors), low strength opioids and acetaminophen
Patients on regular use of NSAIDs, low strength opioids, or acetaminophen PRN should be on 
stable dose for at least 2 weeks before randomization to allow inclusion. They should remain 
on a stable dose during the study up to Week 16; however, they have to refrain from any 
intake at least 1 day before a visit with disease activity assessments.
After the Week 16 assessments are completed, a change in the NSAIDs, low strength opioids, 
or acetaminophen treatment regimen is permitted
Any change of the NSAIDs, low strength opioids, or acetaminophen treatment during the trial 
should be recorded on the corresponding eCRF page.
5.5.8
Prohibited treatment
Patients who received any biologics such as etanercept, infliximab, adalimumab, golimumab, 
certolizumab, ustekinumab, cocilizumab, abatacept or rituximab before this study are not 
allowed to participate in this trial.
Use of the treatments displayed in Table 5-1 below is NOT allowed during the study for any 
indication unless otherwise specified; wash-out periods for these treatments are provided in 
Table 5-1. If the use of any of these treatments is required, then the subject must not be 
randomized into the study.


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Table 5-1
Prohibited medication
Prohibited treatments
Washout period
(before randomization)
Conventional DMARDs (except MTX) 
including 
4 weeks
Leflunomide
8 weeks
Leflunomide with cholestyramine washout
4 weeks
Any investigational treatment or participation in 
any interventional trial
4 weeks or 5 half-lives
(whichever is longer)
Unstable dose of NSAIDs (including 
selective COX-2 inhibitors)
2 weeks
Analgesics other than NSAIDs, 
paracetamol/acetaminophen, and low strength 
opioids PRN
2 weeks
Systemic corticosteroids > 10 mg prednisone 
equivalent
2 weeks
Unstable dose of systemic corticosteroids ≤10 
mg prednisone equivalent 
2 weeks
Intra-articular corticosteroids injections
4 weeks
Intramuscular or intravenous corticosteroid 
treatment
4 weeks
Live vaccinations
6 weeks
Oral or topical retinoids
4 weeks
Photochemotherapy (e.g. PUVA)
4 weeks
Phototherapy (UVA or UVB)
2 weeks
Topical skin treatments (except in face, eyes, 
scalp and genital area during screening, only 
corticosteroids with mild to moderate potency)
2 weeks


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5.5.9
Discontinuation of study treatment
Study treatment must be discontinued if the investigator determines that continuation of study 
treatment 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:
a.
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
b. 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
c.
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 (please refer to section 
5.5.8 for the other prohibited medications. Any protocol deviation that results in a 
significant risk to the subject’s safety
In addition to these requirements 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 thinks that continuation would be detrimental to 
the subject’s well-being.
For any subject whose treatment code has been broken inadvertently for any reason, the 
appropriate personnel from the site and Novartis will assess whether study treatment should 
be discontinued. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
Patients 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.
5.5.10
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore, and does not want any further visits or assessments, and does not want any further 
study-related contacts, and does not allow analysis of already obtained biologic material.


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If premature withdrawal occurs for any reason, the investigator must make every effort (e.g. 
telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information on the appropriate study completion eCRF. 
Patients who prematurely discontinue or withdraw during a specific treatment period should 
return for a final visit (see Table 6-1). The final visit should be scheduled approximately four 
weeks after the last study treatment, and should be performed before any new treatment is 
initiated.
Patients who are prematurely withdrawn from the study will not be replaced by newly 
enrolled patients.
5.5.11
Loss to follow-up
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
subject, e.g. dates of telephone calls, registered letters, etc.
5.5.12
Emergency breaking of assigned treatment code
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
subject safely and efficaciously. Most often, study 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 and CRO study personnel that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the subject how to contact 
his/her backup in cases of emergency when he/she is unavailable.
5.5.13
Study completion and post-study treatment
A subject’s individual study participation is completed once Visit 19/Week 52 Treatment 
Period has been completed. Any SAEs that occur in the following 84 days (12 week s) after 
the dose of study drug must be reported. The investigator will also follow any AEs for which 
there is no outcome that can be reported at the final study visit. 
The study as a whole will be completed once all randomized patients have completed the
study as per the protocol and the clinical database has been locked. Recruitment into the study 
will be terminated by the sponsor once the targeted number of randomized patients has been 
met or is foreseen to be met with the patients already in screening. Patients who have been
screened and have a screening visit recorded in the IRT system at the time that the planned


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enrollment number is met will be allowed to enter the trial and to be randomized if they are
eligible.
Upon completion of their study participation, patients will return to individual treatment, as 
determined by their treating physician.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.5.14
Early study termination
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrollment). Should this be necessary, the 
subject should be seen as soon as possible and treated as a prematurely withdrawn as 
described in Section 5.5.9 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 Institutional Review 
Board/Independent Ethics Committee (IRBs/ECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments, indicated with an “X” at the visits they are performed 
from screening to Week 52.
Patients should be seen for all visits on the designated day, or as closely as possible to the 
original planned visit schedule (recommended visit windows are in Table 6-1). Every effort 
should be made to respect the time frame for the Week 16 visit.

For visits scheduled through Week 4, the study treatment should not be administered 
within less than 7 days after the previous administration

For visits scheduled after Week 4, the study treatment should not be administered within 
less than 14 days after the previous administration
Patient Screening
Screening will be flexible in duration based on the time required to wash out prior anti -
rheumatic medications and have a duration of up to 8 weeks before randomization. During 
which time the subject will sign the informed consent form (ICF), be evaluated for eligibility, 
and allowed sufficient time for medication washout, if required (see Table 5-1), in addition to 
other assessments indicated in Table 6-1.
If patients do not have a chest X-ray available within 3 months of screening, the X-ray should 
be performed only after it is certain the subject meets inclusion/exclusion criteria in order to 
minimize unnecessary exposure to radiation. 
Patients evaluated at visit 1 and 2 for Inclusion/Exclusion criteria should not be screen failed 
on the basis of a medication requiring washout, unless the subject will be unable to complete 
the washout in the appropriate time frame before randomization.


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Premature Discontinuation
For patients who discontinue study treatment prematurely for any reason before the end of
Treatment Period 1, (Visit 10/Week 16 EOT1) must be performed approximately four
weeks after the last dose of study treatment (secukinumab 300 mg, secukinumab 150 mg or 
placebo). Patients should also be contacted via telephone, 84 days (12 weeks) after last dose 
of study drug, to inquire about any AE/SAEs that occurred during this period.
For patients who discontinue study treatment prematurely for any reason before the end of
Treatment Period 2, (Visit 19/ Last visit EOT2) must be performed approximately four
weeks after the last dose of study treatment (300 mg or 150 mg s.c. secukinumab). Patients 
should also be contacted via telephone, 84 days (12 weeks) after last dose of study drug, to 
inquire about any AE/SAEs that occurred during this period.
If patients refuse to return for these assessments or are unable to do so, every effort should be 
made to contact them or a knowledgeable informant by telephone to determine the reason.
At a minimum, patients will be contacted for safety evaluations during the 84 days (12 weeks)  
following the last study visit or following the last administration of study treatment 
(whichever is later), including a final contact at the 84-day point. Documentation of attempts 
to contact the subject should be recorded in the source documentation.
AE/SAE information obtained as a result of these calls must be recorded in the eCRF.
Unscheduled visits
Patients may be seen at any time for an unscheduled visit, e.g., if they experience 
deterioration or AEs that in the opinion of the investigator/qualified site staff need 
intervention or repeat laboratory testing. The assessment(s) performed at an unscheduled visit 
must 
include 
at 
minimum: 
an 
assessment 
of 
concomitant 
medication 
and 
procedures/significant non-drug therapies, vital signs, and an AE/SAE assessment. Any 
additional assessments performed are at the investigator/qualified site staff’s discretion. 
During an unscheduled visit, study treatment will not be administered.


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Table 6-1
Assessment schedule
Period
SCR1
Treatment Period 1
Treatment Period 2
Unscheduled Visit
Week
-8 to BL
BL
1
2
3
4
8
12
16/E
OT
20
24
28
32
36
40
44
48
52/  
EOT
Day 84 
Safety 
Follow-
up4
Visit No
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Visit Window 
(days)2
+/-2
+/-2
+/-2
+/-2
+/-2
+/-2
+/-2
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
Assessments
Obtain informed 
consent
X
Inclusion/exclusio
n criteria
X
X
X
Demographics
X
Psoriasis/PsA 
medical history / 
previous therapies
X
Relevant medical 
history/current 
medical 
conditions
X
Washout 
evaluation/instruct
ion
X
PsA CASPAR 
criteria
X
Smoking and 
alcohol history
X
Cardiovascular 
medical history
X
Physical Exam4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X


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Weight
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray5
X
ECG
X
Prior/Concomitant 
medication/ non-
drug therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization 
via IRT
X
Administration of 
sc study treatment 
via PFS at study 
site
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse 
Events/SAEs3
(incl. injection site 
reaction & 
occurrence of 
infections)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
QuantiFERON 
TB-Gold test
X
Hematology, 
blood chemistry 6
X
X
X
X
X
X
X
Serum pregnancy 
test
X
Urinalysis/Urine 
pregnancy test 7
X
X
X
X
X
X
X
X
Anti-CCP
X
Rheumatoid factor 
(RF)
X
High sensitivity 
C-Reactive 
protein (hsCRP)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Erythrocyte 
Sedimentation 
Rate (ESR) 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tender and 
swollen joint 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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counts
(TJC78, SJC76)
Enthesitis 
evaluation8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dactylitis 
evaluation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician’s global 
assessment of 
disease activity 
(VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PASI 
X
X
X
X
X
X
X
X
X
X
IGA mod 2011 
X
X
X
X
X
X
X
X
X
X
 
 
 
VAS 
physician’s 
assessment of 
nail disease
X
X
X
X
X
X
X
X
X
Health 
Assessment 
Questionnaire 
(HAQ-DI)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s 
assessment of 
PsA pain (VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s global 
assessment of 
disease activity 
(VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s global 
assessment of 
psoriasis and 
arthritis disease 
activity(VAS)
X
X
X
X
X
X
X
X
X
X
SF-12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Responder Status 
Assessment9
X
X
X
X
X
X
X
X
X
X
Treatment period 
1 completion form
X
Treatment period 
2 completion form
X
1 If washout period is < 4 weeks, visit 1 & visit 2 can be performed the same day
2 Patients who discontinued prematurely or withdrawn during a specific treatment period should return for a final visit. The final visit should be scheduled approximately four (4) weeks after 
the last study treatment, and should be performed before any new treatment is initiated
3 AEs/SAEs occurring after informed consent has been obtained must be reported. Patients who discontinued prematurely should be contacted via telephone to collect AE/SAEs 
information. Any   AE/SAEs that occur in the following 84 days (12 weeks) after last dose of study drug must be reported. 
4 These assessments are source documented only and will not be entered into the eCRF
5 Not necessary if done within past 3 months. If not, should be scheduled only after patient has met inclusion/exclusion criteria
6 Fasting sample
7 Tests performed locally using kits supplied by central lab 
 
9Those patients on secukinumab 150 mg who are non-responders at Week 16,  28, or 40 will start receiving secukinumab  300 mg s.c. every 4 weeks up to Week 48.


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6.1
Information to be collected on screening failures 
All patients who sign informed consent but discontinue prior to randomization at Visit 3 are 
considered screening failures. The IRT must be notified about the discontinuation, and the 
primary reason for the screen failure should be entered in the Screening Phase Disposition 
eCRF. 
In addition, only the following eCRFs should be completed: Demography eCRF, Informed 
Consent eCRF, Inclusion/Exclusion eCRF, and the adverse event (AE) eCRF should be 
completed for any Serious Adverse Events (SAEs) that occurred during the screening period. 
Adverse events that are not serious will be followed by the investigator and collected only in 
the source data.
6.2
Patient demographics/other baseline characteristics
All baseline assessments should be performed prior to the first study treatment administration.
6.2.1
Demographics
Subject demographic and baseline characteristic data to be collected on all patients and 
recorded in the eCRF include: 

date of birth, subject initials, gender, race, and child-bearing potential (for females only).
6.2.2
PsA/Psoriasis history/ Prior psoriasis therapies
Disease history will be collected at the screening visit. The information to be collected and 
entered in the eCRF includes the following:

date of first diagnosis of plaque psoriasis (by a physician)

presence of psoriatic arthritis and the date of first diagnosis (by a physician)

disease duration (if different from time since diagnosis)

previous PsA/psoriasis treatments (including previous use of biologic therapies, as well as 
phototherapy and/or photo chemotherapy) and the reason for discontinuation of each 
therapy
6.2.3
Smoking history
The current and/or previous use of tobacco products will be recorded, as well as the estimated 
number of pack-years based on the approximate consumption per year. Non-smokers will be 
advised to not start smoking during the study.
6.2.4
Co-morbidities-Cardiovascular history
Any information pertaining to cardiovascular medical history assessed prior to signing 
informed consent should be reported on the Cardiovascular History eCRF.
6.2.5
Relevant medical history / Current medical conditions
Whenever possible, diagnoses and not symptoms will be recorded.


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Relevant medical history/current medical conditions, not including psoriasis or psoriatic 
arthritis, will be recorded on the Medical History eCRF. 
Relevant medical history/current medical conditions will include data up to six months prior 
to signing of the informed consent. Whenever possible, diagnoses (and not symptoms) will be 
recorded. 
Significant findings that are observed after the subject has provided informed consent, and 
that meet the definition of an AE, must be recorded on the Adverse Event eCRF.
Investigators will have the discretion to record abnormal test findings on the Medical History 
eCRF when in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.2.6
Prior and concomitant medications
Concomitant medications and prior medications taken over the six months preceding study 
enrollment will be captured at the Screening visit, and updated at Visit 3 (Randomization).
6.2.7
Chest X-ray
A chest X-ray, CT scan, or MRI obtained within 3 months prior to randomization will be used 
to determine eligibility. If patients do not have a chest X-ray, CT scan, or MRI available 
within 3 months prior to randomization, a chest X-ray only must be done after it is fairly 
certain the subject meets the other inclusion/exclusion criteria in order to minimize 
unnecessary exposure to X-ray radiation for patients.
If the chest X-ray, CT scan, or MRI evaluated by a qualified physician shows evidence of 
ongoing infection or malignancy and the subject was not treated subsequent to the X-ray (CT 
scan or MRI), the subject will not be eligible to enter the study.
6.2.8
Determination of tuberculosis status
Determination of tuberculosis (TB) status will be required before administration of study 
treatment. TB status must be determined by medical history, signs, symptoms, and TB testing 
(QuantiFERON-TB Gold assay). Any significant findings will be recorded in the appropriate 
eCRF(s), as necessary.
If the QuantiFERON-TB Gold Assay test is positive or indeterminate, a TB workup 
should be performed as defined by local guidelines to determine the subject’s TB status.
QuantiFERON TB-Gold In-Tube assay
A QuantiFERON® TB-Gold In-Tube assay will be performed to assess the TB status at 
screening for all patients. This test will only be used to determine subject’s eligibility for the 
trial. The test will be used to screen the subject population for latent tuberculosis infection 
(Doherty et al 2008).
This blood-based assay is specific for Mycobacterium tuberculosis and is not influenced by 
previous Bacillus Calmette-Guérin vaccination or exposure to other Mycobacteria species.
This test, in contrast to the purified protein derivative (PPD) skin test, is also insensitive to a 
booster effect since the subject is not exposed to the vaccine. The assay measures the 


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production of interferon-gamma and presents it relative to a negative and a positive control 
sample (Manuel and Kumar 2008)
The QuantiFERON®-TB Gold assay test will be supplied by the central laboratory. Details on 
the collection, shipment of samples and reporting of results by the central laboratory are 
provided in the Laboratory Manual.
The results of a TB workup for a subject with a positive or indeterminate test must be 
recorded in the eCRF.

If the test result is negative, the subject may be randomized.

If the test result is positive, the investigator should perform a TB workup for the test result 
as per local procedures.

Patients positive for latent TB per workup may be randomized to the trial if sufficient 
treatment has been initiated according to local routine clinical practice and will be 
maintained for the prescribed duration.

Patients positive for active TB per workup are not eligible for the study.

Patients negative for TB (no signs of latent or active TB) per workup may be randomized 
to the trial.

If the test result is indeterminate, it is recommended to repeat the test once. The 
investigator may decide to skip the repetition of the test and proceed directly to the 
workup (however this is not recommended). If a TB workup was conducted prior to 
screening, results from the workup can be used to assess eligibility if the workup was 
conducted within 12 weeks prior to randomization.

If the second test is negative, the subject may be randomized.

If the second test is positive or indeterminate, the investigator should perform a TB 
workup as per local guidelines. The subject will not be eligible for randomization if: 
“active tuberculosis is present”, or if “latent tuberculosis is present” and is untreated as per 
local guidelines.
6.3
Treatment exposure and compliance
All doses of secukinumab or placebo administration will be recorded on the Dosage 
Administration Record eCRF. Compliance will be assessed by Novartis and CRO study 
personnel using the Dosage Administration Record eCRF, medication numbers, Drug Label 
Form information, and information collected by IRT.
Compliance is expected to be 100% since all doses of study treatment will be administered at 
the site in the presence of the investigator or site staff, unless temporary interruption is 
needed for safety reasons as described in Section 5.5.5.
6.4
Efficacy
The primary efficacy variable is ACR20 response (yes, no). The primary analysis time point 
will be at Week 16.
The secondary efficacy variables are the following:


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1. Dactylitis (yes, no)
2. Enthesitis (yes, no) 
3. ACR50 response (yes, no)
4. ACR70 response (yes, no)
5. Minimal Disease Activity (yes, no)
6. PASI75 response (yes, no)
7. PASI90 response (yes, no)
8. PASI100 response (yes, no)
9. Change from baseline in DAS28-CRP
10. Change from baseline in PASDAS
11. Change from baseline in SF12
12. Change from baseline in HAQ-DI
6.4.1
American College of Rheumatology (ACR) response
The ACR response (Appendix 4) will be used to determine efficacy (Felson 1995)-*A subject 
is defined as e.g. an ACR20 responder if, and only if, the following three conditions hold:


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
they have a ≥ 20% improvement in the number of tender joints (based on 78 joints)

they have a ≥ 20% improvement in the number of swollen joints (based on 76 joints)

they have a ≥ 20% improvement in three of the following five domains:

Patient’s global assessment of disease activity (measured on a VAS scale, 0-100)

Physician’s global assessment of disease activity (measured on a VAS scale, 0-
100)

Patient’s assessment of PsA pain (measured on a VAS scale, 0-100)

Health Assessment Questionnaire (HAQ©) score

Acute phase reactant (hsCRP or ESR) 
ACR50 = 50 % improvement in at least 3 of the 5 domains and 50 % improvement in the swollen and 
tender joint count.
ACR70 = 70 % improvement in at least 3 of the 5 domains and 70 % improvement in the swollen and 
tender joint count.
The ACR response is to be assessed at the visits/time points shown in Table 6-1.
6.4.2
Tender 78 joint count and swollen 76 joint count
Joint counts will be performed by the assessor(s) who must be well trained and part of the site 
personnel. Whenever possible, the same evaluator should perform these assessments at all 
visits.
The 78 joints assessed for tenderness include the 2 temporomandibular, 2 sternoclavicular, 2 
acromioclavicular joints, 2 shoulders, 2 elbows, 2 wrists, 2 first carpometacarpal, 10 
metacarpophalangeal, 10 proximal interphalangeal, 8 distal interphalangeal joints of the hands, 
the 2 hip, 2 knee, 2 talo-tibial, 2 mid-tarsal, 10 metatarsophalangeal, 10 proximal 
interphalangeal, and 8 distal interphalangeal joints of the feet. 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. 
Data is recorded for tender and swollen joints (right or left side), i.e. a box (no, yes or not 
applicable) needs to be ticked for all joints. The total number of tender and swollen joints 
(right and left) will be automatically calculated in the eCRF.
6.4.3
Patient Reported Outcomes (PRO)/QoL Assessments
Patients should complete all assessments prior to any investigator evaluations.

Patient’s Assessment of PsA pain intensity

Patient’s global assessment of disease activity (VAS)

Patient’s global assessment of psoriasis and arthritis disease activity (VAS)
The impact of PsA on various aspects of patients’ health-related quality of life (HRQoL) will 
be assessed using the following validated instruments:


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
Health Assessment Questionnaire (HAQ-DI)

SF-12 
All questionnaires will be completed at the defined visits/ time points listed in Table 6-1, and 
prior to the subject seeing the investigator for any clinical assessment or evaluation. 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. Completed questionnaires should be 
reviewed and assessed by the investigator before the clinical examination, for responses 
which may indicate potential AEs or SAEs. 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).
Guidelines for administering the PRO questionnaires can be found in Appendix 10.
6.4.3.1
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”.
6.4.3.2
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”. 
6.4.3.3
Health Assessment Questionnaire (HAQ-DI)
The HAQ-DI© was developed by Stanford University and is one of the most widely used 
measures to assess the long-term influence of chronic disease on a 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 patients with 
PsA.


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6.4.3.4
Medical Outcome Short Form Health Survey (SF-12) Version 12
The SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey that uses 
just 12 questions to measure functional health and well-being from the patient’s point of view.
Taking only two to three minutes to complete, the SF-12v2® is a practical, reliable and valid 
measure of physical and mental health and is particularly useful in large population health 
surveys or for applications that combine a generic and disease-specific health survey. The SF-
12v2® covers the same eight health domains as the SF-36v2® with one or two questions per 
domain.
As the survey uses norm-based scoring, comparisons can be made among the other generic 
health surveys such as SF-36v2 and it can measure outcomes concisely at the population level, 
and it is a widely used tool for monitoring population health, comparing and analyzing disease 
burden and predicting medical expenses.
The purpose of the SF-12 in this study is to assess the HRQoL of patients. Given the acute 
nature of this disease, version 2, with a 1-week recall period, will be used in this study. 


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6.4.4
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 
subject.
6.4.5
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.
6.4.6
Erythrocyte sedimentation rate (ESR)
ESR tests MUST be performed locally. 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 as indicated in Table 6-1.


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6.4.8
DAS28 and EULAR response
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. EULAR response criteria are based on DAS28 
status in combination with DAS28 improvements.
6.4.9
Psoriatic Arthritis Disease Activity Score (PASDAS)
PASDAS is a new composite measure developed to access disease activity in Psoriasis 
(GRACE Project) (Helliwell 2012). It is calculated by utilizing seven measures; the seven 
components are: Patient reported measures (excluding mental component summary score 
(MCS) of the medical outcomes survey Short Form-36 (SF-36-PCS)), skin, peripheral joint 
counts (Tender and Swollen joint counts), Dactylitis (LDI), 
 acute phase 
response (CRP) and Patient & Physician global VAS scores. 
PASDAS = 
(0.18 x √Physician global VAS) 
+ (0.159 x √Patient global VAS) 
- (0.253 x √SF36-PCS) 
+ (0.101 x LN (Swollen joint count + 1)) 
+ (0.048 x LN (Tender joint count + 1)) 
+ (0.23 x LN (Leeds Enthesitis Count + 1)) 
+ (0.377 LN (Dactylitis count + 1)) 
+ (0.102 x LN (CRP + 1)) +2)*1.5.
VAS for PASDAS assessment: 
Instruct patients to place marks on the lines below to indicate answer to the following 
questions relating to the past week.
Global Disease Activity: The patient’s assessment of PSORIASIS and ARTHRITIS will be 
performed using 100 mm VAS ranging from “Excellent” to “Poor” after the question 


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"Considering all the ways PSORIASIS and ARTHRITIS affects you, please indicate with a 
vertical mark ( | ) through the horizontal line how well you are doing over the past week”.
6.4.10
Minimal disease activity
The proportion of patients achieving minimal disease activity (MDA (Coates 2010) (5 of the 7 
following: ≤ 1 tender joint count, ≤ 1 swollen joint count, PASI  ≤ 1 or IGA ≤ 1, patient pain 
VAS ≤ 15, patient global VAS ≤ 20, HAQ-DI ≤ 0.5, tender entheseal points ≤ 1).
6.4.11
Dactylitis Assessments
 
Presence of dactylitis
If dactylitis is present with any finger or toe, the subject is counted as a subject with dactylitis.
6.4.12
Enthesitis Assessments
Presence of enthesitis:
If enthesitis is present with any of the 18 sites below, the subject is counted as a subject with 
enthesitis.

Medial epicondyle humerus (left/right (L/R)

Lateral epicondyle humerus (L/R)

Supraspinatus insertion into greater tuberosity of humerus (L/R)

Greater trochanter (L/R)

Medial condyle  femur (L/R)

Quadriceps insertion into superior border of patella (L/R)

Patellar ligament insertion into inferior pole of patella or tibial tubercle (L/R)

Achilles tendon insertion into calcaneum (L/R)

Plantar fascia insertion into calcaneum (L/R)


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6.4.14
Psoriasis Area and Severity Index (PASI)
The PASI assessment will be conducted for patients in whom at least 3% of the body surface 
area (BSA) was affected by psoriatic skin involvement at BL. The PASI assesses the extent of 
psoriasis on four body surface areas (head, trunk and upper and lower limbs) and the degree 
of plaque erythema, scaling and thickness. A PASI score (Fredriksson and Pettersson 1978, 
Weisman 2003, Gottlieb 2005) will be derived as indicated in Table 6-2.
The head, trunk, upper limbs and lower limbs are assessed separately for erythema, thickening 
(plaque elevation, induration), and scaling (desquamation). The average degree of severity of 
each sign in each of the four body regions is assigned a score of 0-4. The area covered by 
lesions on each body region is estimated as a percentage of the total area of that particular 
body region. Further practical details help the assessment:
The neck is assessed as part of the head.
The axillae and groin are assessed as part of the trunk.
The buttocks are assessed as part of the lower limbs.
When scoring the severity of erythema, scales should not be removed.


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Table 6-2
The PASI scoring system
Body 
region
Erythema (E)
Thickening
(plaque elevation,
induration)(I)
Scaling
(desquamation) (D)
Area score
(based on true 
area %)( A)*
Head  (H)**
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0 = 0%
1 = 1-9%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
Trunk,   
(T)***
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0 = 0%
1 = 1-9%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
Upper 
limbs (U)
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0 = 0%
1 = 1-9%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
Lower 
limbs 
(L)****
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0 = 0%
1 = 1-9%
2 = 10-29%
3 = 30-49%
4 = 50-69%
5 = 70-89%
6 = 90-100%
* Percentage (not score) of body region (not whole body) affected will be entered in the eCRF
**Neck is assessed as part of the Head (H) body region.
***Axillae and groin are assessed as part of the Trunk (T) body region.
****Buttocks are assessed as part of the Lower limbs (L) body region.
Because the head and neck, upper limbs, trunk and lower limbs correspond to approximately 
10%, 20%, 30% and 40% of the body surface area, respectively, the PASI score is calculated 
using the formula:
PASI = 0.1 (EH+IH+DH)AH + 0.2 (EU+IU+DU)AU + 0.3(ET+IT+DT)AT + 0.4(EL+IL+DL)AL
where E = erythema, I = induration, S = scaling, and A = area, 
H = Head, U = Upper limbs, T = Trunk, and L = Lower limbs
PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a 
theoretic maximum of 72.0. The investigator is only responsible for collecting the components 
or scoring signs and total regional area. More information is provided in Appendix 6. 


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6.4.15
Investigator’s Global Assessment (IGA mod 2011)
IGA mod 2011 will be conducted for overall psoriatic disease as indicated in Table 6-3 for 
patients in whom at least 3% of the body surface area (BSA) was affected by psoriatic skin 
involvement at BL. It is recommended that the same evaluator conducts the assessment 
throughout the study wherever possible.
The IGA mod 2011 rating scale has been developed based on a previous version of the scale 
used in secukinumab phase II psoriasis studies in collaboration with health authorities in 
particular the FDA. The explanations/descriptions of the points on the scale have been 
improved to ensure appropriate differentiation between the points (see Table 6-3).
The IGA mod 2011 used in this study is static, i.e. it refers exclusively to the subject’s disease 
state at the time of the assessments, and does not attempt a comparison with any of the 
subject’s previous disease states, whether at baseline or at a previous visit.  
The IGA mod 2011 score will be recorded in the eCRF at the given visits/time points of Table 
6-1.
Table 6-3
The IGA mod 2011 rating scale
Score
Short Description
Detailed Description
0
Clear
No signs of psoriasis. Post-inflammatory hyperpigmentation may 
be present.
1
Almost clear
Normal to pink coloration of lesions; no thickening; no to minimal 
focal scaling.
2
Mild
Pink to light red coloration; just detectable to mild thickening; 
predominantly fine scaling.
3
Moderate
Dull bright red, clearly distinguishable erythema; clearly 
distinguishable to moderate thickening; moderate scaling.
4
Severe
Bright to deep dark red coloration; severe thickening with hard 
edges; severe / coarse scaling covering almost all or all lesions.
Note: Involvement of nails is not part of the assessment.
Based on this scale, a subject will be considered as IGA 0 or 1 responder if the subject 
achieves a score of 0 or 1 and improved by at least 2 points on the IGA scale compared to 
baseline.


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6.4.17
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”.
6.4.19
Appropriateness of efficacy assessments
The efficacy assessments used in this study are the standard assessments used across many 
psoriatic arthritis trials.


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6.5
Safety 
Evaluation of all AEs and SAEs including injection site reactions, ECGs, physical 
examination, vital signs and laboratory assessments, Assessment of anti-secukinumab 
antibody development (immunogenicity).
All blood draws and safety assessments should be done prior to study treatment 
administration. Appropriate safety assessments (e.g. evaluation of AEs and SAEs including 
injection site reactions) should be repeated after the dose is administered.

Evaluation of AE/ SAE’s

Physical examination

Vital signs

Height and weight

QuantiFERON TB-Gold test or PPD skin test

Electrocardiogram

Local tolerability (Injection site reactions)

Laboratory evaluations (Hematology, Clinical Chemistry, LFTs, Urinalysis)

Pregnancy and assessment of fertility

Tolerability of secukinumab
6.5.1
Physical examination
A complete physical examination will be performed by a professionally trained physician or 
health professional licensed to perform physical examinations and listed on FDA Form 1572, 
at the scheduled study visits as indicated in Table 6-1.
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 
Vital signs include BP and pulse rate measurements. After the subject has been sitting for five 
minutes, with back supported and both feet placed on the floor, systolic and diastolic blood 
pressure will be measured using a validated device with an appropriately sized cuff.
If possible, vital signs assessments should be performed by the same study site staff member 
using the same validated device throughout the study.
Clinically notable vital signs are defined in Appendix 1.


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6.5.3
Height and weight 
Height and body weight (in indoor clothing but without shoes) will be measured at scheduled 
study visits as indicated in Table 6-1. If possible, body weight assessments should be 
performed using the same scale throughout the study. The Body Mass Index will be calculated 
programmably.
6.5.4
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as indicated in Table 6-1. ECGs must be recorded 
after 10 minutes rest in the supine position to ensure a stable baseline. The preferred sequence 
of cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. Each ECG tracing should be labeled with study number, subject 
initials, subject number, date and time, and filed in the study site source documents.
Clinically relevant abnormalities should be recorded on the relevant medical history/Current 
medical conditions eCRF page for the baseline ECG. 
Clinically relevant abnormalities noted after the baseline ECG should be reported as AE (see 
Section 7)
6.5.5
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected listed below (except 
urinalysis). Details on the collection, shipment of samples and reporting of results by the 
central laboratory are provided in the laboratory manual. For the identification of clinically 
notable values, see Appendix 1. All patients with laboratory tests containing clinically 
significant abnormal values are to be followed until the values return to normal ranges or until 
a valid reason, other than treatment related AE, is defined.
6.5.5.1
Hematology
Hemoglobin, platelet, red blood cell (RBC), white blood cell (WBC) and differential white 
blood cell counts will be measured at scheduled visits. 
6.5.5.2
Clinical chemistry
Serum chemistry will include glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, 
total protein, albumin, and uric acid.
6.5.5.3
Urinalysis
Dipsticks will be provided by the central laboratory to the sites for local urinalysis 
assessments. The urinalysis results for standard parameters such as protein, glucose, blood 
and WBCs will be recorded in the appropriate eCRF page. Follow-up of abnormal results is 
left to the discretion of the investigator.


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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).
A serum β-hCG test will be performed in all women of child bearing potential at Screening 
Visit 2; and a local urine pregnancy test at the specified visits as indicated in Table 6-1. A 
positive urine pregnancy test requires immediate interruption of study treatment until serum β-
hCG is performed and found to be negative. If positive, the subject must be discontinued from 
the trial.
6.5.7
Tolerability of secukinumab
Tolerability will be assessed by adverse events, laboratory values and injection site reaction. 
6.5.8
Additional parameters
Blood will be obtained at the first screening visit (Visit 1) for anti-CCP antibodies and the 
Rheumatoid Factor (RF).
6.5.9
Appropriateness of safety measurements
The safety measures used in this study are reliable and relevant standard measures for a 
biologic in PsA. A chest X-ray at screening (or within 3 months prior to screening) is 
performed to rule out the presence of a pulmonary malignancy or infectious process, in 
particular tuberculosis. The radiation exposure that results from the chest X-ray safety 
measurements are estimated to be far below 1 mS. Effective radiation doses under 3 mS (300 
mrem), are considered to be minimal risk. Therefore, the radiation exposure in this study 
involves minimal risk and is necessary to ensure reliable safety measures before the treatment 
with a biologic.
The safety assessments selected are standard and adequate for this indication/subject 
population.
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 
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 patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments.


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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 
patient 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

relationship to the study treatment (no/yes)

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 - See Section 7.2 for definition of SAE)

action taken regarding study treatment 

All adverse events should be treated appropriately. Treatment may include one or more of 
the following: 

no action taken (i.e. further observation only) 

study treatment temporarily interrupted 

study treatment permanently discontinued due to this adverse event 

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged 

outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal or unknown)
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 study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.


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The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information 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 events
7.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
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All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to Novartis DS&E as per Section 7.2.2.
7.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 84 days after the last dose of study medication, must be 
reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced 
after the 84-day period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship of each SAE to study treatment, complete the SAE Report Form in English, and 
send the completed, signed form by fax within 24 hours after awareness of the SAE to the 
local Novartis Drug Safety and Epidemiology Department. The telephone and fax number of 
the contact persons in the local department of Drug Safety and Epidemiology, specific to the 
site, are listed in the investigator folder provided to each site. The original copy of the SAE 
Report Form and the fax confirmation sheet must be kept with the subject’s source 
documentation at the study site. Follow-up information should be provided using a new paper 
SAE Report Form stating that this is a follow-up to a previously reported SAE.
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to relevant ethics committees in accordance with 
regulatory requirements.
7.3
Liver safety monitoring
There has been no safety signal for liver toxicity with secukinumab to date in over 6535 
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.


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7.4
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient 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 the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the
possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to US CFR 21Part 11 


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requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
CRO working on behalf of Novartis. The Investigator must certify that the data entered into 
the Electronic Case Report Forms are complete and accurate. After database lock, the 
investigator will receive copies of the patient data for archiving at the investigational site. 
8.3
Database management and quality control 
A CRO working on behalf of Novartis will review the data entered into the eCRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. Randomization codes and data about all study drug(s) assigned to 
the subject will be tracked using an Interactive Response Technology (IRT). The system will 
be supplied by a vendor, who will also manage the IRT database. The database will be sent 
electronically to Novartis (or a designated CRO). Each occurrence of a code break via IRT 
will be reported to the clinical team and study monitor.  The code break functionality will 
remain available until study completion or upon request of Novartis.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to a 
designated CRO.
PRO questionnaires will be completed by the subject on an electronic tablet, and the data 
transmitted into the eCRF by investigator site staff.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
management.
8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee 
Not required.
9
Data analysis 
A designated Contract Research Organization will perform the statistical analysis.


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It is planned that the data from all centers that participate in this protocol will be combined, so 
that an adequate number of patients will be available for analysis.
Unless otherwise specified, all statistical tests will be conducted against a two-sided 
alternative hypothesis, employing a significance level of 0.05.
Efficacy, safety, and other data will be summarized.  For continuous variables, summary 
statistics (mean, standard deviation, median, 25th and 75th percentiles, interquartile range, 
minimum, and maximum) at each time point and for change from baseline to each time point 
will be reported by treatment group.
9.1
Analysis sets
The following analysis sets will be used for the statistical reporting and analyses:
Randomized Set: The Randomized Set includes all randomized patients.  
Safety Set: The Safety Set includes all patients who received at least one dose of study 
medication.  Patients will be included in the analysis according to treatment received.
Full Analysis Set:  The Full Analysis Set comprises all patients to whom study medication has 
been assigned.  Patients inappropriately randomized (e.g., IRT was called in error for 
randomization of a screen failed subject) will be excluded from this analysis set.  Following 
the intent-to-treat principle, patients will be analyzed according to the treatment they were 
assigned to at randomization.
9.2
Patient demographics and other baseline characteristics
Data will be summarized with respect to demographic and baseline characteristics of all 
patients, the subgroup of patients with dactylitis at baseline, and the subgroup of patients with 
enthesitis at baseline, for the Randomized Set and the Full Analysis Set.
9.3
Treatments 
The number of patients and the length of time (in days) exposed to each treatment will be 
summarized for the Safety Set.
Concomitant medications will be summarized by treatment using frequency counts and 
percentages for the Safety Set.
Any condition entered as medical history or current medical condition at baseline will be 
coded using the MedDRA dictionary for the Safety Set. They will be summarized by system 
organ class and preferred term of the MedDRA dictionary.
9.4
Analysis of the primary variable
9.4.1
Variable
The primary efficacy variable is ACR20 response (yes, no). The primary analysis time point 
will be at Week 16.


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9.4.2
Statistical model, hypothesis, and method of analysis
Let πj denote the probability of an ACR20 response at Week 16 for treatment group j, j = 0, 1, 
2, where 0 corresponds to placebo, 1 corresponds to secukinumab 150 mg, and 2 corresponds 
to secukinumab 300 mg.  Accordingly, πj/(1 – πj) is the odds for treatment group j, j = 0, 1, 2.
The following null hypotheses (H01 and H02) will be tested against their corresponding 
alternative hypotheses (HA1 and HA2):
H01: [π1/(1 – π1)]/[π0/(1 – π0)] ≤1  versus  HA1: [π1/(1 – π1)]/[π0/(1 – π0)] > 1
H02: [π2/(1 – π2)]/[π0/(1 – π0)] ≤ 1  versus  HA2: [π2/(1 – π2)]/[π0/(1 – π0)] > 1
The primary efficacy variable will be analyzed at each time point using a logistic regression 
model with treatment (3 treatment groups), methotrexate usage at baseline (yes, no), and body 
weight as explanatory variables (Stokes, Davis, and Koch, 2012).  The odds ratios for each 
dose of secukinumab versus placebo, 95% confidence intervals for the odds ratios, and p-
values based on the fitted model will be reported.  If the p-value for a dose of secukinumab 
versus placebo is < 0.05 and the corresponding odds ratio is greater than 1, statistical 
significance in favor of that dose of secukinumab is shown.
The primary analysis of the primary efficacy variable will be based on the Full Analysis Set.
9.4.3
Handling of missing values/censoring/discontinuations
Patients who discontinued prematurely for any reason will be considered non-responders from 
the time they discontinued.  Patients who do not have the required data to compute ACR 
response (i.e., tender and swollen joint counts and at least three of the five ACR domains) at 
baseline and at the specific time point will be classified as non-responders.
9.4.4
Supportive analyses 
The primary efficacy variable will also be analyzed at each time point for the Full Analysis 
Set using the Cochran-Mantel-Haenszel (CMH) test to compare each dose of secukinumab 
against placebo, adjusting for methotrexate usage at baseline (yes, no) (Stokes, Davis, and 
Koch, 2012).  If the treatment comparison p-value is < 0.05 and the proportion of patients 
who are ACR20 responders is higher in a secukinumab treatment group compared to the 
placebo treatment group, statistical significance in favor of that dose of secukinumab is shown.  
Two 95% confidence intervals for the difference between each dose of secukinumab versus 
placebo in the proportion of patients who are ACR20 responders will be calculated using the 
normal approximation to the binomial distribution.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
The secondary efficacy variables are the following:
1. Dactylitis (yes, no)


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2. Enthesitis (yes, no)
3. ACR50 response (yes, no)
4. ACR70 response (yes, no)
5. Minimal Disease Activity (yes, no)
6. PASI75 response (yes, no)
7. PASI90 response (yes, no)
8. PASI100 response (yes, no)
9. Change from baseline in DAS28-CRP
10. Change from baseline in PASDAS
11. Change from baseline in SF12
12. Change from baseline in HAQ-DI
Two analyses of dactylitis and enthesitis (secondary efficacy variables 1 and 2) will be 
performed at each time point.  For the first analysis, the data for the subgroup of patients who 
have dactylitis at baseline will be used (similarly for enthesitis) and the analysis of the binary 
response variable (yes, no) will be similar to the analysis of secondary efficacy variables 3-8
below.  In the supporting analysis, the data for all patients will be used and an ordinal variable 
will be created based on presence (yes) or absence (no) of dactylitis at baseline and a post-
baseline visit (similarly for enthesitis).  The three categories for the ordinal variable will be 
no/no (category 1), no/yes and yes/no (category 2), and yes/yes (category 3).  This ordinal 
response variable will be analyzed using a proportional odds regression model with treatment 
(3 treatment groups), methotrexate usage at baseline (yes, no), and body weight as 
explanatory variables (Stokes, Davis, and Koch, 2012). The odds ratios for each dose of 
secukinumab versus placebo, 95% confidence intervals for the odds ratios, and p-values based 
on the fitted model will be reported.
Secondary efficacy variables 3-8 will be analyzed at each time point using a logistic 
regression model with treatment (3 treatment groups), methotrexate usage at baseline (yes, no), 
and body weight as explanatory variables (Stokes, Davis, and Koch, 2012).  The odds ratios 
for each dose of secukinumab versus placebo, 95% confidence intervals for the odds ratios, 
and p-values based on the fitted model will be reported.  
Secondary efficacy variables 9-12 will be analyzed at each time point by an analysis of
covariance (ANCOVA) model with treatment (3 treatment groups), baseline, methotrexate 
usage at baseline (yes, no), and body weight as explanatory variables.  The least squares 
means of the three treatment groups, least squares mean differences between each dose of 
secukinumab and placebo, 95% confidence intervals for the difference between each dose of 
secukinumab and placebo, and p-values based on the fitted linear model will be reported.  
Missing data will be imputed using the last-observation-carried-forward (LOCF) method.
Analyses of the secondary efficacy variables will be based on the Full Analysis Set.


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9.5.2
Safety variables
The assessment of safety will be based mainly on the frequency of adverse events and 
laboratory data. Other safety data (e.g., vital signs and special tests) will be considered, as 
appropriate.
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any adverse event, having an adverse event in each body system 
and having each individual adverse event. Any other information collected (e.g., severity or 
relatedness to study medication) will be listed, as appropriate.


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Adverse events and serious adverse events up to and including Week 16 visit will be included 
in the database for the analysis at the primary analysis time point (Week 16). All Adverse 
events and serious adverse events will be included in the final database analysis (Week 52).
Laboratory variables will be summarized.
Analysis of safety data will be based on the Safety Set.
9.6
Interim analyses
The database of this study will be locked twice, first after the end of Treatment Period 1
(Week 16) and again after the end of Treatment Period 2 (Week 52).  Data analyses will 
follow each database lock.  The main analysis (or test) for the primary objective will be done 
at Week 16.  As Week 16 is the primary analysis time point, no adjustment to the significance 
level of 0.05 will be made.
9.7
Sample size calculation
The sample size was calculated based on the primary efficacy variable (i.e., ACR20 response)
for the primary comparison (i.e., secukinumab 300 mg versus placebo).  ACR20 response 
rates of 50% for secukinumab 300 mg and 20% for placebo (corresponding to an odds ratio of 
4) at Week 16 were assumed, based on results from AIN457F2312 (FUTURE 2) study.  Using 
a continuity-corrected chi-squared test, an allocation ratio of 2:1, a two-sided significance 
level of 0.05, and a power of 0.90, approximately 88 patients in secukinumab 300 mg group 
and 44 patients in placebo group will be needed (nQuery Advisor 7.0).  Assuming a loss to 
follow-up rate of 10% and a 2:2:1 allocation ratio (secukinumab 300 mg: secukinumab 150
mg: placebo), the total number of randomized patients will be approximately 250 (100 on 
secukinumab 300 mg, 100 on secukinumab 150 mg, and 50 on placebo)
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 CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient 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 


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before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
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 patient will not reliably comply, they 
should not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
10.4
Publication of study protocol and results
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
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 


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and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the 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 prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring should be followed.
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.
 
 
 
 
 
 
 
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.
Doherty SD, Van Voohes A, Lebwohl MG (2008) National Psoriasis Foundation consensus
statement on screening for latent tuberculosis infection in patients with psoriasis treated with 
systemic and biologic agents. J Am Acad Dermatol; 59(2):209-17.
EMA guidance document: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00003439.pdf


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FDA guidance document: 
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M071579.pdf
Feldman 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, et al. (1995) American College of Rheumatology. 
Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum; 38(6):727-35.
Finlay AY and Khan GK (1994) Dermatology Life Quality Index (DLQI): A simple practical 
measure for routine clinical use. Clin Exp Dermatol; 19:210-216. 
Fredriksson T and Pettersson U (1978) Severe psoriasis-oral therapy with a new retinoid. 
Dermatologica; 157:238-44.
Fries JF, Spitz P, Kraines G, Holman H. (1980) Measurement of Patient Outcome in Arthritis. 
Arthritis Rheum; 23:137-145.
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.
Helliwell PS, Firth J, Ibrahim GH, et al (2005). Development of an assessment tool for 
dactylitis in patients with psoriatic arthritis. J Rheumatol 32:1745-50.
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. 
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 
erythrocytesedimentation rate. J Rheumatol; 9(2):224-8.
Manuel O, Kumar D (2008) QuantiFERON-TB Gold assay for the diagnosis of latent 
tuberculosis infection. Expert Rev Diagn; 8(3):247-56.
McInnes IB, Kavanaugh A, Gottlieb AB, et al, on behalf of the PSUMMIT 1 Study Group 
(2013)  Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year 
results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 
2013; published online June 13. http://dx.doi.org/10.1016/ S0140-6736(13)60594-2.
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.
Moll JM, Wright V (1973) Psoriatic arthritis. Semin Arthritis Rheum 3:55-78.


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Philip J Mease, Bernard S Goffe, James Metz, Ann VanderStoep, Barbara Finck, Daniel J 
Burge (2000) Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. 
THE LANCET Vol 356: 385-90 
Philip J. Mease,1 Dafna D. Gladman,2 Christopher T. Ritchlin,3 Eric M. Ruderman,4 Serge D. 
Steinfeld,5 Ernest H. S. Choy,6 John T. Sharp,7 Peter A. Ory,8 Renee J. Perdok,9 and Mark A. 
Weinberg,9 for the Adalimumab Effectiveness in Psoriatic Arthritis Trial Study Group (2005) 
Adalimumab for the Treatment of Patients With Moderately to Severely Active Psoriatic 
Arthritis ARTHRITIS & RHEUMATISM Vol. 52, No. 10, pp 3279–3289
Philip J. Mease·April W.Armstrong (2014) Managing Patients with Psoriatic Disease: The
Diagnosis and Pharmacologic Treatment of Psoriatic Arthritis in Patients with
Psoriasis Drugs74:423-441
 
 
Stokes ME, Davis CS, Koch GG (2012) Categorical data analysis using the SAS system. 3rd 
ed; Cary, NC: SAS Institute, Inc.
Taylor W, Gladman D, Helliwell, et al (2006) Classification criteria for psoriatic arthritis. 
Arthritis Rheum 54:2665-73.
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.
Turkiewicz AM, Moreland LW (2007) Psoriatic arthritis: current concepts on pathogenesis-
oriented therapeutic options. Arthritis Rheum 56(4):1051-66.
Van Leeuwen MA, Van Rijswijk MH, Van der Heijde DMFM, 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 BS (1994) F-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.
Wolfe F. (1997) Comparative usefulness of C-reactive protein and erythrocyte sedimentation 
rate in patients with rheumatoid arthritis. J Rheumatol; 24:1477-85.
 
 
12.1
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. Whether or not any action needs to be taken to address notable laboratory or 
vital signs values will be determined by the investigator/qualified site staff, taking into 


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account the overall status of the subject. No specific action is pre-defined within this study 
protocol.
Liver function and related variables 
ALT (SGPT) 
> 3 x Upper Limit of Normal (ULN)
AST (SGOT) 
> 3 x ULN
Total bilirubin 
> 1.5 x ULN
Alkaline phosphatase > 2 x ULN
Renal function and electrolyte variables
Creatinine (serum) 
> 1.5 x ULN
Hematology values
Hemoglobin
≥ 2.0 g/dL decrease from baseline
Platelet count 
< Lower Limit of Normal (LLN)
White blood cell            < 0.8 x LLN
Neutrophils 
< 0.9 x LLN
Eosinophils 
> 1.1 x ULN
Lymphocytes
> 1.1 x ULN
12.2
Appendix 2: The classification criteria for psoriatic arthritis 
(CASPAR)
To meet the Classification of Psoriatic Arthritis (CASPAR) criteria for diagnosis of psoriatic 
arthritis according to (Taylor 2006), a subject must have inflammatory articular disease (joint, 
spine or entheseal) and at least 3 points from the following 5 categories:
1. Evidence of current psoriasis, a personal history of psoriasis, or a family history of 
psoriasis (2 points) 

Current psoriasis is defined as psoriatic skin or scalp disease present today as judged 
by a rheumatologist or dermatologist.† 

A personal history of psoriasis is defined as a history of psoriasis that may be 
obtained from a patient, family physician, dermatologist, rheumatologist, or other 
qualified health care provider. 

A family history of psoriasis is defined as a history of psoriasis in a first- or second-
degree relative according to patient report.
2. Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis 
observed on current physical examination (1 point) 
3. A negative test result for the presence of rheumatoid factor by any method except latex        
(1 point) 


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4. Either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis 
recorded by a rheumatologist (1 point) 
5. Radiographic evidence of juxta-articular new bone formation appearing as ill-defined 
ossification near joint margins (but excluding osteophyte formation) on plain radiographs 
of the hand or foot (1 point)
Total score: _______  
(The CASPAR criteria eCRF will autopopulate the total number of points of the CASPAR 
criteria met by the subject.  If the total score ≥ 3, the subject meets CASPAR criteria for PsA 
diagnosis.)
† Current psoriasis is assigned a score of 2; all other features are assigned a score of 1
12.4
Appendix 4: American College of Rheumatology (ACR) Measures 
and Criteria of Response
Number of tender joints:
Joint counts will be performed by the assessor(s) who must be well trained and part of the site 
personnel. Whenever possible, the same evaluator should perform these assessments at all 
visits.
The 78 joints assessed for tenderness include the 2 temporomandibular, 2 sternoclavicular, 2 
acromioclavicular joints, 2 shoulders, 2 elbows, 2 wrists, 2 first carpometacarpal, 10 
metacarpophalangeal, 10 proximal interphalangeal, 8 distal interphalangeal joints of the hands, 
the 2 hip, 2 knee, 2 talo-tibial, 2 mid-tarsal, 10 metatarsophalangeal, 10 proximal 
interphalangeal, and 8 distal interphalangeal joints of the feet. 
Joint tenderness and swelling are to be graded present (1) or absent (0). 


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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:

Tender joint count,

Swollen joint count.

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)
12.5
Appendix 5: Disease Activity Score (DAS)
The Disease Activity Score (DAS) is a combined index to measure the disease activity in 
patients with RA. It has been extensively validated for its use in clinical trials in combination 
with the EULAR response criteria.


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Evaluation of response to a treatment can be made much easier and more objective using the 
DAS. 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 DAS-CRP has been developed. The C-reactive protein (CRP) may be 
used as an alternative to ESR in the calculation of the DAS or 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 DAS, so when 
the DAS 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 DAS in the clinical trials
Comparing the DAS28 from one patient on two different time-points, it is possible to define 
improvement or response. The EULAR response criteria are defined as follows:
Present DAS28
DAS28 improvement
>1.2
0.6 - 1.2
<0.6
<3.2
good response
moderate 
response
no response
3.2 - 5.1
moderate 
response
moderate 
response
no response
>5.1
moderate 
response
no response
no response
Both the thresholds for high and low disease activity and remission and the abovementioned 
improvement criteria should give you a feel how to interpret your DAS28 scores.
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(tender28) + 0.28 * sqrt(swollen28) + 0.70 * ln(ESR) + 0.014 * GH
The DAS28 provides you with a number on a scale from 0 to 10 indicating the current activity 
of the rheumatoid 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) may be used as an alternative to ESR in the calculation of the DAS 
or 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 


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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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12.6
Appendix 6: The Psoriasis Area and Severity Index (PASI)


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12.8
Appendix 8: 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 


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computed if the patient does not have scores for at least 6 categories. This SDI is the HAQ©
score, which will be used in the statistical analyses of this instrument. The range for this score 
is (0, 3).
HAQ© Data Collection
The HAQ© is to be completed by the patients in their local languages, using an electronic 
device. The questionnaires should be completed by the patients in a quiet area free from 
disturbance, and before any visit assessments. Patients should receive no help from family 
members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the patient’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a patient has missed a question or given more than one response 
per question, then this should be brought to patient. Incomplete questions should not be 
accepted without first encouraging the patient to complete unanswered questions.
The investigator must complete the patient/visit information on the electronic device and 
ensure that the center number, patient’s number and initials are identical to the Case Record 
Form. As there are no source data for this questionnaire, the data queries will be restricted to 
patient/visit information.


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12.10
Appendix 10: Guidelines for administering the PRO
questionnaires
Before trial start
PROs will be administered to patients using an electronic tablet called a SitePad
Study coordinators should familiarize themselves with the PRO questionnaire(s) in the trial 
and identify any items where a patient’s response might highlight issues of potential concern. 
For example, one question in the SF-12 ‘How much of the time in the past 4 weeks- have you 
felt downhearted and blue?’ If a patient responds ‘most or all of the time’, then the study 
coordinator should inform the study investigator.
Before completion
1. The SitePad will have the correct Questionnaires for the patients, at the appropriate visits, 
and in the appropriate language.  

2. Patients should have adequate space and time to complete their questionnaires on the 
SitePad
3. Questionnaires should be administered and completed before the clinical examination
During completion
1. Administrator may clarify the questions but should not influence the response
2. The SitePad will only allow one response for each question 
3. Also see ‘Addressing Problems and Concerns’
After completion
1. The Patient’s data/reports MUST be transmitted so it can be reviewed in StudyWorks.
*If any response is received which may directly impact or reflect the patient’s medical 
condition (e.g. noting of depression), that information should be communicated by the study 
coordinator to the investigator).
Addressing Problems and Concerns
Occasionally a patient may have concerns or questions about the questionnaires administered. 
Guidance related to some of the most common concerns and questions are given below.
The patient does not want to complete the questionnaire(s)
Tell the patient that completion of the questionnaire(s) is voluntary but is an important part of 
their participation in the study. The goal of these questionnaires 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, please ask them to complete the end of visit 


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questionnaire which confirms they have declined to complete the questionnaires. 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-reported. 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, that 
questionnaire will be forfeited since partial response will not be saved. 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 questionnaires are not routinely shared with treating staff, and that their 
responses will only be seen by you 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. 
General Information about all questionnaire(s): 
All questionnaires are to be completed by the patients on the SitePad. 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 verbatim without influencing their answers. The information 
provided is strictly confidential and will be treated as such.


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The investigator must complete the patient/visit information on the SitePad and ensure that 
the center number, patient’s number and initials are identical to the electronic Case Record 
Form. As there are no source data for the questionnaires, the data queries will be restricted to 
patient/visit information

SAP_001.pdf: 
US Clinical Development & Medical Affairs - General Medicine
AIN457/Secukinumab
CAIN457FUS01 / NCT02798211
A randomized, double-blind, placebo-controlled, parallel-
group, multicenter study to evaluate the safety and efficacy 
of secukinumab 300 mg and 150 mg in adult patients with 
active psoriatic arthritis after 16 weeks of treatment 
compared to placebo and to assess the safety, tolerability 
and efficacy up to 52 weeks
Statistical Analysis Plan (SAP)
Author:
Trial Statisticians:
 
Document type:
SAP Documentation
Document status:
Amendment 2.0
Release date:
31-Dec-2018
Number of pages:
68
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Secukinumab/AIN457FUS01
Document History – Changes compared to previous final version of SAP
Date
Time point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
27-Jun-
2016
Prior to DB 
lock
1st Draft 
Version
31-Oct-
2016
Prior to DB 
lock
To keep 
consistency 
with the latest 
protocol
Screening period in study 
design has been changed
1.1
Multiple imputation has been 
added for missing data 
imputation
2.5.3 and 2.7.3
Section containing ECG and 
cardiac imaging data has been 
modified
2.8.4
SAS code has been added for 
multiple imputation
5.4
12-Oct-  
2017
Prior to DB 
lock
Added new 
variables 
suggested by 
clinical team
PD list has been updated
ACR90 and 4-point are 
added for the analysis (not 
mentioned in protocol)
5.5
2.13
20-Feb-
18
Prior to DB 
lock
Added new 
variables 
suggested by 
clinical team
Tables for 
tender joint 
response, 
swollen joint 
response,
Patient’s 
assessment of 
PsA pain 
intensity 
response, 
Patient’s 
global
Assessment 
2.11 and 2.13


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Secukinumab/AIN457FUS01
Date
Time point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
of Disease 
Activity 
response, 
Physician’s 
Global 
Assessment 
of Disease 
Activity 
response,
HAQ-DI 0.5 
response, 
HAQ-DI 
change from 
baseline of at 
least -0.35 
response,
 
 
 
 
IGA 
mod 2011 
response,
VLDA (Very 
Low Disease 
Activity) 
response,
 
 
with their 
respective 
figures are
added.


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Secukinumab/AIN457FUS01
Date
Time point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
2-Nov-
2018
10-Nov-
2018
Post 
Week 
16 DB lock 
Post 
Week 
16 DB lock
Analysis for 
Week 52 
added 
Analysis set 
definition
added
Suggested by 
CTT
ACR90 and 
4-point 
enthesitis 
were 
removed.
Analysis of 
binary and 
continuous 
variables for 
treatment 
period 2 is 
added.
Definition for 
Up-titration 
Set is added.
Definition of 
Very Low 
Disease 
Activity 
(VLDA)
Section 2.5.2 and 
Section 2.7.2
Section 2.2
Section 2.7.2
13-Dec-
2018
Post 
Week 
16 DB lock
Analysis for 
VLDA, TJC, 
SJC, PsA
response, 
Patient’s 
Section 
2.5.2, 
2.7.2, 2.11, 2.13


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Secukinumab/AIN457FUS01
Date
Time point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Global
Assessment 
of Disease 
Activity 
response, 
Physician’s 
Global 
Assessment 
of Disease 
Activity 
response, 
HAQ-DI <= 
0.5, MCID 
response, 
Remission, 
Low disease 
activity
Algorithm of 
ACR 
derivation
Week 52 
analysis for 
VLDA, TJC, 
SJC, PsA
response, 
Patient’s 
Global 
Assessment 
of Disease 
Activity 
response, 
Physician’s 
Global 
Assessment 
of Disease 
Activity 
response, 
HAQ-DI <= 
0.5, MCID 
response, 
Remission, 
Low disease 
activity


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Secukinumab/AIN457FUS01
Table of contents
Table of contents .................................................................................................................6
List of abbreviations............................................................................................................8
1
Introduction .......................................................................................................................10
1.1
Study design...........................................................................................................10
1.2
Study objectives and endpoints .............................................................................12
2
Statistical methods.............................................................................................................15
2.1
Data analysis general information .........................................................................15
2.1.1
General definitions................................................................................16
2.1.2
Visits windows......................................................................................17
2.1.3
Multiple assessments within visit windows..........................................18
2.2
Analysis sets ..........................................................................................................19
2.2.1
Subgroup of interest ..............................................................................20
2.3
Patient disposition, demographics and other baseline characteristics ...................20
2.3.1
Patient disposition.................................................................................20
2.3.2
Patient demographic and other baseline characteristics........................20
2.3.3
Medical history......................................................................................21
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................21
2.4.1
Study treatment / compliance................................................................21
2.4.2
Prior, concomitant and post therapies...................................................23
2.5
Analysis of the primary objective..........................................................................23
2.5.1
Primary endpoint...................................................................................24
2.5.2
Statistical hypothesis, model, and method of analysis..........................24
2.5.3
Handling of missing values/censoring/discontinuations.......................25
2.5.4
Supportive analyses...............................................................................25
2.6
Analysis of the key secondary objective ...............................................................25
2.7
Analysis of secondary efficacy objective(s)..........................................................25
2.7.1
Secondary endpoints .............................................................................25
2.7.2
Statistical hypothesis, model, and method of analysis..........................26
2.7.3
Handling of missing values/censoring/discontinuations.......................29
2.7.4
Supportive analyses...............................................................................29
2.8
Safety analyses.......................................................................................................29
2.8.1
Adverse events (AEs)............................................................................29
2.8.2
Deaths....................................................................................................31
2.8.3
Laboratory data .....................................................................................31
2.8.4
Other safety data ...................................................................................34


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2.9
Pharmacokinetic endpoints....................................................................................34
2.10
PD and PK/PD analyses.........................................................................................34
2.11
Patient-reported outcomes .....................................................................................34
2.12
Biomarkers.............................................................................................................39
39
49
2.14
Interim analysis......................................................................................................49
3
Sample size calculation .....................................................................................................49
4
Change to protocol specified analyses ..............................................................................50
5
Appendix ...........................................................................................................................50
5.1
Imputation rules.....................................................................................................50
5.1.1
Study drug.............................................................................................50
5.1.2
AE date imputation ...............................................................................50
5.1.3
Concomitant medication date imputation .............................................52
5.2
AEs coding/grading ...............................................................................................53
5.3
Laboratory parameters derivations ........................................................................53
5.4
Statistical models...................................................................................................53
5.4.1
Primary analysis....................................................................................53
5.4.2
Key secondary analysis.........................................................................56
5.4.3
Secondary analysis................................................................................57
5.4.4
Exposure-adjusted incidence rate and 100*(1-α)% confidence 
interval...................................................................................................57
5.4.5
Crude incidence and 100*(1-α)% confidence interval..........................58
5.4.6
Mixed-effects repeated measures model...............................................58
5.5
Rule of exclusion criteria of analysis sets..............................................................59
6
References .........................................................................................................................67


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List of abbreviations
ACR
American College of Rheumatology
AE
Adverse event
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
ANCOVA
Analysis of covariance
AS
Ankylosing Spondylitis
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
ATC
Anatomical Therapeutic Classification
BL
Baseline
BMI
Body mass index
CRF
Case Report/Record Form (paper or electronic)
CRP
C-reactive protein
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAS
Disease Activity Score
DMARD
Disease Modifying Antirheumatic Drug
DMC
Data Monitoring Committee 
DS&E
Drug Safety & Epidemiology
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA/EMEA
European Medicines (Evaluation) Agency
ESR
Erythrocyte Sedimentation Rate
EULAR
European League Against Rheumatism
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HAQ-DI©
Health Assessment Questionnaire – Disability Index
HRQoL
Health-related Quality of Life
hsCRP
High sensitivity C-Reactive Protein
IGA mod 2011
Investigator’s Global Assessment modified 2011
IL
Interleukin
IRB
Institutional Review Board
IRT
Interactive Response Technology
LFT
Liver function test
LOCF
Last-observation-carried-forward
MDA
Minimal Disease Activity
MedDRA
Medical Dictionary for Drug Regulatory Affairs


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mmHg
MMRM
Millimeter mercury
mixed-effects model repeated measures
MTX
Methotrexate
NSAID
Non-steroidal anti-inflammatory drug
OS
Overall Survival
PASDAS
Psoriatic Arthritis Disease Activity Score
PASI
Psoriasis Area and Severity Index
PD
Protocol deviation
PFS
Progression-Free Survival
PK/PD
Pharmacokinetics/ Pharmacodynamic
PRO
Patient-reported Outcomes
PsA
Psoriatic arthritis
PSOC
Primary System Organ Class
PT
Preferred Term
QoL
Quality of Life
RF
Rheumatoid factor
SAP
Statistical Analysis Plan
SAE
Serious adverse event
s.c.
Subcutaneous(ly)
SCR
Screening
SF-12
Medical Outcome Short Form (12) Health Survey
SJC
Swollen Joint Count
SMQ
Standardized MedDRA Query
SpA
Spondyloarthritis
SOC
System Organ Class
TFLs
Tables, Figures, Listings
TJC
Tender Joint Count
ULN
Upper limit of normal
VAS
Visual analog scale
WBC
White blood cell
WHO
World Health Organization


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1
Introduction
This document describes the planned statistical methods for all safety and efficacy analyses 
which will be used in the phase 4 clinical trial AIN457FUS01. 
The main purpose of this document is to provide summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
Analysis plans in this document refer to the related statistical analysis sections in clinical 
study reports.
Data will be analyzed by Novartis Product Life-Cycle Services and/or a designated Contract 
Research Organization using statistical software SAS® Version 9.4 according to Section 9 
(Data Analysis) of the study protocol which is available in Appendix 16.1.1 of the CSR.  The 
statistical methodology is described below and the deviations from the protocol are 
documented. Additional detailed information regarding the analysis methodology is contained
in the Appendix section 16.1.9 of CSR.
Please refer to the following document:

Clinical Protocol CAIN457FUS01
1.1
Study design
This study uses a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
design. Approximately 250 adult patients (in 2:2:1 ratio; 100 secukinumab 300 mg, 100 
secukinumab 150 mg and 50 placebo) with active psoriatic arthritis (PsA) and with a target skin 
lesion with PASI score of 1 or greater will be randomized from approximately 65 investigative
sites in the United States. 
Screening will be flexible in duration based on the time required to wash out prior anti-
rheumatic medications and have a duration of up to 8 weeks before randomization, followed by 
a treatment period up to Week 52.
Patients that do not require a washout, can proceed on to the baseline visit once all 
inclusion/exclusion criteria are being met.
At baseline (BL), patients whose eligibility is confirmed will be randomized to one of 
three treatment groups and will enter the Placebo-Controlled Treatment Period.
Treatment Period 1
The Treatment Period 1 is defined as starting from Randomization through Week 16 (prior to
the Week 16 dose). At the start of the Placebo-Controlled Treatment Period, patients will be
randomized via IRT in a 2:2:1 ratio to one of three treatment groups (secukinumab 300 mg s.c., 
secukinumab 150 mg s.c. or placebo s.c.).

Group 1- Secukinumab 300 mg: secukinumab 300 mg (two s.c. injections of the 150
mg dose) once weekly for five weeks (at Baseline, Weeks 1, 2, 3, and 4), followed
by dosing every four weeks. 

Group 2- Secukinumab 150 mg: secukinumab 150 mg (one s.c. injection of the 150
mg dose and one s.c. secukinumab injection of placebo) once weekly for five weeks
(at Baseline, Weeks 1, 2, 3, and 4), followed by dosing every four weeks. 


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
Group 3- Placebo: placebo (two s.c. injection of 150 mg secukinumab 
placebo per dose) once per week for five weeks (at Baseline, Weeks 1, 2, 3, 
and 4), followed by dosing every four weeks. 
Treatment Period 2

Patients receiving secukinumab 300 mg (Group 1) will continue to receive same dose 
up to Week 52.

At Weeks 16, 28 and 40 patients on secukinumab 150 mg (Group 2) will be 
classified as responders (≥ 20% improvement from BL in both tender and swollen 
joint counts) or non-responders.

At Weeks 16, 28 and 40 patients on secukinumab 150 mg (Group 2) who are 
responders will continue to receive secukinumab 150 mg (1.0 mL) plus placebo 
(1.0 mL) every 4 weeks until next evaluation of responder status at weeks 28 or 
40. 

Patients who did not meet the responder criteria at Week 16, 28 or 40 will start 
receiving secukinumab 300 mg every 4 weeks and will continue this dose up to 
Week 48.

Patients on placebo (Group 3) regardless of their responder status will start receiving 
secukinumab 300 mg every 4 weeks from Week 16 up to Week 48.
Those patients whose tender and swollen joint counts both reduce by ≥20% from baseline will 
be classified as ‘responders’ and those patients who do not meet the responder criteria will be 
classified as ‘nonresponders’.
Patients, investigators/site staff, persons performing assessments, and Novartis study personnel 
will remain blinded to individual treatment assignment from the time of randomization until
the final database lock.
Rescue medication will not be allowed during the day of the clinical visit and before
completion of Week 16 assessments. Although no subject will be restricted from receiving 
necessary rescue medications for lack of benefit or worsening of disease, patients will be 
discontinued from the study if rescued with prohibited biologics and should obtain end of 
study assessments at the earliest possible date, provided consent to do so has not been 
withdrawn.
No stratification at randomization will be performed.
The following figure describes the study design.


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Figure 1.1: Study Design
Primary analysis time point
The primary analysis will be performed at Week 16.
Interim analyses
As planned, database lock will be performed at the end of Treatment Period 1 (Week 16), after 
all patients have completed the Week 16 visit. Data analyses will follow after first database lock.  
1.2
Study objectives and endpoints
Table 1.2-1: Objectives and endpoints
Objective
Endpoint
Primary objective
To demonstrate that the efficacy of 
secukinumab 300 mg at Week 16 is
superior to placebo in adult patients with 
active PsA based on the proportion of 
patients achieving an American College of 
Rheumatology 20 (ACR20) response.
ACR20 response (yes, no)
Secondary objectives


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To evaluate the efficacy of secukinumab 
150 mg compared to placebo at
Week 16 in patients with active PsA based 
on the proportion of patients achieving an 
American College of Rheumatology 20 
(ACR20) response.
ACR20 response (yes, no)
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to placebo at 
Week 16 based on the proportion of patients 
withdactylitis in the subset of patients who 
have dactylitis at baseline.
Dactylitis (yes, no)
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to
placebo at Week 16 based on the proportion 
of patients with enthesitis in the subset of 
patients who have enthesitis at baseline.
Enthesitis (yes, no) 
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to
placebo at Week 16 in subset of patients 
with active PsA and number of tender and 
swollen joints less than 10 at baseline based 
on the proportion of patients achieving 
ACR20, ACR50, and ACR70 responses.
ACR20, ACR50, and ACR70 responses
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to placebo at 
Week 16 based on the proportion of patients
achieving ACR50 and ACR70 responses.
ACR50 and ACR70 responses
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to placebo at 
Week 16 based on the proportion of patients
achieving Minimal Disease Activity (5 of 
the following 7 criteria:
≤1 tender joint, ≤1 swollen joint, PASI ≤1 or 
IGA mod 2011 ≤1,, patient assessment of 
pain (0-100 Visual Analog Scale (VAS)) 
≤15, patient global assessment of disease 
(VAS) ≤20, HAQ-DI ≤0.5, tender entheseal 
points ≤1)
Minimal Disease Activity (yes, no) (5 of the 
following 7 criteria: ≤1 tender joint, ≤1 
swollen joint, PASI ≤1 or IGA mod 2011 ≤1, 
patient assessment of pain (0-100 Visual 
Analog Scale (VAS)) ≤15, patient global 
assessment of disease (VAS) ≤20, HAQ-DI 
≤0.5, tender entheseal points ≤1) 
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to
placebo at Week 16 based on the proportion 
of patients achieving a PASI75, PASI90, 
and PASI100 responses
PASI75, PASI90, PASI100 responses (yes, 
no)


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To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to placebo at 
Week 16 based on the change from baseline 
in
DAS28-CRP.
Change from baseline in DAS28-CRP 
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to placebo at 
Week 16 based on the change from baseline 
in Psoriatic Arthritis Disease Activity Score 
(PASDAS).
Change from baseline in Psoriatic Arthritis 
Disease Activity Score (PASDAS) 
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to placebo at 
Week 16 based on the change from baseline 
in SF12.
Change from baseline in SF12 
To evaluate the efficacy of secukinumab 
300 mg and 150 mg compared to placebo at 
Week 16 based on the change from baseline 
in HAQDI.
Change from baseline in HAQ-DI 
To evaluate the overall safety and 
tolerability of secukinumab 300 mg and 150 
mg compared with placebo as assessed by 
vital signs,
clinical laboratory values, and adverse events 
(AE) monitoring.
Overall safety, as measured by frequency and 
severity of adverse events (AE) monitoring 
and changes in clinical laboratory values and  
vital signs from baseline


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2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by Novartis Product Life-Cycle Services and/or a designated Contract 
Research Organization.
It is planned that the data from all centers that participate in this protocol will be combined, so 
that an adequate number of patients will be available for analysis. Analysis datasets and 
statistical outputs will be produced using the most recent SAS® Version 9.4 (SAS Institute Inc., 
Cary, NC, USA), and stored in Novartis global programming & statistical environment (GPS).
As the primary analysis time point is Week 16, there will be a database lock after all patients 
have completed the Week 16 visit and data are clean and complete. At that time, only the 
statistician and programmer(s) from Novartis and/or a designated CRO will be unblinded in 
order to perform the analysis. Results from the analyses of all data through Week 16 will be 
shared internally. For publication purposes, summary results from the Week 16 primary 
analysis time point may be shared with the health care community; however, individual subject-
level data will remain blinded until the end of the trial. A final database lock will occur when 
all patients have completed the study.
Summary statistics for continuous variables will include mean, standard deviation, standard 
error of mean, median, 25th and 75th percentiles, interquartile range, minimum, and maximum
at each time point. Summary statistics for discrete variables will be presented in the number and 
percent of patients in each category. Summary statistics will also be presented graphically 
wherever applicable. If not otherwise specified, p-values and confidence interval (CI) will be 
presented as two-sided and the default level of significance will be set to 0.05 (two-sided). For
all continuous variables (efficacy and safety), change from baseline and percentage change from 
baseline by visit will also be presented.


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Data analyses will be presented by treatment group. Efficacy and safety data for the placebo-
controlled period (or the entire Treatment Period as appropriate) will be presented by the 
following 3 treatment groups. Patients may be included in more than one treatment group for 
some analyses (e.g. exposure-adjusted adverse events over the entire treatment period).
Eligible patients will be randomized to secukinumab 300 mg (Group 1), secukinumab 150 mg 
(Group 2) or placebo (Group 3) for the first 16 weeks (until Week 16 treatment). Note that the 
treatment groups above for a patient may differ depending on the time period of the analysis 
and whether one assesses the patient for efficacy or safety.
The analysis will be conducted on all patients’ data at Week 16 and at the time the trial ends 
(Week 52). 
For Treatment Period 2, all data analyses will be presented by Weeks 16, 28 and 40, based on
the number of patients who switched to secukinumab 300 mg and number of patients who 
continued in secukinumab 150 mg at the respective visits.
All the assessments from scheduled visits will be included for summaries and analyses, 
whereas the listing will include available data.
Comparative efficacy data
Comparative efficacy analyses (i.e. inferential efficacy comparisons with placebo) will focus
on the time period when both active drug and the placebo are given in a manner suitable for
making comparisons (i.e., first 16 weeks of treatment). Comparative efficacy will be performed 
based on the FAS using the randomized treatment. After week 16 till week 52, the efficacy 
variables will be summarized descriptively or otherwise specified using inferential analysis, on 
the FAS.
2.1.1
General definitions
Study treatment

Investigational Treatment:
Secukinumab 150 mg provided in 1.0 mL in PFS for s.c. injection. 
Secukinumab placebo provided in 1.0 mL in PFS for s.c. injection.
Dates and time windows
Study treatment start and end date
Study treatment start date is defined as the first date when a non-zero dose of study drug is 
administered and recorded on the Drug Administration Record (DAR) CRF page. Similarly, 
study treatment end date is defined as the last date when a non-zero dose of study drug is 
administered and recorded on the DAR CRF page of the core study.


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Study day
Study day will be calculated as (event date – study drug start date + 1 day) for events that 
occurred on or after study drug start date (e.g., visit, lab samples, AEs). For events prior to study 
drug start date (e.g., time of diagnosis), study day will be negative and calculated as (event date 
– study drug start date). Note that study drug start date is study day 1 and the day before study 
drug start date is study day -1 (i.e. no study day 0).
Due to the study drug dosing schedule, one month will be considered as 28 days. However, for 
“time since event” data (e.g., medical history), one month will be considered as 365.25/12 days 
for events that occurred prior to study Day 1. Time from events prior to the start of study drug, 
e.g., time since diagnosis, is calculated as the difference between the start date of study drug 
and the date of prior event. 
Note that, the first dose day is Day 1, and the day before the first dose day is counted as Day -
1 (not Day 0).
Baseline and post-baseline definitions
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. A post-baseline value refers to a measurement taken after the first 
dose of study treatment.
Treatment Period: There are 2 Treatment Periods for this study defined as:
Treatment Period 1 is defined as the 16-week, placebo-controlled, double-blind Treatment 
Period starting from baseline till Week 16.
Treatment Period 2 is a 36-week, double-blind active Treatment Period starting from Week 16
till Week 52.
Lost to follow up: The patients whose study completion status is unclear because they fail to 
appear for study visits without stating an intention to withdraw
On-treatment period: The period where the patients are exposed to the study treatment. For 
this study the treatment phase consists of 52 weeks.
2.1.2
Visits windows
Visit-windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are the protocol defined scheduled visits around which visit windows were created to 
cover the complete range of days within the study. The visit windows are shown in Table 2-1. 
These apply to measurements taken at every visit. For assessments collected less often, different 
visit windows will be applied as detailed below.
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. For example, if the Week 4 visit of a subject is delayed and occurs on Day 
46 instead of on Day 29, say, it will be re-aligned to visit window Week 8. In the case of major 
deviations from the visit schedule, or due to unscheduled visits, several assessments of a subject 


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may fall in a particular visit window (either scheduled or unscheduled). Statistical approaches 
to handle multiple assessments in a given visit window are specified below.
Of note, subjects are allowed to have gaps in visits.
Table 2-1
Assessment windows for scheduled visits 
Analysis Visit
Week
Scheduled Day
Visit Window
Baseline
BSL
1
-28 days to Day 1*
Week 1
1
8
Day 2-11
Week 2
2
15
Day 12-18
Week 3
3
22
Day 19-25
Week 4
4
29
Day 26-43
Week 8
8
57
Day 44-71
Week 12
12
85
Day 72-99
Week 16
16
113
Day 100-127
Week 20
20
141
Day 128-155
Week 24
24
169
Day 156-183
Week 28
28
197
Day 184-211
Week 32
32
225
Day 212-239
Week 36
36
253
Day 240-267
Week 40
40
281
Day 268-295
Week 44
44
309
Day 296-323
Week 48
48
337
Day 324-351
Week 52
52
365
Day 352-379
* Baseline measurement before the first drug administration for safety assessments and before the 
randomization for efficacy assessments. For efficacy, visit windows refer to date of randomization.
2.1.3
Multiple assessments within visit windows
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the subject in summary statistics in a visit window (See Table
2-2).
For baseline assessment definition, see section 2.1.1. For post-baseline visit windows, the 
following applies (unless otherwise specified):

for quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen); 

for qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined.

in case qualitative variables are based on quantitative variables, e.g., PASI 75 response, the 
visit will be assigned to the quantitative variable, and this visit will be used for the derived 
qualitative variable.


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2.2
Analysis sets
The following analysis sets will be used for the statistical reporting and analyses:
Randomized Set: The Randomized Set includes all randomized patients.  
Safety Set: The Safety Set includes all patients who received at least one dose of study 
medication.  Patients will be included in the analysis according to treatment received.
Full Analysis Set (FAS):  The Full Analysis Set comprises all patients to whom study
medication has been assigned. Patients inappropriately randomized (e.g., IRT was called in 
error for randomization of a screen failed patient) will be excluded from this analysis set.  
Psoriasis Subset: The Psoriasis Subset comprises patients in whom at least 3% of body surface 
area was affected by psoriatic skin involvement at baseline.
Dactylitis Subset: The Dactylitis Subset comprises patients who have LDI >= 1 at baseline.
 
 
 


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Up-titrated Subset: Up-titration Subset includes all completed patients who were up-titrated 
from 150 mg to 300 mg in Treatment Period 2, based on the response.
For efficacy analyses, following the intent-to-treat principle, patients will be analyzed according 
to the treatment they were assigned to at randomization.
2.2.1
Subgroup of interest
Planned subgroups of interest are the subsets defined in Section 2.2. 
2.3
Patient disposition, demographics and other baseline 
characteristics
Summary statistics will be presented for continuous demographic and baseline characteristics
and the number and percentage of patients in each category will be presented for categorical 
variables for each treatment group of all patients, and also by the subgroup of patients with 
dactylitis at baseline, and the subgroup of patients with enthesitis at baseline. The summaries 
will be reported for both the Randomized Set and the Full Analysis Set (FAS).
2.3.1
Patient disposition
The number and percentage of patients screened will be presented. In addition, the reasons for 
screen failures will be provided. 
The number and percentage of patients in the Randomized Set and FAS who are enrolled, and 
who completed the treatment periods and who discontinued the study prematurely (including 
the reason for discontinuation) will be presented at the end of each Treatment Period (Week 16 
and Week 52), if appropriate, for each treatment group and all patients.
For each protocol deviation (PD), the number and percentage of patients for whom the PD 
applies will be tabulated. Type of protocol deviation will also be reported.
2.3.2
Patient demographic and other baseline characteristics
The following demographic and baseline variables, if collected, will be summarized:
Continuous variables:

Age (which is derived from date of birth and the screening assessment date)

Height

Weight

Body mass index (BMI) = (body weight in kilograms) / (height in meters)2

RAPID3
Categorical variables:


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
Age categories (≥18 - <40, ≥40 - <65, ≥65 - <75, 75 years and older)

Sex

Race

Ethnicity

Child-bearing status (for females only)
Baseline disease characteristics will also be summarized for the following variables:

The time (years) since first PsA diagnosis, PsA disease duration (if different from time 
since diagnosis)

History and, duration of psoriasis, including time (years) since first diagnosis of 
psoriasis 

Smoking status at baseline

Alcohol status at baseline

Tuberculosis (TB) status
2.3.3
Medical history
Any condition entered on the relevant medical history / current medical conditions eCRF will
Be coded using the MedDRA dictionary. They will be summarized by system organ class
(SOC) and preferred term (PT) of the MedDRA dictionary. 

Summary will be provided for cardiovascular medical history.

Previous PsA/psoriasis treatments of each therapy will also be summarized.

Chest X-ray (screening) results will also be listed.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Study Treatment
The summaries by treatment group will be performed cumulatively by the actual treatment 
received (as follows) for every visit until Week 16. 
Treatment groups in Treatment Period 1:

Secukinumab 300 mg

Secukinumab 150 mg

Placebo


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For entire treatment period, the summaries by treatment group will be performed cumulatively 
by the actual treatment received (as follows) for every visits till Week 52, including the patients 
who switched at Weeks 16, 28, 40.
Treatment groups for entire treatment period analysis:
For efficacy variables:

Secukinumab 300 mg

Secukinumab 150 mg - 150 mg (R)

Secukinumab 150 mg - 300 mg (NR)

Any Secukinumab 150 mg

Placebo - Secukinumab 300 mg
For safety variables

Any Secukinumab 150 mg

Any Secukinumab 300 mg

Any Secukinumab
The analysis of study treatment data will be based on the Safety Set. The number of active and
placebo injections will be summarized by treatment group up to Week 52.
Duration of exposure
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number and percentage of 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 of study Treatment Period 1 will be defined as the time from first dose of 
study treatment till the end of Treatment Period 1 (Week 16).
Duration of exposure of switched treatment group (for patients switching from placebo to 
secukinumab 300 mg, or secukinumab 150 mg to 300 mg) in Treatment Period 2 will be defined 
as the time from treatment switch to end of Treatment Period 2 (Week 52). 
The duration of exposure of initial treatment group in Treatment Period 2 will be defined as the 
time from first dose (Week 16) till the end of Treatment Period 2 (for secukinumab 300 mg
group) or until the switch (for secukinumab 150 mg group).
For patients who discontinue, this will be the patient’s last visit in the corresponding treatment 
period.
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 patient years) = duration of exposure (years) / 100
The analyses of duration of exposure described above will be done for the entire study
treatment periods.


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2.4.2
Prior, concomitant and post therapies
Prior and concomitant therapies
Prior medications are defined as treatments taken and stopped prior to first dose of study
treatment. Any medication given at least once between the days of first dose of randomized
study treatment and the date of the last study visit will be a concomitant medication, including
those which were started pre-baseline and continued into the period where study treatment is
administered. Safety Set will be used for the analysis.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification
(ATC) codes and grouped by anatomical main group. Tables will show the overall number
and percentage of patients receiving at least one treatment of a particular ATC code and at
least one treatment in a particular anatomical main group.
Significant prior and concomitant surgeries and procedures will be summarized by primary
system organ class and MedDRA preferred term.
Prespecified concomitant medications
(Methotrexate (MTX), Folic acid, Systemic 
corticosteroids, Non-steroidal anti-inflammatory drugs (NSAIDs) (including selective COX-2 
inhibitors), low strength opioids and acetaminophen) will be summarized by categories, route 
of administration and preferred term.
In addition, prior and concomitant medication data will be listed.
Rescue medication
Rescue medication is defined as medication used to control symptoms that are not adequately 
controlled on study treatment.
Rescue medication must not be used before completion of Week 16 assessments.
Changes in NSAIDs concomitant therapy is permitted after Week 16 assessments per 
investigator’s clinical judgment.  
Rescue medication will be summarized similarly to concomitant medication.
2.5
Analysis of the primary objective
The primary objective is to demonstrate that the efficacy of secukinumab 300 mg at Week 16 
is superior to placebo in patients with active PsA based on the proportion of patients achieving 
an American College of Rheumatology 20 (ACR20) response.
A patient will be considered as improved according the ACR20 criteria if she/he has at least
20% improvement in the two following measures:
Tender joint count,
Swollen joint count.
and at least 20% improvement in at least 3 of the following 5 measures:


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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. Acute phase reactant (high sensitivity C-reactive protein (hsCRP) or ESR) Primarily,
CRP will be used to calculate ACR response. ESR will only be used in the event CRP is
missing.
2.5.1
Primary endpoint
The primary efficacy variable is ACR20 response (yes, no). The primary analysis time point 
will be at Week 16. 
The primary analysis of the primary efficacy variable will be based on the Full Analysis Set.
2.5.2
Statistical hypothesis, model, and method of analysis
Let πj denote the probability of an ACR20 response at Week 16 for treatment group j, j = 0, 1, 
2, where 0 corresponds to placebo, 1 corresponds to secukinumab 150 mg, and 2 corresponds 
to secukinumab 300 mg.  Accordingly, πj/(1 – πj) is the odds for treatment group j, j = 0, 1, 2.
The following null hypotheses (H01 and H02) will be tested against their corresponding 
alternative hypotheses (HA1 and HA2):
H01: [π1/(1 – π1)]/[π0/(1 – π0)] ≤1  versus  HA1: [π1/(1 – π1)]/[π0/(1 – π0)] > 1
H02: [π2/(1 – π2)]/[π0/(1 – π0)] ≤ 1  versus  HA2: [π2/(1 – π2)]/[π0/(1 – π0)] > 1
The primary efficacy variable will be analyzed at Week 16 using a logistic regression model 
with treatment (3 treatment groups), methotrexate usage at baseline (yes, no), and body weight 
(in kg) as explanatory variables (Stokes, Davis, and Koch, 2012). The odds ratios for each dose 
of secukinumab versus placebo, 95% confidence intervals for the odds ratios, and p-values 
based on the fitted model will be reported. If the p-value for a dose of secukinumab versus 
placebo is < 0.05 and the corresponding odds ratio is greater than 1, statistical significance in 
favor of that dose of secukinumab is shown.
Methotrexate usage at baseline and body weight are assumed to have possible impact on the 
variable, so those will be included in the logistic regression model, even though the factors 
will not be used to stratify at randomization.
The primary variable will also be analyzed at each time point till Week 16 using the same model.
Number and percentages of ACR20 responders will be reported for each treatment group by 
visit in entire treatment period up to Week 52 using oberved data. Similar summary will be 
provided for ACR20 using non-responder imputation.
Number and percentages of ACR20 responders will be reported for each treatment group, 
concomitant methotrexate usage at baseline and by visit in entire treatment period up to Week 
52. Similar summary will be provided for ACR20 using non-responder imputation.


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2.5.3
Handling of missing values/censoring/discontinuations
Patients who discontinued prematurely for any reason will be considered non-responders from 
the time they discontinued.  Patients who do not have the required data to compute ACR20
response (i.e., tender and swollen joint counts and at least three of the five ACR components) 
at baseline and at the specific time point will be classified as non-responders.
In an additional analysis, missing data for ACR20 response variable will be handled by multiple 
imputation. Multiple imputation is a simulation-based approach where missing values are 
replaced by multiple Bayesian draws from the conditional distribution of missing data given the 
observed data and explanatory variables, creating multiple completed data sets. These 
completed data sets can then be analyzed using standard methods. Within this analysis, the ACR 
components will be imputed and response variables will be derived based on the imputed scores. 
In the multiple imputation analysis, the response status will be imputed based on the individual 
treatment arm information.
2.5.4
Supportive analyses
The primary efficacy variable will also be analyzed at each time point till Week 16 for the Full 
Analysis Set using the Cochran-Mantel-Haenszel (CMH) test to compare secukinumab 300 mg
against placebo, adjusting for methotrexate usage at baseline (yes, no) (Stokes, Davis, and Koch, 
2012).
If the treatment comparison p-value is < 0.05 and the proportion of patients who are ACR20 
responders is higher in a secukinumab treatment group compared to the placebo treatment group, 
statistical significance in favor of that dose of secukinumab is shown.  Two 95% confidence 
intervals for the difference between each dose of secukinumab versus placebo in the proportion 
of patients who are ACR20 responders will be calculated using the normal approximation to 
the binomial distribution.
2.6
Analysis of the key secondary objective
There is no key secondary objective.
2.7
Analysis of secondary efficacy objective(s)
Refer to Table1.2-1 of Section 1 for the list of secondary objectives.
2.7.1
Secondary endpoints
All the secondary efficacy evaluation will be performed on FAS.
The secondary efficacy variables are the following:
1. Dactylitis (yes, no)
2. Enthesitis (yes, no)
3. ACR50 response (yes, no)


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4. ACR70 response (yes, no)
5. Minimal Disease Activity (yes, no)
6. PASI75 response (yes, no)
7. PASI90 response (yes, no)
8. PASI100 response (yes, no)
9. Change from baseline in DAS28-CRP
10. Change from baseline in PASDAS
11. Change from baseline in SF12
12. Change from baseline in HAQ-DI
2.7.2
Statistical hypothesis, model, and method of analysis
Dactylitis and enthesitis
Analyses of dactylitis and enthesitis will be performed at each time point up to Week 16. The
data for the subgroup of patients who have dactylitis at baseline (similarly for enthesitis) will 
be used and the data will be analyzed using a logistic regression model with treatment (3 
treatment groups), methotrexate usage at baseline (yes, no), and body weight as explanatory 
variables.  The odds ratios for each dose of secukinumab versus placebo, 95% confidence 
interval for the odds ratios, and p-values based on the fitted model will be reported.
 
Number and percentages of patients with presence of enthesitis will be reported for each 
treatment group and by visit in entire treatment period up to Week 52. Similar summary will be 
provided for patients with presence of enthesitis using non-responder imputation. 
The above analyses will be done on Dactylitis Subset, 
 
ACR20, ACR50, and ACR70 responses
ACR20, ACR50, ACR70 responses at each time point up to Week 16, and in subsets of patients 
with active PsA and number of tender and swollen joints < 10 and ≥10 at baseline will be 
analyzed using a logistic regression model with treatment (3 treatment groups), methotrexate 
usage at baseline (yes, no), and body weight as explanatory variables.  The odds ratios for each 
dose of secukinumab versus placebo, 95% confidence intervals for the odds ratios, and p-values
based on the fitted model will be reported.  


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Additionally, ACR50 and ACR70 responses will be analyzed as analogous to primary efficacy 
variable at each time point up to Week 16.
Number and percentages of ACR50 and ACR70 responders will be reported for each treatment 
group, concomitant methotrexate usage at baseline and by visit in entire treatment period up to 
Week 52. Similar summary will be provided for ACR50 and ACR70 using non-responder 
imputation. 
Number and percentages of ACR50 and ACR70 responders in subsets of patients with active 
PsA and number of tender and swollen joints < 10 and ≥10 at baseline will be reported for each 
treatment group and by visit in entire treatment period up to Week 52. Similar summary will be 
provided for ACR50 and ACR70 using non-responder imputation.
Minimal Disease Activity
Minimal Disease Activity response at each time point up to Week 16 will be analyzed using a 
logistic regression model with treatment (3 treatment groups), methotrexate usage at baseline 
(yes, no), and body weight as explanatory variables.  The odds ratios for each dose of 
secukinumab versus placebo, 95% confidence intervals for the odds ratios, and p-values based 
on the fitted model will be reported.
Number and percentages of Minimal Disease Activity response will be reported for each 
treatment group and by visit in entire treatment period up to Week 52. Similar summary will be 
provided for Minimal Disease Activity response using non-responder imputation method.    
Very Low Disease Activity
Very Low Disease Activity (yes, no) is achived when 7 out of the following 7 criteria are met: 
≤1 tender joint, ≤1 swollen joint, PASI ≤1 or IGA mod 2011 ≤1, patient assessment of pain (0-
100 Visual Analog Scale (VAS)) ≤15, patient global assessment of disease (VAS) ≤20, HAQ-
DI ≤0.5, tender entheseal points ≤1.
Very Low Disease Activity response at each time point up to Week 16 will be analyzed using 
a logistic regression model with treatment (3 treatment groups), methotrexate usage at baseline 
(yes, no), and body weight as explanatory variables.  The odds ratios for each dose of 
secukinumab versus placebo, 95% confidence intervals for the odds ratios, and p-values based 
on the fitted model will be reported.   
Number and percentages of Very Low Disease Activity response will be reported for each 
treatment group and by visit in entire treatment period up to Week 52 for the observed data.
Similar summary will be provided for Very Low Disease Activity response using non-
responder imputation method.    
PASI75, PASI90, PASI100 responses 
Response to PASI75, PASI90, PASI100 at each time point up to Week 16 will be analyzed 
using a logistic regression model with treatment (3 treatment groups), methotrexate usage at 
baseline (yes, no), and body weight as explanatory variables. The odds ratios for each dose of 
secukinumab versus placebo, 95% confidence intervals for the odds ratios, and p-values based 
on the fitted model will be reported.   


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The above analyses will be done on Psoriasis Subset.
Number and percentages of PASI75, PASI90, and PASI100 responders will be reported for 
each treatment group and by visit in entire treatment period up to Week 52. Similar summary 
will be provided for PASI75, PASI90, and PASI100 responders using non-responder imputation 
method. 
DAS28-CRP 
The change from baseline in DAS28-CRP at each time point up to Week 16 will be analyzed 
by an analysis of covariance (ANCOVA) model with treatment (3 treatment groups), baseline, 
methotrexate usage at baseline (yes, no), and body weight as explanatory variables.  The least 
squares means (LS Means) of the three treatment groups, least squares mean differences 
between each dose of secukinumab and placebo, 95% confidence intervals for the difference 
between each dose of secukinumab and placebo, and p-values based on the fitted linear model 
will be reported.  
Summary statistics for observed DAS28-CRP score and change from baseline in score will be 
reported for each treatment group and by visit in entire treatment period up to Week 52.
PASDAS 
The change from baseline in PASDAS at each time point up to Week 16 will be analyzed by an 
analysis of covariance (ANCOVA) model with treatment (3 treatment groups), baseline, 
methotrexate usage at baseline (yes, no), and body weight as explanatory variables.  The least 
squares means (LS Means) of the three treatment groups, least squares mean differences 
between each dose of secukinumab and placebo, 95% confidence intervals for the difference 
between each dose of secukinumab and placebo, and p-values based on the fitted linear model 
will be reported. 
Summary statistics for observed PASDAS score and change from baseline in score will be 
reported for each treatment group and by visit in entire treatment period up to Week 52.
SF12
Refer to Section 2.11.
HAQ-DI
Refer to Section 2.11.
Summary statistics will include relative and absolute frequencies for the binary variable
(ACR20, ACR50, ACR70, dactylitis, enthesitis, Minimal Disease Activity, Very Low Disease 
Activity, PASI75, PASI90, PASI100) and the number of patients (N), mean, standard deviation, 


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median, 25th and 75th percentiles, interquartile range, minimum, and maximum for the 
continuous variables (DAS28-CRP, PASDAS,  etc.,) for each treatment group and by visit. 
Graphical representation will also be performed if required.
2.7.3
Handling of missing values/censoring/discontinuations
Patients who discontinued prematurely for any reason will be considered non-responders from 
the time they discontinued.  Patients who do not have the required data to compute ACR
response (i.e., tender and swollen joint counts and at least three of the five ACR domains) at 
baseline and at the specific time point will be classified as non-responders. For all other binary 
variables, non-responder imputation will be applied. 
Missing data for continuous variables will be imputed using the last-observation-carried-
forward (LOCF) method.
2.7.4
Supportive analyses
Not applicable.
2.8
Safety analyses
All the safety analysis will be performed on Safety Set.
Summaries may performed separately for initial (Weeks 1-16) and entire Treatment Period till 
Week 52.
The analyses for treatment-emergent adverse events, serious adverse events and risks based on 
adverse events will be summarized. 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 from the
treatment assigned at randomization only if a subject received the wrong treatment during the
entire study.
For those patients who received not the treatment randomized, i.e. who received erroneously
the wrong treatment at least once, an additional AE listing will be prepared displaying which
events occurred after the treatment errors.
2.8.1
Adverse events (AEs)
The crude incidence of treatment emergent adverse events (i.e. events started after the first
dose of study treatment or events present prior to the first dose of study treatment but
increased in severity based on preferred term) will be summarized by primary system organ
class and preferred term. Confidence intervals for the crude rate will be reported, using the 
statistical methods described in Section 5.4.5.
In addition, exposure time-adjusted rates (incidence rate) including 95% confidence intervals 
will be provided for Treatment Period 1 and Treatment Period 2 to adjust for differences in 


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exposure. The description of exposure calculation is mentioned in Section 2.4.1. The statistical 
methods for calculation of exposure-adjusted incidence rate and its 95% confidence interval are 
described in Section 5.4.4. A graphical display of the crude incidence rates and exposure-
adjusted rates will be presented for all AEs and serious AEs by system organ class.
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having at least one AE, having an AE in each primary system organ class 
and having each individual AE (preferred term). Summaries (crude incidences only) will also 
be presented for AEs by severity and for study treatment related AEs. If a particular AE 
‘severity’ is missing, this variable will be listed as missing and treated as missing in summaries. 
If a subject reported more than one adverse event with the same preferred term, the adverse
event with the greatest severity will be presented. If a subject reported more than one adverse 
event within the same primary system organ class, the subject will be counted only once with 
the greatest severity at the system organ class level, where applicable.
Separate summaries will be provided for 

adverse events suspected to be related to study drug by the investigator

deaths

serious adverse events

adverse events leading to discontinuation

adverse events leading to temporary dose interruption

non-serious adverse events
Adverse events will also be reported separately by SMQ according to MedDRA, using a
narrow search. The MedDRA version used for reporting the study will be described in a
footnote.
A listing of non-treatment emergent adverse events will be done. These adverse events 
occurred before the first dose of the study treatment. The crude incidence rate will be
provided without treatment information.
Algorithms for date imputations will be provided in Programming Specifications.
For SAEs occurred during screening a listing will be prepared for all patients screened
including screening failures.
An overview of the safety analyses and which will be performed for each analysis period is
described in Table 2.1 below.
Table 2.8-1
Overview of analyses on some safety data
Analysis 
period
AEs & 
SAEs
AEs by 
severity
Study drug 
related 
AEs 
AEs-SMQ
Risk
Notables for
(vitals/ECG
), lab
criteria


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Day 1 –
Week 16
Crude 
Incidenc
e
Exposure
time 
adjusted 
incidence 
*
Crude 
Incidence
Crude 
Incidence
Crude 
Incidence
Crude 
Incidence
Crude 
Incidence
Entire 
Treatment 
(upto 
Week 52)
Crude 
Incidenc
e
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 
secukinumab 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 secukinumab groups during the entire 
treatment period
• at Level 1 for Risks and SMQ analyses
2.8.1.1
Adverse events of special interest / grouping of AEs
Adverse events of special will be summarized by presenting, for each treatment group, the 
number and percentage of patients having at least one AE, having an AE in each primary system 
organ class and having each individual AE (preferred term).
2.8.2
Deaths
Separate summaries and listings will be provided for deaths for each treatment period.
2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests
(hematology, chemistry and urinalysis). 
For urinalysis, frequency tables will be presented.
Descriptive summary statistics for the change from baseline to each study visit will be
presented. These descriptive summaries will be presented by laboratory variable and treatment
group. Change from baseline will only be summarized for patients with both baseline and


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post-baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value
For each variable, the maximum change (maximum decrease and maximum increase) from 
baseline within each study period will be analyzed analogously.
QuantiFERON TB-Gold test will also be analyzed by the central laboratory.
In addition, shift tables will be provided for all variables to compare a patient’s baseline
laboratory evaluation relative to the visit’s observed value. For the shift tables, the reference 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. Also the shifts to the most extreme laboratory test value within a Treatment Period will 
be presented as well (including category “high and low”). These summaries will be presented 
by laboratory test and treatment group.
The following laboratory variables will be analyzed with respect to numerical Common
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2.8-2: hemoglobin,
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL),
gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG).
Table 2.8-2
CTCAE grades for laboratory variables to be analyzed
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
HGB decreased
(Anemia)
<LLN – 100 g/L
<100 – 80 g/L
<80 g/L
Platelet count
Decreased
<LLN – 75.0 x10e9 
/L
<75.0 - 50.0 x10e9 
/L
<50.0 – 25.0 x10e9 /L
<25.0 x 10e9 /L
White blood cell
Decreased
<LLN - 3.0 x 10e9 /L <3.0 - 2.0 x 10e9 /L
<2.0 - 1.0 x 10e9 /L
<1.0 x 10e9 /L
Neutrophil count
Decreased
<LLN - 1.5 x 10e9 /L <1.5 - 1.0 x 10e9 /L
<1.0 - 0.5 x 10e9 /L
<0.5 x 10e9 /L
Lymphocyte 
count
Decreased
<LLN - 0.8 x 10e9/L
<0.8 - 0.5 x 10e9 /L
<0.5 - 0.2 x 10e9 /L
<0.2 x 10e9 /L
Creatinine 
increased*
>1 - 1.5 x baseline;
>ULN - 1.5 x ULN
>1.5 - 3.0 x
baseline; 
>1.5 - 3.0 xULN
>3.0 baseline;
>3.0 - 6.0 x ULN
>6.0 x ULN
TBL increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALP increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN


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Glucose 
increased
(Hyperglycemia 
)
>ULN - 8.9 mmol/L
>8.9 - 13.9 mmol/L
>13.9 - 27.8 mmol/L
>27.8 mmol/L
Glucose 
decreased
(Hypoglycemia)
<LLN - 3.0 mmol/L
<3.0 - 2.2 mmol/L
<2.2 - 1.7 mmol/L
<1.7 mmol/L
Cholesterol high
>ULN - 7.75 mmol/L
>7.75 - 10.34 
mmol/L
>10.34 - 12.92 mmol/L >12.92 mmol/L
Hypertriglycerid
emia
1.71 - 3.42 mmol/L
>3.42 - 5.7mmol/L
>5.7 - 11.4 mmol/L
>11.4 mmol/L
*Note: for “creatinine increased” the baseline criteria do not apply
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the
worst results (expressed in CTCAE grade) during the treatment phase (either initial or entire)
analyzed. Of note, baseline will be defined as last assessment prior to first dosing in initial
treatment phase. Patients with abnormal laboratory values will be listed and values outside
the normal ranges will be flagged.
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on
the event criteria given in Table 2.8-3 below:
Table 2.8-3
Liver-related events
Parameter
Criterion
ALT
AST
ALT or AST
TBL
ALP
ALT or AST & 
TBL
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
>1.5xULN, >2xULN, >3xULN,
>2xULN, >3xULN. >5xULN
ALT or AST>3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >8xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN
ALP & TBL
ALP >3xULN & TBL >2xULN
ALP >5xULN & TBL >2Xuln
ALT or AST &
TBL & ALP
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law)
Note: elevated ALP may suggest obstruction as a consequence of gall 
bladder or bile duct disease; ALP may also be increased in 
malignancy. FDA therefore terms Hy’s Law cases as indicators of 
pure hepatocellular injury. This does not mean that cases of ALT or 
AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result
in severe DILI.
Notes:
In studies which enroll patients with pre-existing liver disease, baseline LFT may be increased above
ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the abnormality
Criteria
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit.
The criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for
ALT >3xULN and ALT>5x ULN.


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Individual subject data listings will be provided for patients with abnormal laboratory data.
Data of patients with newly occurring or worsening liver enzyme abnormalities will be listed
in an additional listing.
Separate summaries and listings will be provided for urine pregnancy results by visit for each 
treatment period.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
All available ECG related data will be listed.
2.8.4.2
Vital signs
Analysis in vital sign measurement using descriptive summary statistics for the change from
baseline for each post-baseline visit will be performed. These descriptive summaries will be
presented by vital sign and treatment group. Change from baseline will only be summarized
for subjects with both baseline and post-baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value
The number and percentage of subjects with newly occurring notable vital signs will be
presented. Clinically notable vital signs are provided in the table below
Table 2.8-4
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
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
All HR-QoL variables will be evaluated based on FAS patients.


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The secondary efficacy variables related to patient-reported outcomes are:

Change from baseline in SF12 

Change from baseline in HAQ-DI
SF12
The change from baseline in SF12 at each time point till Week 16 will be analyzed by an 
analysis of covariance (ANCOVA) model with treatment (3 treatment groups), baseline SF12 
score, methotrexate usage at baseline (yes, no), and body weight as explanatory variables.  The 
least squares means of the three treatment groups, least squares mean differences between each 
dose of secukinumab and placebo, 95% confidence intervals for the difference between each 
dose of secukinumab and placebo, and p-values based on the fitted linear model will be reported. 
The SF-12v2 score will be computed in the following steps:
1. Enter the data
2. Recode out-of-range item values as missing
3. Reverse score and/or recalibrate scores for four items
4. Compute raw case scores
5. Transform raw scale scores to 0-100
Table: Scale Items Aggregated and Range of possible Scores
SF-12v2 scale
Sum 
Final 
item
values
Lowest possible raw 
scores
Possible raw score 
range
Physical functioning 
(PF)
Items 2a+2b
2
4
Role Physical (RP)
Items 3a+3b
2
8
Bodily Pain (BP)
Item 5
1
4
General Health (GH)
Item 1
1
4
Vitality (VT)
Item 6b
1
4
Social 
Functioning 
(SF)
Item 7
1
4
Role Emotional (RE)
Items 4a+4b
2
8
Mental Health (MH)
Items 6a+6c
2
8
Transformed scale = ((Actual raw score-lowest possible raw score)/Possible raw score    
range)*100


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HAQ-DI
The HAQ-DI was developed by Stanford University and is one of the most widely used
measures to assess the long-term influence of chronic disease on a 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 patients with
PsA.
Analysis of HAQ-DI total score will be analogous to the analysis of SF12 for all time points up 
to Week 16.
In addition, the following two binary variables will be analyzed:

HAQ-DI response, where response = yes if HAQ-DI score <= 0.5).

HAQ-DI MCID, where response = yes if HAQ-DI change from baseline <= -0.35).
The above analysis will be done at each time point using a logistic regression model with 
treatment (3 treatment groups), methotrexate usage at baseline (yes, no), and body weight as 
explanatory variables. The odds ratios for each dose of secukinumab versus placebo, 95%
confidence intervals for the odds ratios, and p-values based on the fitted model will be 
reported.
In addition, number and percentages will be provided for HAQ-DI responders by treatment 
group at each visit for entire treatment period. Similar analysis will be performed using non-
responder imputation.


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2.12
Biomarkers
Not applicable.


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2.14
Interim analysis
The database of this study will be locked twice, first after the end of Treatment Period 1 (Week 
16) and again after the end of Treatment Period 2 (Week 52).  Data analyses will follow after 
database lock at Week 16. The main analysis for the primary objective will be done at Week 
16. As Week 16 is the primary analysis time point, no adjustment to the significance level of 
0.05 will be made.
3
Sample size calculation
The sample size was calculated based on the primary efficacy variable (i.e., ACR20 response) 
for the primary comparison (i.e., secukinumab 300 mg versus placebo).  ACR20 response rates 
of 50% for secukinumab 300 mg and 20% for placebo (corresponding to an Odds ratio of 4) at 
Week 16 were assumed, based on results from AIN457F2312 (FUTURE 2) study.  Using a 
continuity-corrected chi-squared test, an allocation ratio of 2:1, a two-sided significance level 
of 0.05, and a power of 0.90, approximately 88 patients in secukinumab 300 mg group and 44 
patients in placebo group will be needed.  
Assuming a loss to follow-up rate of 10% and a 2:2:1 allocation ratio (secukinumab 300 mg: 
secukinumab 150 mg: placebo), the total number of randomized patients will be approximately 
250 (100 on secukinumab 300 mg, 100 on secukinumab 150 mg, and 50 on placebo).
The sample size estimation was done using query Advisor 7.0.


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4
Change to protocol specified analyses
Not applicable.
5
Appendix
This section will be used later for drafting CSR Appendix 16.1.9.
5.1
Imputation rules
5.1.1
Study drug
Not applicable
5.1.2
AE date imputation
The following table explains the notation used in the logic matrix. Please note that
missing start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSTD)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON 
MISSIN
MON < TRTM
MON = TRTM
MON > TRTM
YYYY 
MISSIN
NC
Uncertain
N
C
N
C
N
C
YYYY < TRTY
( D )
Before Treatment Start
( C
)
( C
)
( C
)
YYYY = TRTY
(B)
Uncertain
( C
)
Before Treatment
(A
)
Uncertai
(A
)
After Treatment
YYYY > TRTY
(E)
After Treatment Start
(A
)
After Treatment
(A
)
After Treatment
(A
)
After Treatment
The following table is the legend to the logic matrix.
If AE end date is complete and AE end date < Treatment start date or AE end date
is partial and AE imputed end date < Treatment start date, then AE start reference 
= min (informed consent date, earliest visit date from SV) Else if AE end date is
partial, AE end date > = Treatment start date or AE is ongoing, then AE start
reference = treatment start date.
Relationship
Time imputation


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Before AE start reference
Partial date indicates AE start 
date prior to AE start
After AE start reference
Partial date indicates AE
start date after AE start
f
Uncertain
Partial date insufficient to
determine relationship of AE 
start date to AE start
f
Imputation Calculation
NC/Blank
No convention
(A)
MAX( 01MONYYYY, AE
start reference+1 day)
(B)
AE start reference+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
Complete date
No date imputation
If time is captured for the study
Case1: if AE start date is not 
equal to AE start reference
then do the following:
Relationship                                                                 Time imputation
If minutes missing then AESTMF = M
and time is imputed to hh: 00
If minutes missing then AESTMF = H 
and time is imputed to 00:00
Case2: if AE start date = AE start
reference then AESTMF = H and time is 
imputed to treatment start time + 1 hour
  
Adverse Event End Date Imputation
Imputed date = date part of original date, if complete date
Imputed date = min (completion/discontinuation visit date, DEC 31, date of death), if 
month is missing
Imputed date = min (completion/discontinuation visit date, last day of the month, date 
of death), if day is missing
Adverse Event End Time Imputation
If the AE end date is complete and time is captured in the study then:
Case 1. if AE end date is not equal to Treatment end date, then do the following:
if minutes missing then time is imputed to hh: 00 if time missing then time is imputed to
00:00


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Case 2: if AE end date = Treatment end date then time is imputed to treatment end time
If the AE end date is partial then end time is imputed to 00:00.
Imputed Date Flag
If year of the imputed date is not equal to YYYY then date flag = Y
else if month of the imputed date is not equal to MON then date flag = M
else if day of the imputed date is not equal to day of original date then date_flag = D
else date flag = null
Imputed Time Flag
If hours of the imputed time is not equal to hours of original time then time flag = H
else if minutes of the imputed time is not equal to minutes of original time then time flag =
M
else time flag = null.
5.1.3
Concomitant medication date imputation
This algorithm is used when event is the partial start date of the concomitant
medication. The following table explains the notation used in the logic matrix. Please
note that missing start dates will not be imputed.
Day 
                    
Year
Partial CM Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSDT)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY 
MISSING
(C2)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
YYYY < TRTY
(D)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
YYYY = TRTY
(C2)
Uncertain
(A)
Before Treatment Start
(C1)
Uncertain
(B)
After Treatment Start
YYYY > TRTY
(E)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
The following table is the legend to the logic matrix.
Relationship
Before Treatment Start
Partial date indicates CMD start date prior to Treatment Start Date
After Treatment Start
Partial date indicates CMD start date after Treatment Start Date
Uncertain
Partial date insufficient to determine relationship of CMD start date relative to Treatment
Start Date
Imputation Calculation
(A)
15MONYYYY


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(B)
01MONYYYY
(C1 or C2)
IF         relative reference start = before treatment start THEN TRTSDT-1
ELSE IF relative reference start = ‘ ’ THEN TRTSDT+1
(D)
01JULYYYY
(E)
01JANYYYY
Concomitant Medication End Date Imputation
If not ongoing then -
Imputed date = date part of CMENDTC, if complete date
Imputed date = min (completion/discontinuation visit date, DEC 31), if month is
missing, (C2, D, E)
Imputed date = min (completion/discontinuation visit date, last day of the Month), if
day is missing. (A, B, C1)
Concomitant Medication Date Flag
If not a complete date then
Y - If year of the imputed date is not equal to YYYY else M – If month of the imputed
date is not equal to MON else D.
5.1.3.1
Prior therapies date imputation
Same as above.
5.1.3.2
Post therapies date imputation
Same as above.
5.1.3.3
Other imputations
Same as above.
5.2
AEs coding/grading
Not applicable.
5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
5.4.1
Primary analysis
The primary analysis will be performed comparing treatments with respect to the primary


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efficacy variable in a logistic regression model with treatment, methotrexate usage at baseline
(yes, no), and body weight as explanatory variables.
Proc logistic data=aaa;
Class TRT MTX/ param=glm;
Model AVAL= TRT MTX weight;
Lsmeans TRT / diff cl exp;
Ods output diffs=lsm_diff;
Run;
Logistic regression will be applied to response variables at each visit.
In cases where logistic regression doesn’t converge, Fisher’s exact test will be applied for 
comparisons between AIN457 doses. In this case, no odds ratios or confidence intervals will be 
estimated, but p-values may be calculated.
Proc freq data=aaa;
Table TRT * AVAL / fisher;
Where TRT in (“AIN457 xx mg” “Placebo”);
Run;
In cases where separation is a concern, e.g. 0% response in one treatment (sub) group, an 
exact logistic regression model will be applied. 
Proc logistic data=aaa exactonly;
Class TRT MTX / param=glm;
Model AVAL = TRT MTX weight;
Exact TRT / estimate;
Ods output exactoddsratio=exactoddsratio;
Run;
For supportive analysis using Cochran-Mantel-Haenszel (CMH) test to compare treatment 
adjusting methotrexate usage at baseline, the following code will be used.
proc freq data=aaa;
   tables TRT*MTX / cmh; 
run;
where AVAL= dependent variable
TRT= Treatment 
MTX= Methotrexate usage at baseline
     
Weight= body weight
Multiple Imputation


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A multiple imputation will be performed based on MAR with treatment (3 treatment groups), 
methotrexate usage at baseline (yes, no), and body weight (in kg) as explanatory variables of 
primary efficacy variable (ACR20 response) for visits up to the primary time point (Week 16) 
using Markov Chain Monte Carlo (MCMC) method with EM algorithm.
Impute the missing values 100 times (NIMPUTE) with a seed=457<studycode> as shown 
below:
proc mi data= min= max= out=imp minmaxiter=10000000 nimpute=100 seed=457;
           by trt;
           var weight_base mtxuse_base var1_week1-var1_week16;
           mcmc chain=multiple initial=em;  
run;
Where var1 is the 1st component of ACR and this step will be repeated for every components 
of ACR, e.g., as follows: 
proc mi data=imp min=<min of scale> max=<max of scale> out=imp2 minmaxiter=10000000 
nimpute=100 seed=457;
           by trt _imputation_;
           var weight_base mxtuse_basevar2_week1-var2_week16;
           mcmc chain=multiple initial=em;  
run;
The score and ACR response can now be calculated based on the complete data. The response 
rate will be calculated for each imputation and then combined using Rubin’s rules.
In order to calculate the response rate for each imputation, PROC FREQ will be used as follows.
Calculate binomial proportion and standard error for each imputation.
proc freq data=<ACR20>;
by trt visit _imputation_ ;
tables <response> / binomial (level=2 cl=wilson correct) ;
ods output BinomialProp=imp_bpr;
run;
Transpose the dataset for subsequent use with PROC MIANALYZE.
proc transpose data=imp_bpr out=imp_trs(drop=_name_) ;
by trt visit _imputation_ ;


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var nvalue1; id name1; idlabel label1;
run;
Apply LOGIT transformation: y=log(p/(1-p)) and std. err. transformation: <new se> = se/(p*(1-
p)) 
data logit;
set imp_trs(rename=(_bin_=p e_bin=se));
by trt visit _imputation_ ;
lmean=log(p/(1-p));
lse=se/(p*(1-p));
run;
The transformed binomial proportion estimates and standard errors are combined by applying 
Rubin’s rules for multiple imputed data sets.
proc mianalyze data=logit;
by trt visit ;
modeleffects lmean;
stderr lse;
ods output ParameterEstimates=logitres;
run;
The combined data should be transformed back using the following formula: p=1/(1+exp(-y))
data miexpres;
set logitres;
by trt visit ;
resti = 1/(1+exp(-estimate));
rlow = 1/(1+exp(-lclmean));
rupp = 1/(1+exp(-uclmean));
run;
Of note, sometimes all responses may be imputed to 0 or 1 at a given combination of response 
variable, treatment group and visit. Such cases should be considered separately. The combined 
final response rate would be the same as the original response but the 95% CI will be undefined.
5.4.2
Key secondary analysis
Not applicable.


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5.4.3
Secondary analysis
Categorical variables will be analyzed using the logistic model, using the code described above.
Continuous variables will be analyzed using an analysis of covariance (ANCOVA) model 
with treatment, baseline value, methotrexate usage at baseline (yes, no), and body weight as 
explanatory variables. 
Proc mixed data=aaa order=internal;
Class TRT MTX;
Model change=TRT MTX BLV weight/ ddfm=kr;
Lsmeans TRT/ cl diff;
Contrast “sec300 vs plb” TRT 1 0 -1/ cl diff alpha=0.05;
Contrast “sec150 vs plb” TRT 0 1 -1/ cl diff alpha=0.05;
Run;
For supportive analysis using Cochran-Mantel-Haenszel (CMH) test to compare treatments
adjusting for methotrexate usage at baseline, the same code will be used as described above.
5.4.4
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 T = ∑tj, (j=1,..., n)and D is the number of 
subjectswith at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval 
for aPoisson variable with parameter θT and observed value D can be obtained based on 
(Garwood,1936), from which an exact 100*(1-α)% confidence interval for D/T will be 
derived asfollows (Sahai and Anwer, 1993; Ulm, 1990):
Lower confidence limit:
Upper confidence limit: 
where cα,k is the αth quantile of the Chi-square distribution with k degrees of freedom.


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5.4.5
Crude incidence and 100*(1-α)% confidence interval
For n subjects, each at risk to experience a certain event with probability π, the crude
incidence is estimated as p=x/n, where x is the number of subjects with the event.
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the 
relative frequency based on the score method including continuity correction (Newcombe 
1998).
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z=PROBIT (1-alpha/2), 
n as total number of subjects (i.e. number of subjects in the denominator), and p as estimated 
crude incidence (number of subjects with event / n) it is q 1p.
Then the lower limit is:
In addition, if L > p x 100 then L = p x 100 and if U < p x 100 then U = p x 100.
5.4.6
Mixed-effects repeated measures model
Change from baseline in log (hsCRP) will be analyzed using mixed-effects model repeated 
measures (MMRM) with treatment (3 treatment groups), visit, baseline hsCRP, methotrexate 
usage at baseline (yes, no), and body weight (kg) as explanatory variables.  An unstructured 
covariance structure will be assumed for this model.
SAS code for mixed model:
proc mixed data=aaa;
class TRT USUBJID AVISITN;
model CHG=TRT AVISITN WEIGHT BASE 
/ s ddfm=kr;


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lsmeans TRT*AVISITN / diff cl;
repeated AVISITN / type=un subject=USUBJID;
run;
In case the MMRM model does not converge the following sequential steps will be used:
1. change ddfm=kr to ddfm=bw. If still no convergence, perform step 2.
2. change type=un to type=cs. 
5.5
Rule of exclusion criteria of analysis sets 
Table 5.5-1
Protocol deviations that cause subjects to be excluded
Protocol 
deviation 
ID
Deviation text description
Severity 
code
Excluded from 
analysis set
INCL01
Patients have not signed Informed Consent 
Form prior to initiation of any study related 
procedure.
1
Exclude from Full 
Analysis Set and 
Safety Set
INCL02A
Age criteria not met.
1
Include in 
everything
INCL02B
Non-pregnant, Non-lactating female patients.
1
Include in 
everything
INCL03A
Diagnosis of PsA classified by CASPAR 
criteria and with symptoms for at least 6 
months with moderate to severe PsA who 
must have had at Baseline ≥ 3 tender joints 
out of 78 and ≥ 3 swollen joints out of 76 
(dactylitis of a digit counts as one joint 
each).
1
Include in 
everything
INCL03B
Diagnosis of PsA classified by CASPAR 
criteria and with symptoms for at least 6 
months with moderate to severe PsA who 
must have had  Diagnosis of PsA classified 
by CASPAR criteria and with symptoms for 
at least 6 months with moderate to severe 
PsA who must have had at Baseline < 3 
tender joints out of 78 and ≥ 3 swollen joints 
out of 76 (dactylitis of a digit counts as one 
joint each)
1
Include in 
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INCL03C
Diagnosis of PsA classified by CASPAR 
criteria and with symptoms for less than 6 
months with moderate to severe PsA who 
must have had  Diagnosis of PsA classified 
by CASPAR criteria and with symptoms for 
at least 6 months with moderate to severe 
PsA who must have had at Baseline  ≥ 3 
tender joints out of 78 and < 3 swollen joints 
out of 76 (dactylitis of a digit counts as one 
joint each)
1
Include in 
everything
INCL03D
Diagnosis of PsA classified by CASPAR 
criteria and with symptoms for less than 6 
months with moderate to severe PsA who 
must have had Diagnosis of PsA classified 
by CASPAR criteria and with symptoms for 
at least 6 months with moderate to severe 
PsA who must have had at Baseline  < 3 
tender joints out of 78 and < 3 swollen joints 
out of 76 (dactylitis of a digit counts as one 
joint each)
1
Include in 
everything
INCL04
Subject's target psoriatic skin lesion with a 
PASI score should be  1 or greater will be 
included in the study
1
Include in 
everything
INCL05
RF and/or Anti-cyclic citrullinated peptide 
(anti-CCP) antibodies should be negative at 
screening.
1
Include in 
everything
INCL06
Patients regularly using NSAIDs, as part of 
their PsA therapy should be on stable dose 
for at least 2 weeks before randomization to 
allow inclusion. And, they should remain on 
a stable dose in the study up to Week 16.
1
Include in 
everything
INCL07A
Patients taking corticosteroids are on a stable 
dose of less than or equal to 10mg per day 
prednisone or equivalent for at least 2W 
before randomization and should remain on 
a stable dose up to week 16.
1
Include in 
everything
INCL07B
Patients taking corticosteroids are on a stable 
dose of less than or equal to 10mg per day 
prednisone or equivalent for at least 2W 
before randomization and should remain on 
a stable dose up to week 16.
1
Include in 
everything
INCL08
Patients taking MTX (≤ 25 mg/week) are 
allowed to continue their medication if the 
dose is stable for at least 4 weeks before 
1
Include in 
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randomization and must remain on a  stable 
dose up to study completion
INCL09
Patients on MTX must be on stable folic acid 
supplementation at randomization
1
Include in 
everything
INCL10
Patients who are on a DMARD other than 
MTX must discontinue the DMARD 4 
weeks prior to randomization, except for 
leflunomide, which has to be discontinued 
for 8 weeks prior to randomization unless a 
cholestyramine washout has been performed.
1
Include in 
everything
EXCL01
Subjects with Chest X-ray or MRI with 
evidence of ongoing infectious or malignant 
process, obtained within 3 months prior to 
screening and evaluated by a qualified 
physician should not be included in the 
study.
1
Include in 
everything
EXCL02
Subjects with  previous exposure to 
Secukinumab or any other biologic drug 
directly targeting IL-17 or IL-17 receptor  
should not be included in the study
1
Include in 
everything
EXCL03
Subjects in use of any investigational drug 
and/or devices within 4 weeks before 
randomization, or a period of 5 half-lives of 
the investigational drug, whichever is longer  
should be excluded from the study
1
Include in 
everything
EXCL04
Ongoing use of prohibited psoriasis 
treatments / medications (e.g., topical 
corticosteroids, UV therapy) at 
randomization OR
Insufficient washout of prohibited psoriasis 
treatments:
-Oral or topical retinoid are excluded  4 
weeks prior to randomization
-Photochemotherapy (e.g. PUVA) is 
excluded  4 weeks prior to randomization
-Photoherapy (e.g. UVA or UVB) is 
excluded 2 weeks prior to randomization
-Topical skin treatments (except in face, 
eyes, scalp and genital area during screening, 
only corticosteroids with mild to moderate 
potency) is are excluded 2 weeks prior to 
randomization
1
Include in 
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EXCL05
Subjects with history of hypersensitivity to 
the study drug or its excipients or to drugs of 
similar chemical classes should not be 
included in the study.
1
Include in 
everything
EXCL06
Subjects with any  intramuscular or 
intravenous corticosteroid treatment within 4 
weeks before randomization should not be 
included in the study
1
Include in 
everything
EXCL07
Subjects with  intra-articular injections 
therapy (e.g. corticosteroid) within 4 weeks 
before randomization should not be included 
in the study.
1
Include in 
everything
EXCL08
Patients who ever received biological 
immunomodulating agents  those targeting 
TNF alpha, IL6 and IL12/ IL23 
investigational or approved should not be 
included in the study
1
Include in 
everything
EXCL09
Patients with previous treatment with any 
cell-depleting therapies including but not 
limited to anti-CD20, investigational agents 
(e.g.,alemtuzumab, anti-CD4, anti-CD5, 
anti-CD3, anti-CD19) should not be included 
in the study.
1
Include in 
everything
EXCL10
Subjects ,who are pregnant or nursing 
(lactating) women, where pregnancy is 
defined as the state of a female after 
conception and until the termination of 
gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory 
test should not be included in the study.
1
Include in 
everything
EXCL11
Women of child-bearing potential, defined 
as all women physiologically capable of 
becoming pregnant, unless they are using 
effective methods of contraception during 
entire study or longer if required by locally 
approved prescribing information.
Effective contraception methods include: 
• Total abstinence, when this is in line with 
the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable 
methods of contraception 
1
Include in 
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• Female sterilization (have had surgical 
bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six 
weeks before taking study treatment. In case 
of oophorectomy alone, only when the 
reproductive status of the woman has been 
confirmed by follow up hormone level 
assessment 
• Male sterilization (at least 6 months prior 
to screening). For female patients on the 
study, the vasectomized male partner should 
be the sole partner for that patient 
• Barrier methods of contraception: Condom 
or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository 
• Use of oral, injected or implanted hormonal 
methods of contraception or other forms of 
hormonal contraception that have 
comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or 
transdermal hormone contraception 
• Placement of an intrauterine device or 
intrauterine system 
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. 
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 six months
of spontaneous amenorrhea as defined by 
Central Lab FSH and/or estradiol levels
EXCL12
Subjects with active ongoing inflammatory 
diseases other than PsA that might confound 
the evaluation of the benefit of Secukinumab 
therapy,  should not be included in the study.
1
Include in 
everything
EXCL13
Subjects with underlying metabolic, 
hematologic, renal, hepatic, pulmonary, 
neurologic, endocrine, cardiac, infectious or 
1
Include in 
everything


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gastrointestinal conditions, which in the 
opinion of the investigator 
immunocompromises the patient and/or 
places the patient at unacceptable risk for 
participation in an immunomodulatory 
therapy should not be included in the study.
EXCL14
Subjects with significant medical problems 
or diseases, including but not limited to the 
following: uncontrolled hypertension (≥ 
160/95 mmHg), congestive heart failure 
(New York Heart Association status of class 
III or IV), uncontrolled diabetes,  should  be 
excluded from  the study.
1
Include in 
everything
EXCL15
Subjects with the  history of clinically 
significant liver disease or liver injury as 
indicated by abnormal liver function tests 
such as SGOT (AST), SGPT (ALT), alkaline 
phosphatase, or serum bilirubin should not 
be included in the study.
1
Include in 
everything
EXCL16
Subjects with the  history of renal trauma, 
glomerulonephritis, or patients with one 
kidney only, or a serum creatinine level 
exceeding 1.5 mg/dL (132.6 μmol/L) should 
not be included in the study.
1
Include in 
everything
EXCL17
Subjects  with  total WBC count <3,000/μL, 
or platelets <100,000/μL or neutrophils 
<1,500/μL or hemoglobin <8.5 g/dL (85 g/L) 
at screening should not be included in the 
study.
1
Include in 
everything
EXCL18
Subjects with active systemic infections 
during the last two weeks prior to 
randomization (exception: common cold) 
should be excluded from the study.
1
Include in 
everything
EXCL19A
Subjects with the  history of ongoing, 
chronic or recurrent infectious disease or 
evidence of tuberculosis infection as defined 
by either a positive purified protein 
derivative (PPD) skin test (the size of 
induration will be measured after 48-72 
hours, and a positive result is defined as an 
induration of ≥ 5 mm or according to local 
practice/guidelines) or a positive 
QuantiFERON TB-Gold test as indicated in 
the assessment schedule
1
Include in 
everything


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EXCL19B
No history of ongoing, chronic or recurrent 
infectious disease or evidence of tuberculosis 
infection as defined by either a positive 
purified protein derivative (PPD) skin test 
(the size of induration will be measured after 
48-72 hours, and a positive result is defined 
as an induration of ≥ 5 mm or according to 
local practice/guidelines) or a positive 
QuantiFERON TB-Gold test as indicated in 
the assessment schedule
1
Include in 
everything
EXCL20
Subject with Known infection with human 
immunodeficiency virus (HIV) or human 
immunodeficiency virus , hepatitis B or 
hepatitis C at screening or randomization 
should be excluded from the study.
1
Include in 
everything
EXCL21
Subjects with the  history of 
lymphoproliferative disease or any known 
malignancy or history of malignancy of any 
organ system within the past 5 years  should 
not be included in the study 
(except for basal cell carcinoma or actinic 
keratoses that have been treated with no 
evidence of recurrence in the past 3 months, 
carcinoma in situ of the cervix or non-
invasive malignant colon polyps that have 
been removed)
1
Include in 
everything
EXCL22
Subjects with  current severe progressive or 
uncontrolled disease which in the judgment 
of the clinical investigator renders the patient 
unsuitable for the trial.
1
Include in 
everything
EXCL23
Subject's inability or unwillingness to 
undergo repeated venipuncture (e.g., because 
of poor tolerability or lack of access to 
veins) should not be included in the study.
1
Include in 
everything
EXCL24
Subject with any medical or psychiatric 
condition which, in the Investigator’s 
opinion, would preclude the participant from 
adhering to the protocol or completing the 
study per protocol  should not be included in 
the study
1
Include in 
everything
EXCL25
Subject donation or  subject with loss of 400 
mL or more of blood within 8 weeks before 
1
Include in 
everything


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dosing (randomization)  should not be 
included in the study
EXCL26
Subjects with the history or evidence of 
ongoing alcohol or drug abuse, within the 
last six months before randomization  should 
not be included in the study
1
Include in 
everything
EXCL27
Subjects who have plans for administration 
of live vaccines during the study period or 6 
weeks prior to randomization  should not be 
included in the study
1
Include in 
everything
TRT01
Incorrect study medication administered by 
subject
4
Include in 
everything
TRT02
Any incorrect route of administration of 
study drug used at any time during the study, 
per protocol
4
Include in 
everything
TRT03
Two records with same "Date of dose" (i.e., 
Injection A and B)
4
Include in 
everything
TRT04
At Weeks 16, 28 and 40 patients on 
secukinumab 150 mg (Group 2) who are 
responders will continue to receive 
secukinumab 150 mg (1.0 mL) plus placebo 
(1.0 mL) every 4 weeks until next evaluation 
of responder status at weeks 28 or 40.
4
Include in 
everything
TRT05
Patients who did not meet the responder 
criteria at Week 16, 28 or 40 will start 
receiving secukinumab 300 mg s.c.every 4 
weeks and will continue this dose up to 
Week 52.
4
Include in 
everything
TRT06
Missed or partial doses of study medication 
administered by subject
4
Include in 
everything
COMD01
Use of prohibited medication at any time 
during the study after randomization until 
Week 16
5
Include in 
everything
COMD02
Use of prohibited medication with potential 
impact on key efficacy and/or safety 
evaluations at any time during the study after 
Week 16
5
Include in 
everything
COMD03
subject received a live virus vaccination 
during the study
5
Include in 
everything
OTH01
If Date of visit is recorded then 
the Physician’s Global Assessment 
QSRSFLT at corresponding visits are not 
expected to be null.
998
Include in 
everything


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OTH02
PASI score is blank when visit date is 
present and PASI total score is missing.
998
Include in 
everything
OTH03
If the sex of the subject is Female and the 
response to "Is subject of child bearing 
status" is recorded as "Able to bear children" 
on Demography CRF then the "Date of 
assessment" Urine pregnancy test CRF is not 
expected to null at Visits Baseline, Week 4, 
Week 12, Week 16, Week 32, Week 24, 
Week 40
998
Include in 
everything
OTH04
What was the result of the tuberculosis 
workup? = "Latent" then on prior conmed 
page, medication with reason 'tuberculosis' 
(% preferred term) is present with start date 
prior to <Date of assessment> on 
tuberculosis assessment page. If false, then 
Screening disposition page 2 with subject 
status as Screen Failure should appear.
998
Include in 
everything
OTH05
Screening and Baseline visits occurred on 
the same date so eligibility could not be
confirmed at time of randomization
998
OTH06
ICH-GCP non-compliance of study site in 
the study
998
OTH07
Failure to perform key study procedures  
998
6
References

Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika; 46: 441–
453.

Newcombe RG (1998) Two-sided confidence intervals for the single proportion: 
comparison of seven methods. Statistics in Medicine; 17: 857-872.

Sahai H, Khurshid Anwer (1993) Confidence intervals for the mean of a poisson
distribution: a review. Biom J, 35 (7): 857-867.

Stokes ME, Davis CS, Koch GG (2012) Categorical data analysis using the SAS 
system. 3rd ed; Cary, NC: SAS Institute, Inc.


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
Ulm K (1990) A simple method to calculate the confidence interval of a standard 
mortality ratio. American Journal of Epidemiology, 131(2): 373-375.